You are on page 1of 29

See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/6395909

Allergic rhinitis and its pharmacology

Article  in  Pharmacology [?] Therapeutics · July 2007


DOI: 10.1016/j.pharmthera.2007.01.012 · Source: PubMed

CITATIONS READS

44 827

2 authors, including:

Yousuf Al Suleimani
Sultan Qaboos University
31 PUBLICATIONS   184 CITATIONS   

SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Effect of some novel agents in experimental chronic kidney disease and acute kidney injury View project

All content following this page was uploaded by Yousuf Al Suleimani on 14 October 2018.

The user has requested enhancement of the downloaded file.


Pharmacology & Therapeutics 114 (2007) 233 – 260
www.elsevier.com/locate/pharmthera

Allergic rhinitis and its pharmacology


Yousuf M. Al Suleimani a,b,⁎, Michael J.A. Walker a
a
Department of Pharmacology and Clinical Pharmacy, College of Medicine and Health Sciences, Sultan Qaboos University, Oman
b
Department of Anaesthesiology, Pharmacology and Therapeutics, UBC, 2176 Health Sciences Mall, Vancouver, BC, Canada V6T 1Z3

Abstract

The pathophysiology of allergic rhinitis and its drug treatment is reviewed. Special emphasis is placed upon potential new treatments. Allergic
rhinitis is characterized by allergen(s), symptoms (sneezing, itching, rhinorrhea, nasal congestion and nasal hypersensitivity), and signs such as
invasion of nasal mucosa by inflammatory cells. Such pathological changes are due to inflammatory responses mediated by way of allergen-
immunoglobulin E (IgE)-cell complex formation. The complexity of the disease and the multiple pathways involved offer many targets for drug
treatment, but to date no single drug is totally effective. This review summarizes the current knowledge of allergic rhinitis, its prevalence,
pathophysiology and experimental and clinical treatments. In the search for new drugs, different experimental animal models of allergic rhinitis are
required. As a result the models have also been reviewed. Furthermore, particular aspects of the pathophysiology of allergic rhinitis are discussed
in greater detail including the immune cells involved in the mediation of the disease, chemical mediators, their actions, and the receptors on which
they act. Therapy, particularly that with current drugs, targets many of the known mediators and some of the cellular processes with varying
success. Other drugs, for example, vasoconstrictors given to reduce rhinorrhea, provide symptomatic relief by counteracting symptoms. Since the
incidence of allergic rhinitis is prevalent and growing in many parts of the world and current treatments are not ideal, it is important to continue to
study the pharmacology of this disease as part of a search for better drugs.
© 2007 Elsevier Inc. All rights reserved.

Keywords: Allergic rhinitis; Pathophysiology; Treatment of rhinitis; Rhinitis mediators; Rhinitis pharmacology

Contents

1. An introduction to allergic rhinitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234


1.1. Definition of allergic rhinitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
1.2. Prevalence and epidemiology of human allergic rhinitis . . . . . . . . . . . . . . . . . 234
1.3. Classification and initial overview of the treatment of rhinitis. . . . . . . . . . . . . . . . 234
2. Pathophysiological of allergic rhinitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
2.1. Relevant nasal anatomy and physiology . . . . . . . . . . . . . . . . . . . . . . . . . 235
2.2. Process of allergen sensitization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
2.3. Rhinitic responses to allergen challenge . . . . . . . . . . . . . . . . . . . . . . . . . 239
2.3.1. Acute phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239
2.3.2. Chronic phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240
2.4. Pathophysiological events in allergic rhinitis . . . . . . . . . . . . . . . . . . . . . . . 240
2.4.1. Neuronal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240
2.4.2. Vascular . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240
2.4.3. Glandular. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241
2.4.4. Nasal airway hyperresponsiveness . . . . . . . . . . . . . . . . . . . . . . . . 241

⁎ Corresponding author. Department of Anaesthesiology, Pharmacology and Therapeutics, UBC, 2176 Health Sciences Mall, Vancouver, BC, Canada V6T 1Z3.
Tel.: +1 604 822 9531; fax: +1 604 822 9578.
E-mail address: rsdaa@interchange.ubc.ca (Y.M. Al Suleimani).

0163-7258/$ - see front matter © 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.pharmthera.2007.01.012
234 Y.M. Al Suleimani, M.J.A. Walker / Pharmacology & Therapeutics 114 (2007) 233–260

2.5. Pathological factors in allergic rhinitis . . . . . . . . . . . . . . . . . . . . . . . . . . . 241


2.5.1. Immune cell mediators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241
2.5.2. Chemical mediators of allergic rhinitis . . . . . . . . . . . . . . . . . . . . . . 243
3. An overview of animal models of allergic rhinitis . . . . . . . . . . . . . . . . . . . . . . . . 246
4. Treatments for allergic rhinitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247
4.1. Currently used drugs for allergic rhinitis and limitations to their use . . . . . . . . . . . 247
4.2. Possible novel targets for treating allergic rhinitis . . . . . . . . . . . . . . . . . . . . . 248
4.2.1. Mediator receptor antagonists. . . . . . . . . . . . . . . . . . . . . . . . . . . 248
4.2.2. Mast cell stabilizers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
4.2.3. Inhibitors of neuronal pathways . . . . . . . . . . . . . . . . . . . . . . . . . 249
4.2.4. Immunotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
4.2.5. IgE targeting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
4.2.6. Cytokines and chemokines inhibitors . . . . . . . . . . . . . . . . . . . . . . . 250
4.2.7. Adhesion molecules inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . 251
4.2.8. Selective phosphodiesterase 4 inhibitors . . . . . . . . . . . . . . . . . . . . . 251
4.2.9. Heparin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
4.2.10. Phototherapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
5. Drugs effects in animal models of allergic rhinitis . . . . . . . . . . . . . . . . . . . . . . . . 251
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253

1. An introduction to allergic rhinitis 17% are 45–64, and only 8% are 65 years or older (Law et al.,
2003).
1.1. Definition of allergic rhinitis In 1996, the overall direct costs of treating allergic rhinitis
exceeded $3 billion with an additional $4 billion for treating
Allergic rhinitis is defined as an abnormal inflammation of comorbidities that are triggered or exacerbated by rhinitis. To
the membrane lining the nose. It is characterized by nasal this cost must be added indirect costs such as lowered
congestion, rhinorrhea, sneezing, itching of the nose, and/or productivity and lost work time. In the United States alone,
postnasal drainage (Bousquet et al., 2001). Additionally, airway the number of lost workdays is estimated as ∼ 3.5 million a year
hypersensitivity may develop. A loss of the sense of smell and (Holgate & Broide, 2003; Mahr & Sheth, 2005).
an inability to taste may occur. Moreover, some patients Up to 40% of patients with allergic rhinitis also have asthma,
experience sleep disturbances, decreased emotional well-being whereas 80% with asthma have nasal symptoms. Allergic
and social functioning, headache, and irritability. On physical rhinitis patients are at 3 times the normal risk of developing
examination, nasal obstruction can often be seen with pale to asthma. Children who develop rhinitis in the first year of life
bluish nasal mucosa, enlarged or boggy turbinates, clear nasal have twice the chance of developing asthma (Settipane et al.,
secretions, and pharyngeal cobble-stoning (streaks of lymphoid 1994; Wright et al., 1994).
tissue). Other characteristic signs of allergic rhinitis in children
include allergic shiners (darkening of lower eyelids due 1.3. Classification and initial overview of the treatment of rhinitis
edematous nasal tissue compressing the veins that drain the
eye region thereby leading to pooling of blood under the orbits) Traditionally, allergic rhinitis is classified as seasonal or
and an allergic crease (a transverse skin line below the bridge of perennial, and either mild, moderate, or severe. Mild allergic
the nose caused by constant upward rubbing of the nose with the rhinitis involves no sleep interruption, no impairment of daily
palm of the hand (the “allergic salute”). Due to chronic nasal activities, and no troubling symptoms. Moderate-to-severe
airway obstruction, some children become chronic mouth allergic rhinitis involves one or more of those factors. A
breathers leading to craniofacial abnormalities and orthodontic newer classification system characterizes allergic rhinitis as
disturbances, such as palatal arching, increased facial length, intermittent, or persistent. In the intermittent form symptoms
and a flattened mid-face. Many patients do not show all such last less than 4 days per week with a total duration of less than
abnormalities, although most do have sneezing, rhinorrhea, and 4 weeks. In the persistent form symptoms occur for more than
mucosal edema (Nayak et al., 2001; Mahr & Sheth, 2005). 4 days per week for longer than 4 weeks (Noble et al., 1995;
Bousquet et al., 2001). Seasonal rhinitis is periodic due to the
1.2. Prevalence and epidemiology of human allergic rhinitis occurrence of seasonal allergens. Pollens that cause seasonal
allergic rhinitis in the Northern Hemisphere are from trees in
Although the onset of allergic rhinitis may occur at any age, springtime, grass pollens from May to July and weed pollen and
it is most common in children and at adolescence. Allergic mould spores in late summer and autumn. Perennial (year
rhinitis is the most common atopic disorder in the United States round) disease involves nonseasonal allergens in the air, most
and affects about 24 million (8% of the population), both males commonly from mites (25%; Dermatophagoides pteronyssinus/
and females equally. The prevalence varies with age: 32% of farinae), animal dander antigens (15%; cats, dogs, rodents),
patients are 17 years or younger, 43% are 18–44 years of age, fungal spores (10%; Alternaria, Cladosporium, Aspergillus,
Y.M. Al Suleimani, M.J.A. Walker / Pharmacology & Therapeutics 114 (2007) 233–260 235

Penicillium), or exposure to workplace antigens (Platts-Mills finger-like cytoplasmic expansions increase the surface area of
et al., 1987; Raab, 1989; Howarth & Holgate, 1990; Noble epithelial cells, thus promoting exchange processes. Microvilli
et al., 1995). also prevent drying by retaining moisture that is essential for
Allergic rhinitis should be differentiated from other respira- ciliary function. Cilia have a typical ultrastructure (0.3 μm wide
tory related nonallergenic nasal diseases such as infectious and 5 μm long) with each cell possessing about 100 cilia
rhinitis and perennial nonallergic rhinitis (vasomotor rhinitis). (Halama et al., 1990). The anterior third of the nasal cavity is
Infectious rhinitis is characterized by constitutional symptoms nonciliated. Ciliated cells begin just behind the front edge of the
and purulent rhinorrhea. Nasal smears show neutrophils rather inferior turbinate and cover the posterior part of the nasal cavity.
than the eosinophils that predominate in allergic rhinitis. Paranasal sinuses are densely covered by cilia.
Perennial nonallergic rhinitis is more frequent in women and The distribution pattern of ciliated cells corresponds well with
is precipitated by such nonspecific factors such as changes in the distribution of nasal airflow; thus, the density of ciliated cells
temperature, humidity, and barometric pressure; strong odours; at any site in the nasal cavity is inversely proportional to the linear
alcohol; and cigarette smoke. Nasal congestion frequently shifts velocity of inspired air at that site (Cole, 1982). Another charac-
from one nasal passage to the other (see later) and is often teristic cell of airway epithelium is the goblet cell, the majority of
alleviated by exercise (Zeiger et al., 1989). which are located in the posterior part of the nasal cavity at
The 2 major classes of drugs used to treat symptoms of an average concentration of 4000–7000 cells/mm2 (Tos, 1983).
allergic rhinitis are oral H1 antihistamines and intranasal Goblet cells produce small amounts of viscous mucus that contri-
corticosteroids used either as immunotherapy, or in combina- butes little to the total volume of nasal secretions. Secretions
tion, depending on the predominant symptoms and the patient's from goblet cells have been shown to be under cholinergic control
response to therapy. Alternative drugs, such as chromolyn, may (Tokuyama et al., 1990).
be appropriate in some patients. The symptoms of rhinorrhea There are 2 types of glands in the nose: anterior serous and
can be temporarily alleviated with adrenergic amine vasocon- seromucous glands. There are 100–150 anterior serous glands
strictors. Their prolonged use can induce a paradoxical rhinitis on each side of the nose each of which has long excretory ducts
known as rhinitis medicamentosa (Black & Revison, 1980). with large openings into the upper part of the internal ostium.
Although each of these treatments provide short or long term Small droplets of watery secretion can be seen after stimulation
relief from one or more of the symptoms of allergic rhinitis, of the nasal mucosa. Secretions produced in the anterior portion
none totally controls the disease. of the nose are more watery and have a lower viscosity than
those in the posterior portion (Brofeldt et al., 1979).
2. Pathophysiological of allergic rhinitis There are about 100,000 seromucous glands in the human
nose, a number that remains constant throughout life (Tos,
2.1. Relevant nasal anatomy and physiology 1983). Thus, infants have a secretory capacity comparable to an
adult. However, since the ciliated surface area is much smaller
The external dermal aspects of the human nose surround the in children, limited glandular hypersecretion in children may
nostrils and cover one-third of the nasal cavities. These dual result in more nasal discharge than occurs in adults.
chamber cavities are 5-cm high and 10-cm long with a total Blood from the ophthalmic and internal maxillary arteries
surface area of about 150 cm2 and volume of about 15 mL. feeds an extensive network of arterioles, venules, capillaries,
Approximately 1.5 cm from the nares is the narrowest point of capacitance vessels, and shunt vessels in the nose. These supply
the cavities is the internal ostium (or nasal valve). This has a and drain the nasal mucosa with a greater blood flow per unit
cross-sectional area of about 30 mm2 on each side. The nasal volume of tissue than even the liver or brain (Grevers &
valve provides ∼ 50% of the total resistance to normal respi- Kastenbauer, 1996). Nasal arterioles conspicuously lack an
ratory airflow (Baroody, 1997). Each of the 2 nasal cavities is internal elastic membrane. As a result, the endothelial basement
bounded by septal and lateral walls and is dominated by inferior, membrane is continuous with the basement membrane system
middle, and superior turbinates. The turbinates maintain a slit- of smooth muscle cells (Cauna, 1970). The capillaries, lying just
like cavity and facilitate humidification and temperature below the surface epithelium, and surrounding the glands, are of
regulation of inspired air (Dahl & Mygind, 1998). the fenestrated type. Thus, they are well suited for rapid
The nostrils are covered by skin, the anterior one-third of the movement of water through the vascular wall so that it escapes
nasal cavity by a squamous and transitional epithelium. The into the airway lumen and, via evaporation, conditions (i.e.,
upper part of the cavity is covered by an olfactory epithelium and humidifies) inspired air (Cauna & Hinderer, 1969).
the remaining portion by a typical airway epithelium, which is Large venous cavernous sinusoids, mainly localized in the
ciliated, pseudostratified, and columnar. The latter consists of 4 inferior turbinates, are characteristic of nasal mucous membranes.
major cell types: basal cells, ciliated columnar cells, nonciliated They are normally in a semicontracted condition as a result of
columnar cells, and goblet cells. Basal cells, which are sympathetic nerve-mediated smooth muscle tone. These cavern-
progenitors of the other cell types, lie on the basement membrane ous sinusoids appear to be specialized vessels that meet the
and do not directly have contact with the airway lumen (Evans & functional demands of heating and humidifying inhaled air. When
Plopper, 1988). Each of the columnar cells, ciliated and distended with blood the mucosae swell and thereby tend to block
nonciliated, are covered by about 300 microvilli uniformly the nasal airway lumen (Dahl & Mygind, 1998). In addition,
distributed over the entire apical surface. These short and slender inflammation-induced extravasation through the walls of
236 Y.M. Al Suleimani, M.J.A. Walker / Pharmacology & Therapeutics 114 (2007) 233–260

postcapillary vessels occurs as a result of opening of intercellular There is a rich parasympathetic innervation to nasal glands.
junctions between endothelial cells (Cauna, 1970). Nervous stimulation of glandular cholinoceptors causes marked
Blood can bypass the capillary bed via arteriovenous hypersecretion and is often part of a reflex arc. Blood vessels
anastomoses. The role of the arteriovenous anastomoses is have both sympathetic and parasympathetic innervation but are
probably related to temperature and water control. At least 50% controlled mainly by sympathetic fibers. A continuous release of
of the blood flow in the nasal mucosa is normally shunted norepinephrine is postulated to keeps the sinusoids part-
through arteriovenous anastomoses and, as indicated earlier, the ly contracted since the vasoconstrictor effects of stimulation of
total blood flow per cubic centimeter of tissue is greater in the α-adrenoceptors is more marked than vasodilatation resulting
upper nasal airway mucosa than in muscle, brain or liver from stimulation of β2-receptors (Dahl & Mygind, 1998). The
(Anggard, 1974; Drettner & Aust, 1974). release of the classic neurotransmitters, norepinephrine and
Nasal blood vessels are under endothelial and neuronal control. acetylcholine, has in recent years been found to be accompanied
A dual (endothelial and neuronal) control exists in arterioles by a number of peptide neurotransmitters. These neurotransmit-
whereas control of the subendothelial muscular swelings of the ters are secreted by afferent unmyelinated C fibers (substance P
cushion veins appears to be mainly neuronal (Riederer et al., [SP], calcitonin gene-related peptide [CGRP], neurokinin A
2002). The swelling of the nasal mucosa is achieved by a [NK-A], gastrin-releasing peptide); efferent parasympathetic
simultaneous relaxation of all smooth muscle cells which leads to nerve endings (vasoactive intestinal peptide [VIP], peptide
dilatation of arteries as well as venous sinuses. The drainage of the histidine methionine), and from efferent sympathetic nerve
vascular bed is reduced by venous muscular bolsters that protrude endings (neuropeptide Y, NPY; Uddman et al., 1987; Lundblad,
into the lumen of the venous sinuses. Vice versa, a contraction of 1990; Baroody, 1997). Neuropeptides are capable of generating
all smooth muscle cells leads to a contraction of the arteries and local reflexes that cause an increase in vascular permeability,
consequently to a reduction in blood supply. Simultaneously the plasma leakage, vasodilatation, and subsequent tissue oedema
muscular bolsters rise out of the lumen of venous sinusoids (Baraniuk, 1997; Fig. 2).
allowing blood drainage to be increased thereby reducing nasal Apart from being the first part of the airways, the nose has 2
congestion (Riederer et al., 2002; Fig. 1). major functions: firstly, olfaction, and secondly, conditioning of
The nasal mucosa, including glands and blood vessels, are the inspired air to make it suitable for the lungs by heating,
supplied by both afferent and efferent neurons. The afferent humidifying and cleansing. The normal nose is characterized by
neuronal supply can be divided into 2 parts: the first, the slit-like passages that provide for efficient exchange of heat and
olfactory nerve (cranial nerve I), projects into the olfactory moisture. The width of these nasal cavities is actively regulated
mucosa, and conducts the sensation of smell; the second, the via the sympathetic innervation, plus tone in the venous sinusoids.
trigeminal nerve (cranial nerve V), projects to the epithelium Nasal cycling is the cyclic alteration between resistance on
and detects perception of airflow via A fibers, and noxious the 2 sides of the nose. This cycling changes from one side to
stimuli via unmyelinated C fibers and Aó fibers. Activation of the other at 2–4 h intervals with 80% of humans showing this
these afferent nerves leads to local axonal and central reflexes nasal cycle (Hanif et al., 2000). It has also been demonstrated in
(Baraniuk, 1998). rats, rabbits, and pigs. In addition, the nasal cycle is perceived

Fig. 1. Schematic representation of different endothelial and neuronal control of blood flow in nasal blood vessels. NA: norepinephrine, NPY: neuropeptide Y, VIP:
vasoactive intestinal peptide, NO: nitric oxide, ACh: acetylcholine, SP: substance P, ET-1: endothelin 1, CGRP: calcitonin gene-related peptide. Adapted from Riederer
et al. (2002).
Y.M. Al Suleimani, M.J.A. Walker / Pharmacology & Therapeutics 114 (2007) 233–260 237

Fig. 2. Schematic representation of the nasal neuronal control. NANC: nonadrenergic noncholinergic, CGRP: calcitonin gene-related peptide, Sub-P: substance P,
NK-A: neurokinin A, ACh: acetylcholine, VIP: vasoactive intestinal peptide, NO: nitiric oxide, NEP: norepinephrine, NPY: neuropeptide Y.

by subjects with a deflected septum and by rhinitis patients water condensation of exhaled air in the anterior nose
(Dahl & Mygind, 1998). The nasal cycle seems to be predom- where the temperature is 3–4 °C lower than in the lungs.
inantly vascular, and it is mediated via the nervous control of the This water may contribute to rhinorrhea in cold weather.
sinusoidal erectile tissue. Cutting the cervical sympathetic
nerves or blocking the sympathetic supply by local anesthesia The nose acts as a filter of particulate matter. Most particles
abolishes the nasal cycle in human and in lower animals (Wid- larger than 10 μm (e.g., pollen grains) are retained in the nose
dicombe, 1986). during normal breathing at rest, whereas particles smaller than
The nose is well suited to its role as air conditioner for the 2 μm (mould spores) can bypass this. The nose also acts as a
following reasons: protective sponge for water-soluble gases (e.g., sulfur dioxide,
formaldehyde). Trapped inhaled particles are cleared from the
(i) the slit-like shape of nasal cavities ensure close contact nose by mucociliary transport within 30 min (Hilding, 1963;
between inhaled air and mucous membranes; Andersen et al., 1974).
(ii) the cavity width adapts rapidly to changing air flow needs
by alteration in sinusoid capacity; 2.2. Process of allergen sensitization
(iii) heat exchange is facilitated by the extensive blood flow in
arteriovenous anastomoses; The allergic sensitization that characterizes allergic rhinitis
(iv) nasal mucosa has a high secretory capacity. In addition has a strong genetic component. Thus, the chance of developing
the body saves about 100 mL of water per day, due to immunoglobulin E (IgE)/mast cell/TH2 lymphocyte immune
238 Y.M. Al Suleimani, M.J.A. Walker / Pharmacology & Therapeutics 114 (2007) 233–260

responses and atopy, in general, is inherited. The hygiene cells. This could be the dominant mechanism of uptake of
hypothesis is one explanation for an increasing incidence of particulate allergens (Banchereau et al., 2000).
allergies, such as allergic rhinitis (Strachan, 1989). The hypo- After being taken up by any of the above mechanisms,
thesis arose from epidemiological observations that suggested antigens accumulate in the endocytic compartment where they
an inverse relationship between family size and prevalence of are loaded on newly synthesized and recycling MHC class II
allergies. It was proposed that reduced contact with microbes molecules. However, they may also be transported into the
and a diminished burden of infectious disease early in life lead cytosol where they become accessible to the class I antigen
to weakened immunological drive in the Th1 direction that presentation pathway (Rodriguez et al., 1999; de Baey &
results in over-activity of Th2 responsiveness. However, other Lanzavecchia, 2000). Within the endocytic compartment,
evidence does not substantiate a causal relationship between antigen is cleaved into short immunogenic peptides by
infection and atopic diseases (Liu & Murphy, 2003). proteolytic enzymes. Antigen is loaded on MHC class II
Exposure to threshold concentrations of dust mite fecal pro- molecules in an acidic cellular compartment rich in newly
teins, cockroach allergen, cat, dog, and other danders, pollen synthesized MHC class II molecules called the MIIC compart-
grains, or other allergens for prolonged periods of time leads to ment (Nijman et al., 1995). Alternatively, immunogenic
the presentation of the allergen by antigen presenting cells to peptides can be loaded onto pre-formed MHC II molecules
CD4+ T lymphocytes, which then release different cytokines that have been internalized into mildly acidic endosomal
along with the differentiated TH2 cytokines (see below). These vesicles after being expressed on the cell surface (Cella et al.,
cytokines drive proinflammatory processes, such as IgE pro- 1997). In addition, antigen processing by proteases can occur
duction, that act against the allergens via mucosal infiltration resulting in extracellularly generating peptides that can be
and plasma cells, mast cells, and eosinophils. Once sensitized to loaded onto empty cell surface-expressed MHC class II.
allergens, subsequent exposures trigger a cascade of events that Surprisingly, proteolysis of antigen by immature dendritic
result in the symptoms of allergic rhinitis. cells can also occur extracellularly by the actions of secreted
Allergic rhinitis is characterized by a 2-phase allergic proteases. This results in the generation of peptides that can be
reaction: an initial sensitization phase where allergen exposure loaded onto empty cell surface-expressed MHC class II
results in IgE formation, as well as induction of the humoural (Santambrogio et al., 1999). Subsequently, dendritic cells
response and subsequent clinical disease after repeated antigen migrate through the submucosa and present the processed
exposure. The clinical phase can also be further subdivided into antigen to naïve undifferentiated THelper (TH) lymphocytes.
early- and late-phase responses. Antigen-specific T cells bind the dendritic cell MHC class II-
The first step towards generation of a T helper lymphocyte peptide complex with CD4 and this interaction, along with other
response is the recognition and uptake of antigen by antigen- cell–cell signals, triggers the T cells to differentiate into TH2
presenting cells (e.g., dendritic cells, macrophages, B cells) that cells and activation of B lymphocytes which produce antigen-
have the capacity to digest antigen into short peptides that specific IgE (Bousquet et al., 1996).
associate with major histocompatibility complex (MHC) IgE is the principal trigger for allergic rhinitis. IgE interacts
molecules and provide co-stimulation for naive T cells with both FcεR1 and the lower-affinity receptor FcεR2 (CD23).
(Lambrecht, 2001). Dendritic cells have been identified as the Differentiation of B cells into IgE-secreting plasma cells
most effective antigen presenting cells for inducing and requires at least 2 distinct signals in IL-4 (or IL-13) and CD40L
regulating the primary immune response in vivo and in vitro on the surface of TH2 cells with CD40, a costimulatory molecule
(Banchereau et al., 2000). The mucosa of the nose is covered on B cells which triggers isotype switching to IgE. IgE binds to
with an extensive network of dendritic cells that reside in the the α-chain of the tetrameric FcεR complex on mast cells,
para and intercellular channels surrounding the basal epithelial basophils, monocytes, and dendritic cells. The molecular
cells (Evans & Plopper, 1988). interactions responsible for high-affinity binding are complex
There are 3 dominant mechanisms by which immature and involve several sites in the Cε3 domain of IgE (Chang, 2000).
dendritic cells can uptake an antigen. First, antigenic material In its free form, IgE has a half life of only a few days.
can be acquired via receptor-mediated endocytosis involving However, when bound by FcεRs it is protected against degra-
clathrin-coated pits. Immature dendritic cells express a plethora dation and can remain on the surface of inflammatory cell for
of specialized cell receptors for chemical sequences that are months (Brostoff, 1986). Circulating antigen-specific IgE binds,
associated with foreign antigens, such as the C-type lectin via the Fc region, to FcεRI receptors on the surface of nasal
carbohydrate receptors (Cochand et al., 1999; Ariizumi et al., mast cells and basophils and thereby exposes the antigen-
2000; Geijtenbeek et al., 2000; Mahnke et al., 2000; Valladeau specific Fab region to the local environment and ready to be
et al., 2000). Secondly, an antigen can be taken up by a consti- activated by further allergen exposure.
tutive macropinocytosis that involves the actin skeleton-driven The initial exposure and the process of priming the inflam-
engulfment of large amounts of fluid and solutes (∼1 cell matory cells responsible for executing responses to antigen is
volume/hr) by the ruffling membrane of the dendritic cell fol- referred to as sensitization. Re-exposure to the same allergen on a
lowed by concentration of soluble antigen in the endocytic mucosal surface results in a coupling or cross-linking of the IgE
compartment (de Baey & Lanzavecchia, 2000). Thirdly, den- molecule that leads to cellular degranulation and the release of
dritic cells have been shown to phagocytose particulate antigens inflammatory mediators, a process resulting in both an acute and
such as latex beads, and even whole bacteria, as well as apoptotic chronic phases (Fig. 3).
Y.M. Al Suleimani, M.J.A. Walker / Pharmacology & Therapeutics 114 (2007) 233–260 239

Fig. 3. Schematic representation of the pathophysiology of allergic rhinitis.

2.3. Rhinitic responses to allergen challenge 2.3.1. Acute phase


During the period of sensitization, increasing numbers of IgE-
Classically the sensitized human nasal response to challenge coated mast cells traverse the epithelium, and once challenged,
with a relevant antigen can be itemized as consisting of the these recognize the mucosally deposited allergen and degranulate
following symptom and sign profile: (Naclerio, 1991). Products of degranulation include preformed
mediators such as histamine, tryptase (mast cell specific marker),
(i) sneezing, generally occurs as multiple events and for chymase (“connective tissue”-mast cells only), kininogenase (gene-
extended periods; rates bradykinin [BK]), heparin, and other enzymes. In addition,
(ii) itching, in and around the nose and nasal mucosa; mast cells create some inflammatory mediators de novo (i.e., ones
(iii) rhinorrhea, a copious water secretion from the nose; not preformed or stored) including prostaglandin D2 and the
(iv) nasal congestion with airflow through one of both nasal sulfidopeptidyl leukotrienes LTC4, LTD4, and LTE4 (see below).
passages being impaired, even to the point of complete These mediators cause blood vessels leakage, produce mu-
blockade. cosal edema, and the watery rhinorrhea characteristic of allergic
rhinitis. Glands secrete mucoglycoconjugates and antimicro-
The acute signs of allergic rhinitis include the following: bial compounds and help dilate blood vessels to cause sinusoi-
dal filling with resulting occlusion and congestion of nasal air
i) engorged nasal mucosa, with obvious congestion and passages.
obstruction; Mediators also stimulate sensory nerves to cause nasal itch
ii) infiltration of immune cells into the nasal mucosa as shown and congestion as well as recruit systemic reflexes such as
by taking swabs of the nasal passages or by nasal lavage. sneezing. The above responses develop within minutes of aller-
gen exposure and are termed the early phase, or “immediate,”
The above signs and symptoms vary with the phase of the allergic response (Mygind & Naclerio, 1993). Sneezing, itching,
allergic response (see below). and copious clear rhinorrhea are characteristic symptoms during
240 Y.M. Al Suleimani, M.J.A. Walker / Pharmacology & Therapeutics 114 (2007) 233–260

the early phase of allergic responses although nasal congestion together with other mediators, such as NPY (Groneberg et al.,
may also occur. 2004) and GCRP (Springer et al., 2003), may participate in the
pathophysiological mechanisms underlying allergic rhinitis.
2.3.2. Chronic phase The inflammatory mediators released by allergic responses
Mast cell-derived mediators released during early phase can sensitize and activate sensory nerve endings by inhibiting
responses, as well as mediators released by basophils during the neuronal after-hyperpolarization and increasing phosphokinase
late phase, are thought to act on postcapillary endothelial cells to C phosphorylation of neuronal ion channels. Additionally,
promote the expression of vascular cell adhesion molecule and E- exposure of nerve endings to cytotoxic proteins (e.g., MBP and
selectin to facilitate adhesion of circulating leukocytes to ECP) as well as increasing expression of the neuronal mem-
endothelial cells. Chemoattractant cytokines such as IL-5 promote brane receptors induced by cytokines (e.g., IL-1β and tumor
the infiltration of the mucosa with eosinophils, neutrophils, and necrosis factor-α [TNF-α]) may also increase neuronal hyper-
basophils, T lymphocytes, and macrophages (Naclerio et al., excitability (Christiansen et al., 2002).
1985; Bascom et al., 1988b). At 4–8 hr after allergen exposure Neurotrophins change both sensory and other nerve phe-
these cells become activated and release inflammatory mediators notypes. Nerve growth factor (NGF) is one such potent trophic
which in their turn reactivate many proinflammatory reactions substance. In sensory nerves, especially C fibers, NGF appears
involved in the immediate response. to be the only active neurotrophin. NGF is released by several
The late cellular-driven inflammatory reaction is the “late types of cells, including possibly mast cells. It can have acute
phase response.” This reaction is clinically indistinguishable effects that change neuroterminal function and even reaches the
from the immediate reaction except that congestion tends to nucleus via retrograde transport, thereby producing signals that
predominate (Skoner et al., 1988). Eosinophil-derived increase neuropeptide content in nerves and stimulate nerve
mediators such as major basic protein (MBP), eosinophil growth. NGF is present in the nasal fluids of individuals with
cationic protein (ECP), and leukotrienes have been shown to active chronic allergic rhinitis and it is also acutely released
damage the epithelium, leading ultimately to the clinical and upon nasal allergen challenge (Sanico et al., 2000; Togias,
histological picture of chronic allergic disease. Subsets of the 2000).
T-helper lymphocytes orchestrate the chronic inflammatory In allergic rhinitis, sensory neuron activation results in
response to allergens. TH2 lymphocytes promote allergic sneezing and bilateral parasympathetic reflexes (Baraniuk,
responses by releasing IL-3, IL-4, IL-5, and other cytokines 2000; Casale et al., 2001). Activation by mediators (histamine
that promote IgE production, eosinophil chemoattraction, and being the most prominent) of sensory neurons results in
their own survival in tissues, as well as mast cell recruitment depolarization. In the CNS, trigeminal nociceptive neurons
(Durham et al., 1992). Cytokines released from TH2 lym- enter the pons through the sensory root, turn caudally in the
phocytes may be the cause of the fatigue, malaise, irritability, trigeminal spinal tract and terminate in the pars caudalis of the
and neurocognitive deficits commonly noted in allergic lower medulla and upper 3 cervical segments of the spinal cord.
rhinitis patients (Sim et al., 1995). Pars caudalis interneurons cross the midline to enter the
trigeminothalamic tract and terminate in the medial part of the
2.4. Pathophysiological events in allergic rhinitis ventral posterior thalamic nucleus (arcuate or semilunar
nucleus). Pain and itch stimuli are received at the thalamic
2.4.1. Neuronal level. Connections between the afferent interneurons of the
Apart from sympathetic and parasympathetic nerves which nuclei of the trigeminal spinal tract, and the solitary tract with
contain norepinephrine and acetylcholine, respectively, nasal the nucleus ambiguous, establish the sneezing reflex. Similar
sensory nasal afferent innervation also plays a role (Baraniuk & connections regulate parasympathetically mediated glandular
Kaliner, 1991). Thus, sensory airway nerves have been demon- secretion in the nose (superior salivatory nucleus and facial
strated to play an important role in allergic rhinitis (Heppt et al., nerve; Calliet, 1992).
2004).
Nasal sensory nerve fibers contain a number of different 2.4.2. Vascular
peptides, including CGRP and the tachykinins, SP, and NK-A. Acetylcholine, catecholamines, various peptides and also
These neuropeptides, metabolised by the enzyme neutral nitric oxide (NO) participate in nasal vascular control by
endopeptidase (NEP), are released from sensory nerves of the inducing vasconstriction or vasodilation (Lund, 1996). These
nonadrenergic noncholinergic (NANC) nervous system. They bioactive molecules arise from both sensory and autonomic
are capable of activating local reflexes which causes an increase nerve fibers, and from neuroendocrine cells widely dispersed in
in vascular permeability, plasma leakage, vasodilation, and the nasal mucosa. Adult human nasal mucosa has dense nerve
subsequent tissue oedema (Baraniuk, 1997). This response, networks containing VIP, NPY, or its C-terminal peptide
known as neurogenic inflammation, is mediated by tachykinin (CPON), SP, CGRP among other putative neurotransmitters.
NK-1 and NK-2 receptors. In addition, eosinophils are capable Sympathetic fibers have both norepinephrine and NPY.
of producing VIP and SP (Metwali et al., 1994). Increased Immunoreactivities for NPY and CPON show them to be
levels of SP and vasoactive intestinal polypeptide (VIP) have colocalized and mainly in perivascular nerve fibers. The nasal
been found in nasal secretions from allergic rhinitis patients subepithelial region contains a dense plexus of SP- and CGRP-
subjected to nasal irritation (Mosimann et al., 1993). These immunoreactive fibers, although these nerves also appear
Y.M. Al Suleimani, M.J.A. Walker / Pharmacology & Therapeutics 114 (2007) 233–260 241

around blood vessels (Lacroix et al., 1992; Anggard et al., 1983; epithelial goblet and serous cells, the submucosal seromucous
Hauser-Kronberger et al., 1993). glands, and the anterolateral deep glands in the nose
Nasal congestion is a common symptom of acute and chronic (Widdicombe & Wells, 1982; Wells & Widdicombe, 1986). In
rhinitis. It is caused by swelling of nasal blood vessels that addition transudation may contaminate secreted mucus. Nasal
expand and so restrict or obstruct airflow through nasal mucus secretion is controlled predominantly by parasympa-
passages (Broms, 1982). During allergic reactions, a large thetic cholinergic nerves (Widdicombe, 1990). In allergic
number of inflammatory and immunological mediators derived rhinitis, neurotransmitters (ACh, SP) and inflammatory media-
from leukocytes, plasma, and neurons (e.g., leukotrienes, ki- tors (histamine, BK, leukotrienes) cause increases in glandular
nins, histamine, neuropeptides, NO, ACh) act via their receptors secretions (Widdicombe & Wells, 1982; Wells & Widdicombe,
in nasal vasculature to cause either vasodilatation or vasocon- 1986; Knowles et al., 1987). In the nasal mucosa of human
striction (Lung et al., 1984; Widdicombe, 1986, 1990). The inferior turbinates, nerve fibers are found in the periglandular
inferior turbinate of human nasal mucosa contains arterioles and tissue around the acini, ducts and in the periglandular
venous sinuses that are constricted (decongestion) by norepi- connective tissue. It has been found that VIP is in contact
nephrine, NPY, and endothelin-1 and dilated (congestion) by with acinus cells and CGRP is found in the connective tissue
acetylcholine, VIP, NO, CGRP, and SP (Riederer et al., 2002). around glandular cells suggesting a role in controlling glandular
Changes in vascular innervation could be one of the factors secretions (Knipping et al., 2001).
involved in the maintenance of rhinitis. Nasal vascular
hyperinnervation has been detected in patients with allergic 2.4.4. Nasal airway hyperresponsiveness
rhinitis when compared with nonallergic individuals (Figueroa Nasal airway hyperresponsiveness (AHR) is a hallmark of
et al., 1998). allergic rhinitis (Druce et al., 1985; Mullins et al., 1989). Those
Plasma extravasate (via vascular leakage or exudation) is with allergic rhinitis show an increased response to nasal
unfiltered plasma containing albumin, antibodies and comple- challenge to many stimuli, including histamine, BK (both
ment fractions (Bousquet et al., 1996). An increase in vascular released by allergen challenge), methacholine, tobacco smoke,
permeability occurs in both seasonal allergic rhinitis and and perfume (Baraniuk, 1997; Gerth van Wijk et al., 1999).
perennial allergic rhinitis (Wilson et al., 1998). Additionally, Hyperresponsiveness is associated with nasal congestion,
vascular permeability is increased by histamine and/or BK increased mucus production, and oedema following allergen
challenge in individuals with allergic rhinitis (Rajakulasingam challenge in both upper and lower airways. It is usually
et al., 1993). The concentrations of both increase dramatically associated with the late phase reaction but can continue well
after allergen challenge (Baroody et al., 1994; Paul et al., 1994). beyond this stage. In fact, it is induced, regardless of whether
Histamine appears to be responsible for exudation of bulk the late phase of inflammation occurs (Togias et al., 1988). Most
plasma in seasonal rhinitis (Svensson et al., 1995). patients with allergic rhinitis, besides having chronic inflam-
A role for kinins inducing vascular permeability has also mation in their nasal mucosa that results from allergic reactions,
been proposed since nasal stimulation with histamine or LTC4 also have chronic inflammation in the lower respiratory tract
results in an increase in nasal vascular permeability that that can lead to AHR (Ma et al., 2000).
correlates with kinin concentrations found in the nasal lavage There are a number of potential mechanisms by which AHR
fluid formed during allergic rhinitis (Shirasaki et al., 1989). might occur: greater receptor activation due to increased
An increase in vascular permeability is particularly marked mediator release after initial exposure to allergen; increased
in postcapillary venules where the opening of the intercellular exposure of receptors to any stimulus present (due to damage
gaps, together with anatomical visible fenestrations provides the and destruction of epithelial and interstitial cells, and muco-
plasma with an alternative route for exudation other than blood ciliary clearance system by platelet activating factor (PAF) and
vessels (Widdicombe, 1997). Inflammatory mediators act on cytotoxic proteins like MBP and eosinophil chemotactic
specific receptors in blood vessels to cause extravasation in a protein); reduced the metabolism of mediators (due to loss of
process involving vasodilation and increases in intravascular epithelial function); increased receptor expression (e.g., metha-
pressure (especially in post capillary venules) and/or increases choline causes more secretion in allergic subjects than in
in interendothelial gaps. The exudate forms in the interstitial nonallergic subjects); and alteration of intracellular pathways
space, and then is lost to the nasal cavity. (Laitinen et al., 1985; Devillier et al., 1988; Koga et al., 1992;
Beside nasal congestion and exudation, cellular infiltration White, 1993; Teixeira et al., 1997).
also occurs in allergic rhinitis. The expression of adhesion
molecules on endothelial cells is induced by the acute and 2.5. Pathological factors in allergic rhinitis
chronic release of inflammatory mediators a process that
enhances the extravasation of leukocytes to the site of 2.5.1. Immune cell mediators
inflammation. The role of the inflammatory cells in allergic One of the hallmarks of allergic diseases is accumulation of
rhinitis is described in the following section. inflammatory cells in tissue locations at specific mucosal sur-
faces. The presence of an increased number of mast cells,
2.4.3. Glandular basophils, T cells, and particularly eosinophils, has been de-
Rhinorrhea (watery secretion) is one of the symptoms of tected in nasal smears and biopsies from patients with allergic
allergic rhinitis. Nasal secretions come from 3 main sources: the rhinitis. It has also been shown that in response to certain
242 Y.M. Al Suleimani, M.J.A. Walker / Pharmacology & Therapeutics 114 (2007) 233–260

mediators these inflammatory cells undergo local activation and role in allergy, asthma, parasitic diseases, granulomatous
release of their own mediators in a positive feedback that disorders, fibrotic conditions, and several malignant tumors
contributes to pathological features of the disease. (Munitz & Levi-Schaffer, 2004).
Immunohistochemistry of nasal mucosa shows eosinophils
2.5.1.1. Mast cells. Mast cells are constitutive cells within the within the submucosa and epithelium in those with symptom-
normal nasal mucosa. They are recognized as key cells in type 1 atic rhinitis (Bentley et al., 1992; Bradding et al., 1993).
hypersensitivity reactions. Mast cells divide into connective and Eosinophils are mainly involved in the late-phase reaction after
mucosal phenotypes. Connective tissue mast cells express they have infiltrated from the blood into tissue. Cytokines
chymase, tryptase, and TNF-α (Bradding et al., 1995) and secreted by Th-2 cells help recruit and activate eosinophils in
constitute 85% of the IL4 positive mast cells population in the the nose. IL-4 is considered to be pivotal since it up-regulates
nasal lamina propria. adhesion molecules that are selective for eosinophil recruitment
During allergen exposure, there is an increase in the (Krouse, 2002; Ciprandi et al., 2004).
proportion of mast cells in the epithelial cell layer (Juliusson Eosinophils contain granules composed of 4 basic proteins.
et al., 1995). These mucosal mast cells which produce The core is MBP, whereas the surrounding matrix is ECP,
predominantly tryptase and are without chymase, constitute eosinophil-derived neurotoxin (EDN), and eosinophil peroxidase
the remaining 15% of the IL4 positive mast cells. (EPO; Gleich et al., 1994). The levels of ECP, EPO, and MBP are
In sensitized individuals, the nasal mucosa is full of IgE- raised following antigen challenge in allergic rhinitis (Knani et al.,
binding mast cells (Enerback et al., 1986). Mast cells have long 1992; Shin et al., 1994; Nishioka et al., 1995). Another
been considered to serve primarily as important effector cells in mechanism by which eosinophils stimulate the late-phase allergic
acute IgE-associated allergic reactions. Such cells, from patients inflammation is by generation of arachidonic acid metabolites,
with allergic rhinitis, produce Th2 type cytokines and induce such as prostglandins and leukotrienes (Krouse, 2002; Saito et al.,
IgE synthesis in B cells. They can also autoactivate via the mast 2004). Additionally, human eosinophils express and synthesize a
cell–IgE–FcεRI cascade. In addition, mast cells up-regulate the number of cytokines, including GMCSF, IL-6, IL-1α, IL-2, IL-3,
production of a variety of cytokines/chemokines by epithelial IL-4, IL5, IL-8, RANTES, and TNF-α (Moqbel et al., 1991;
cells and fibroblasts, and also induce the recruitment of Hamid et al., 1992; Costa et al., 1993). Thus eosinophils are
basophils, T cells and eosinophils to sites of allergic inflam- equipped to play a major role in allergic inflammation since they
mation. In a recruiting response they also induce their own are recruited to allergic sites where their cationic proteins,
intraepithelial accumulation by up regulation of adhesion cytokines, and lipid mediators contribute to damage and
molecules like VCAM-1, and through the interactions of nasal dysfunction of other cell types.
mast cells with the extracellular matrix proteins, and nasal
epithelial cells. Thus, it is increasingly evident that mast cells 2.5.1.3. Basophils. Basophils are present in very low numbers
are not only important for the genesis of allergic reactions, but in peripheral blood, and although not found in normal noninflamed
also contribute to the late-phase allergic reaction as well as tissues, they are recruited to sites of inflammation by mediators
to on-going allergic inflammation (Pawankar et al., 2000; released from other cell types. Basophils are found in nasal smears
Pawankar, 2005). in allergic rhinitis (Okuda et al., 1985; Otsuka et al., 1985) and
Activation of mast cells by antigen and IgE occurs via their number increases in allergic patients following nasal allergen
interactions with the high-affinity receptor for IgE (FcεRI). challenge (Bascom et al., 1988a). Evidence of basophil infiltration
Liberation of proteases, leukotrienes, lipid mediators, and his- into the nasal mucosa during allergen challenge can be found in the
tamine contribute to tissue inflammation and allow recruitment profile of mediators found in nasal secretions (Naclerio et al., 1985;
of inflammatory cells into tissue. In addition, the synthesis and Bascom et al., 1988a). Basophils, like mast cells, possess high
expression of a plethora of cytokines and chemokines (such as affinity IgE receptors and are derived from CD34-positive proge-
granulocyte-macrophage colony-stimulating factor [GM-CSF], nitor cells (Knapp, 1990). When activated, basophils are prominent
interleukin [IL]-1, IL-3, IL-5, TNF-α, and the chemokines IL-8, sources of the inflammatory mediators found in allergic late-phase
regulated upon activation normal T cell expressed and secreted reactions.
[RANTES], monocyte chemotactic protein-1 [MCP-1], and Basophils possess fewer larger granules and differ from mast
eotaxin) by mast cells have profound influences on leukocytes cells in that they contain less histamine. Following IgE-
biology and therefore allergic inflammation (Shakoory et al., dependent activation, basophils release only 20–30% of the
2004). histamine released from a comparable number of mast cells
(Castells et al., 1987). Human basophils have also been shown to
2.5.1.2. Eosinophils. Eosinophils, granular bilobed leuko- secrete cytokines, particularly IL-4 and IL-13, when activated by
cytes readily stained by eosin, comprise ∼ 2–5% of granulocytes IgE-dependent stimuli. As a result they modulate the immune
in a nonallergic individual. Eosinophil progenitors released from responses of the other cell types that participate in allergic
the blood marrow into the circulation are chemically attracted to rhinitis (MacGlashan et al., 1994; Schroeder et al., 1994, 1997).
tissue sites by various chemotactic factors. The development and
maturation of eosinophils also occurs in situ at peripheral sites of 2.5.1.4. T lymphocytes. T lymphocytes coordinate and amplify
inflammation where there are increased numbers of tissue the effector functions of antigen-specific and -nonspecific inflam-
eosinophils (Adamko et al., 2005). Activated eosinophils play a matory cells such as B cells and eosinophils. T lymphocytes
Y.M. Al Suleimani, M.J.A. Walker / Pharmacology & Therapeutics 114 (2007) 233–260 243

are divided into 2 subtypes based upon their effector functions. monocytes, B cells (Bachert et al., 1998) although their crucial
CD4+ T cells represent the T-helper cells, which are important in role in the responses to allergen challenge is controversial.
the regulation of antigen-driven inflammatory processes. Via
antigen-specific T-cell receptors, CD4 T cells are capable of 2.5.2. Chemical mediators of allergic rhinitis
recognizing processed foreign antigen in association with MHC
class II on specialized antigen-presenting cells (e.g., macrophages 2.5.2.1. Histamine. Histamine plays a pivotal role in allergic
and dendritic cells; Horiguchi & Okamoto, 2005). inflammation. It is released from the granules of FcεRI+ cells
CD8+ T cells, T-suppressor cells, drive the cell-mediated (e.g., mast cells and basophils), after the cross-linking of surface
response and respond to APC-presenting antigen in conjunction IgE by allergen, or through mechanisms independent of IgE
with MHC class II molecule. The T lymphocyte represents a (Enerback et al., 1986; Kaliner, 1994; Howarth, 1995). Nasal
significant nonstructural cell within the nasal mucosa and their challenge with histamine causes sneezing, pain, pruritus, rhinor-
number increases in the nose of rhinitic patients. These are rhea, and nasal blockade (Doyle et al., 1990). Sensory neurone
generally CD4+ TH2 cells displaying the activated phenotype activated by histamine causes sneezing and pruritus (Mygind,
(CD25+; Varney et al., 1992; Calderon et al., 1994). 1982) in addition to activating a neuronal increase in nasal
CD4+ TH2 lymphocytes appear to play a crucial role in the parasympathetic activity (Hilberg et al., 1995). Increased release
induction and maintenance of chronic allergic inflammation. The of parasympathetic neurotransmitters (e.g., acetylcholine) stimu-
presence of T lymphocytes in allergic inflammation has been well lates nasal submucosal glands which, together with increase in
demonstrated. However, the major reason for their importance lies vascular permeability, cause rhinorrhea (Baroody et al., 1994).
on the profile of cytokines they express upon activation. Although Molecular biology studies have found that 4 histamine
individual T cells have the capacity to produce a wide range of receptors sub types (H1, H2, H3, and H4) occur in normal nasal
cytokines, a restricted profile of cytokines is seen in chronic mucosa studies (Nakaya et al., 2004) with higher expression of
inflammatory diseases (Kelso, 1995). H1 and H2 in atopic individuals (Iriyoshi et al., 1996; Hirata
A major feature of allergic diseases is the high expression of et al., 1999). Most of the effects of histamine in allergic disease
Th2-type cytokines. T lymphocytes of the T-helper 2 subpop- are mediated through H1 receptors (Schmelz et al., 1997;
ulation can generate IL-3, IL-4, IL-5, GM-CSF and TNF-α Schneider et al., 2002; Akdis & Blaser, 2003), but cutaneous
(Mosmann & Coffman, 1989). The Th2 phenotype is thought to itch and nasal congestion may involve both H1 and H3 receptors
influence subsequent T cell activation and IgE production by B (McLeod et al., 1999; Sugimoto et al., 2004). Histamine also
cells in addition to promoting the attraction, activation, growth, activates the H2 receptors on the smooth muscle cells that
and differentiation of specific leukocytes such as eosinophils. In surround nasal capacitance vessels. Their activation causes
this way, activated T cells can initiate and propagate allergic smooth muscle relaxation thereby increase the blood volume in
inflammation and participate directly in the events responsible mucosa thereby increasing its volume. In addition, H4 receptors
for allergic diseases. modulate immune cell function (Riechelmann, 2005).
Epithelial cells are part of the nasal mucosal barrier that In addition to its role in early allergic responses to antigen,
generates the proinflammatory cytokines and chemokines histamine acts as a stimulatory signal for production of cytokines,
that play roles in allergic rhinitis (Calderon et al., 1997). expression of cell adhesion molecules and class II antigens. All
Following exposure to allergen, in-vitro nasal epithelial cells contribute to the late allergic response (Fujikura et al., 2001;
from atopic individuals release increased greater amounts of MacGlashan, 2003).
IL-1β, IL-8, GM-CSF, TNF-α and the chemokine RANTES, H1 receptors exhibit agonist-independent signal transduction
as compared with nasal epithelial cells from non-atopic that is blocked by H1 antihistamines probably by stabilizing an
individuals (Nonaka et al., 1996). Nasal epithelial cells from inactive conformation of the H1-histamine receptor by acting as
people with a genetic predisposition to upper airway disease appear inverse agonists (Bakker et al., 2000). H1-receptor activation
to release increased amounts of proinflammatory cytokines upon has proinflammatory activity, and is involved in the develop-
exposure to allergen, thereby contributing to the allergic response ment of several aspects of antigen-specific immune response,
(Calderon et al., 1997). including the maturation of dendritic cells, and modulation of
In medium conditioned by epithelial cells human upper airway the balance between type 1 helper (Th1) T cells, and type 2
epithelial cells secrete GM-CSF, whereas epithelial cells from helper (Th2) T cells. Histamine may increase the proliferation of
inflamed nasal tissue secrete larger amounts of proinflammatory Th1 cells and the production of interferon gamma and thereby
cytokines, as compared with normal nasal epithelial cells (Ohtoshi block humoural immune responses by this mechanism. Hista-
et al., 1991). During inflammation, complement activation has mine also induces the release of proinflammatory cytokines and
been shown to occur at the nasal epithelial cell membrane with the lysosomal enzymes from human macrophages and has the
nasal epithelium being capable of regulating this process. The capacity to influence the activity of basophils, eosinophils, and
integrity of the nasal epithelium in inflammatory states is thought fibroblasts (Ma et al., 2002; Akdis & Blaser, 2003).
to depend on the maintenance of equilibrium between comple-
ment activation and cell membrane regulation of this activation 2.5.2.2. Eicosanoids. Eicosanoids are proinflammatory med-
(Varsano et al., 1996). iators resulting from metabolic degradation of arachidonic acid
Other cells types have also been shown to increase in allergic a constituent of cell membranes. Eicosanoids include leuko-
rhinitis, including neutrophils, macrophages, dendritic cells, trienes, prostaglandins, and thromboxanes.
244 Y.M. Al Suleimani, M.J.A. Walker / Pharmacology & Therapeutics 114 (2007) 233–260

Leukotrienes. The name leukotriene describes their source 2.5.2.3. Platelet activating factor. PAF is not stored, but
(leukocytes) and chemical structure (3 double bonds). The first produced from phospholipids mobilized from cell membranes by
discovered was leukotriene C, initially described as the “slow phospholipase A2 in many cell types (e.g., basophils, neutro-
reacting smooth muscle-stimulating substance” (SRS) first phils, monocytes, macrophages, or endothelial cells). The PAF
described almost 7 decades ago as being released by snake produced by monocytes and polymorphonuclear leukocytes is
venom and histamine (Feldberg & Kellaway, 1938; Kellaway & secreted, whereas PAF is synthesized by vascular endothelial
Trethewie, 1940). cells due to activation by various physiologic agonists (e.g.,
Leukotrienes are generated by the action of 5-lipoxygenase thrombin, BK, histamine, hydrogen peroxide, and leukotrienes
on arachidonic acid. They are released in both the early and late C4 and D4) and not released (Sisson et al., 1987; Leirisalo-Repo,
phase responses in allergic rhinitis, and in the early phase 1994; Cuss, 1999; Krump & Borgeat, 1999).
response perennial allergic rhinitis (Naclerio et al., 1985; de Of all the known inflammatory mediators possibly involved
Graaf-in t Veld et al., 1996). The 2 classes of leukotrienes, LTB4 in allergic rhinitis, PAF is the most effective at inducing
and the peptidyl-cysteinyl leukotrienes (CysLT; LTC4, LTD4 vascular leakage, an action that contributes to rhinorrhea and
and LTE4) have important mediator functions in the upper nasal congestion (Cuss, 1999; Oppenheimer & Casale, 2002).
airways, with implications in allergic rhinitis. There are 2 PAF has potent proinflammatory properties that have been
classes of receptors for cysLT1 and cysLT2 (Nicosia et al., implicated in bronchial asthma (Naclerio et al., 1985). However,
1999). CysLT1 receptors occur in human airway (smooth its role in allergic rhinitis is less well established. Studies with
muscle cells and macrophages), on other proinflammatory cells the PAF receptor antagonist CV-3988 have shown in sensitized
(eosinophils and certain myeloid stem cells) and in nasal guinea pigs that it blocks vascular permeability and decreased
vascular beds. CysLT have been related to the pathophysiology nasal airway resistance due to topical application of PAF,
of asthma and allergic rhinitis. whereas SM-10661 (another antagonist) attenuated antigen-
With specific regard to allergic rhinitis, leukotrienes are induced increase in late-phase nasal airway resistance (Honda
synthesized by mast cells, eosinophils and basophils, whereas et al., 2002). The antagonist ABT-491 inhibits both antigen-
LTC4 and LTD4 and are found at measurable concentrations induced vascular leakage and decreased airway resistance in rats
in nasal secretions after allergen challenge (Howarth et al., and guinea pigs (Bousquet, 1998). Clinically, nasal insuflation
2000). Ragweed-sensitive patients, when challenged with var- of PAF induces many of the symptoms of rhinitis, such as an
ious doses of antigens, have a dose-dependent increase in nasal increase in nasal airway resistance, rhinorrhea, nasal neutrophil
lavage concentrations of LTC4, LTD4, and LTE4; concentrations influx, and nasal hyperresponsiveness (Andersson & Pipkorn,
that correlates with nasal congestion, sneezing, and mucous 1988; Leggieri et al., 1991; Miadonna et al., 1996). Both PAF,
secretion (Creticos et al., 1984). LTC4, LTD4, and LTE4 also and its metabolite (lyso-PAF), have been detected in the nasal
cause long-lasting eosinophil infiltration and have been fluid and plasma of patients with rhinitis (Labrakis-Lazanas
associated with AHR in rats and man (Christie et al., 1992; et al., 1988; Miadonna et al., 1989; Shirasaki & Asakura, 1990).
Wang et al., 1993).
Nasal challenges with CysLT produce symptoms of allergic 2.5.2.4. Cytokines. Cytokines, as intercellular messenger
rhinitis that can be inhibited by leukotriene receptor antagonists. peptides, are released by a variety of cells to influence the
In normal subjects, nasal delivery of LTD4 produces dose- activity of other cells. Three cytokines are of importance in the
dependent increases in nasal mucosal blood flow, and nasal development and regulation of eosinophil function: interleukins
airway resistance. A similar, but more marked, response has IL-3 and IL-5 and GM-CSF. All 3 prevent apoptosis and
been seen in allergic subjects given LTD4 (McLeod et al., 1999). prolong the survival of eosinophils in vitro. In particular, IL-5 is
The leukotriene antagonist, pranlukast, inhibits the nasal essential for the differentiation of progenitor cells into
mucosal swelling induced by topical administration of LTD4 eosinophils (Sanderson, 1993).
(Numata et al., 1999). Both IL-4 and IL-5 have been implicated in the development
Prostaglandins and thromboxanes. The most important of AHR (Hogan & Foster, 1997). In animals, IL-5 causes
prostaglandins are prostaglandins D2, E2, F2α, tromboxane marked eosinophilia, eosinophil activation, and AHR (Van
A2, and prostacyclin (Raskovic et al., 1998). Increased concen- Oosterhout et al., 1996). IL-4 regulates the activity of CD4+ T-
trations of prostaglandins PGD2 and PGE2 are found in lavage lymphocytes, cells that release a range of cytokines capable of
fluid following allergen challenge in subjects with seasonal priming and activating eosinophils (Mauser et al., 1993). IL-4
allergic rhinitis (Sugimoto et al., 1994; Wagenmann et al., also activates neutrophils (Howarth, 1995). Furthermore,
1996), as well as in those with perennial allergic rhinitis (Ramis memory T cells in the nasal mucosa of patients with nasal
et al., 1991). These changes are only seen in the early and not in allergy can produce IL-4 during allergen exposure. This could
the late response phases. More importantly cyclooxygenase up-regulate inflammatory responses (Boey et al., 1989).
inhibitors (NSAIDS) do not affect response to antigen challenge Patients with seasonal allergic rhinitis, or perennial allergic
in human rhinitis (Naclerio et al., 1985). rhinitis, have a raised number of CD4+ T cells (Hellquist &
Thromboxane A2 induces vascular permeability, eosinophil Karlsson, 1992).
infiltration, and nasal congestion after antigen challenge in Following nasal allergen challenge in humans, levels of IL-
allergic patients, whereas the level of nasal thromboxane A2 1ά, IL-1β, IL-5, IL-6, IL-8, and GM-CSF are elevated in nasal
increases after challenge (Motobayashi et al., 2001). secretions (Bradding et al., 1993; Gosset et al., 1993; Sim et al.,
Y.M. Al Suleimani, M.J.A. Walker / Pharmacology & Therapeutics 114 (2007) 233–260 245

1995). Eosinophils are one potential source of these cytokines mediator of inhibitory NANC transmission. Thus, inhibition of
(Lantero et al., 1996), whereas epithelial cells from allergic NOS could potentially reduce the activity of inhibitory NANC
rhinitic patients showed increased immunostaining for GM- nerves, thereby potentiating neurogenic inflammation mediated
CSF, IL-8, the receptors for IL-1 and TNF-α (Galli et al., 1994), by excitatory NANC nerves. In chronic allergy, excessive NO
and also they release more IL-1β, IL-8, GM-CSF, and TNF-α production causes AHR via the formation of the peroxynitrite
compared to epithelial cells from nonallergic subjects (Nonaka free radical in guinea pigs airways (Sadeghi-Hashjin et al.,
et al., 1996). Similar increases in IL-4-, IL-5-, and GM-CSF- 1996). Furthermore, other NO metabolites, such as nitryl
positive cells are observed in the nasal mucosa of atopic patients chloride, can be synthesized by neutrophils resulting in
(Calderon et al., 1997). Both interferon-gamma and TNF-α (and inactivatation of angiotensin-converting enzyme in endothelial
possibly other cytokines) cause an up regulation of ICAM-1 on cell (Eiserich et al., 1998). This enzyme is involved in the
human nasal epithelial cells (Durham et al., 1992), whereas IL-4 degradation of kinins and possibly tachykinins in allergic
up regulates the expression of VCAM-1. Both these adhesion rhinitis (Lurie et al., 1994; Chatelain et al., 1995). Inhibition of
molecule are unregulated in allergic rhinitis (Bradding et al., the enzyme may therefore exacerbate rhinitis.
1993).
2.5.2.7. Kinins. Kinins are proinflammatory peptides that
2.5.2.5. Chemokines. Chemokines divided into groups mediate some of the vascular and pain responses to tissue injury.
depending upon chemical structure but all have chemotactic Two kinin receptor subtypes have been identified, B1 and B2
actions. With CC chemokines, 2 cysteine residues are adjacent (Regoli et al., 1977). The B2 receptor mediates the action of BK
to each other (e.g., RANTES, MIP-1α, eotaxin), whereas in and lysyl-BK (Lys-BK), whereas the B1 receptor mediates the
CXC chemokines, 2 cysteine residues are separated by a third action of des-Arg9-BK and Lys-des-Arg9-BK (Leeb-Lundberg
amino acid (e.g., IL-8; Barnes et al., 1998). Concentrations of et al., 2005).
RANTES, MIP-1α, eotaxin, and IL-8 in nasal lavage fluids rise Recent studies (Turner & Foreman, 1999) suggest that AHR
following nasal allergen challenge in man (Sim et al., 1995; in human nasal airway may be kinin dependent since icatibant, a
Gosset et al., 1997; Minshall et al., 1997, Rajakulasingam et al., BK B2 receptor antagonist, prevents PAF-induced AHR. In
1997). In addition, mucosal cells obtained from rhinitics show addition PAF causes an increase in kinin concentration in nasal
increased expression of mRNA for RANTES (Rajakulasingam lavage fluid. Kinins are produced in both perennial allergic
et al., 1997), and eotaxin (Minshall et al., 1997). rhinitis, and seasonal allergic rhinitis. BK causes sensitisation of
It is generally accepted that RANTES and eotaxin are C fibers in the guinea pig trachea (Fox et al., 1996), and there is
important in IL-5-mediated eosinophilia. The latter mobilizes evidence that, in the human nose, enhanced responsiveness to
eosinophils into the circulation, whereas the local release of BK is mediated by neural reflexes (Riccio & Proud, 1996). BK
chemokines provides a ‘homing’ mechanism for the migration can also release SP and other neuropeptides from sensory nerve
of eosinophils into tissue (Barnes et al., 1998). Nasal admin- endings (Saria et al., 1988; Geppetti et al., 1990); thus, actions
istration of RANTES in those with allergic rhinitis causes on AHR are possibly neuropeptide-dependent. Alternatively,
accumulation of eosinophils, but not other inflammatory cells BK initiates production of cytokines IL-1, IL-6, and IL-8 in
(Kuna et al., 1998). However, the same study also found that vivo (Ferreira et al., 1993), and stimulate the release of TNF-α/
after allergen challenge the administration of RANTES also β and IL-1 from macrophages (Tiffany & Burch, 1989). Also
caused an influx of basophils, neutrophils, lymphocytes, and BK increases the expression of the CXC chemokine receptors
monocytes, as well as causing epithelial shedding, a response CXCR1 and CXCR2 in patients with allergic rhinitis (Eddleston
similar to that observed in nasal hyperresponsiveness. It is et al., 2003). This could contribute to nasal AHR.
therefore likely that chemokines have an important role in the
recruitment of inflammatory cells observed during the devel- 2.5.2.8. Neuropeptides. Neuropeptides have been previously
opment of nasal hyperresponsiveness. discussed in the neuronal events subchapter. They are contained
in, and released from a wide range of nerves. They vary in their
2.5.2.6. Nitric oxide. NO is produced by NO synthase (NOS) amino acid compositions and have characteristic patterns of
acting on L-argenine. Different isoforms of NOS exist: neuronal, localization in the peripheral and central nervous systems. All
inducible, and endothelial forms. NOS activity increases in are capable of producing a range of diverse responses.
perennial allergic rhinitis (Garrelds et al., 1995) and in seasonal Primarily unmyelinated sensory C-fibers and myelinated Aδ-
allergic rhinitis (Martin et al., 1996; Kharitonov et al., 1997). In fibers contain and release neuropeptides. Such nerves provide a
mice with allergic rhinitis, the distribution of the different NOS in dense innervation to most organs and tissues, particularly blood
nasal mucosa showed that neuronal and endothelial NOS were vessels where perivascular nerves often terminate in close
found on the surface of epithelial and vascular endothelial cells, association with endothelial cells.
but there were no differences in this respect between allergic and Parasympathetic nerve endings contain VIP, peptide histidine
control mice. However, the amount of inducible NOS was methionine, and efferent sympathetic nerve endings contain
elevated in allergic mice (Oh et al., 2003). NPY. Nasal sensory nerve fibers contain a number of different
NO possibly has a role in the production of the cytokines peptides, including CGRP and the tachykinins SP and NK-A.
necessary for eosinophil survival, such as IL-4 and IL-5 (Barnes These neuropeptides which are all metabolised by the enzyme
& Liew, 1995). Interestingly, NO is thought to be the main NEP, are released from the sensory nerves that belong to the
246 Y.M. Al Suleimani, M.J.A. Walker / Pharmacology & Therapeutics 114 (2007) 233–260

NANC nervous system. Such nerves can generate local reflexes and given daily for 7 days (Mizutani et al., 1999; Nabe et al.,
causing increases in vascular permeability, plasma leakage, 2001; Yamasaki et al., 2001; Fukuda et al., 2003; Zhao et al.,
vasodilatation and subsequent tissue oedema (Baraniuk, 1997). 2005). Alternatively, animals can be exposed to 1% aerosol
ovalbumin twice for 10 min, 1 week apart (Yamasaki et al.,
3. An overview of animal models of allergic rhinitis 1997). Ovalbumin absorbed in aluminum hydroxide can be
injected peritoneally as an initial sensitization dose (Namimatsu
While much of the work described above was performed in et al., 1991; Narita et al., 1997; Fujita et al., 1999; Imai et al.,
humans there is a permanent need for good animal models of 2000; McLeod et al., 2002; Sakairi et al., 2005).
allergic rhinitis for both mechanism of action, and drug Sensitization can be passive by intravenous, subcutaneous, or
discovery purposes. Allergic diseases are very uncommon in intraperitoneal administration of anti-OVA serum (Mizuno et al.,
the animal world and research animals suffering spontaneously 1991; Kaise et al., 1998, 2001a, 2001b). Following initial
from allergic rhinitis are not known (Szelenyi et al., 2000). sensitization dose(s), animals are either exposed to repeated
However, allergic rhinitis can be induced in animals using doses of allergen boosters, over a period of time, or directly
different strategies. challenged with allergen. The waiting period from first
A variety of laboratory species have been used to create sensitization to first challenge varies between studies, but
animal models of allergic rhinitis, using a variety of antigens but generally in the range of 2–4 weeks. Conscious animals are
there is no single model that mimics all of the human condition. challenged by the intranasal route using inhalation of aerosol-
As a result there has been a tendency, for the sake of simplicity, ized allergen, or by instillation of microliters of allergen
to concentrate on single symptoms induced in a chosen species. dissolved in saline. Anaesthetized animals can be challenged
Among the species, guinea pigs have gained more attention as a either via the intranasal route or from the tracheal side into the
suitable experimental model for in vivo studies of pharmaco- nasal cavity by infusion of high volumes of allergen (Albert
logical and pathophysiological aspects of the acute and chronic et al., 1998; Mizutani et al., 1999; Sakairi et al., 2005).
phases of allergic rhinitis. This is probably because of the ease Sneezing typically follows challenge in conscious animals,
of use of this species coupled to the fact that this species as probably does itching. While itching cannot be measured
produce many of the responses to allergic rhinitis seen in human directly, it can be assumed to be the stimulus that results in the
allergic rhinitis. Furthermore guinea pigs have long been a rubbing and/or scratching of the nose with paws, analogue to
commonly used species in allergic respiratory diseases. itching reported by humans. Thus individual guinea pigs can be
The Dunken Hartley strain of guinea pig has been widely challenged and episodes of sneezing and nose rubbing counted
used to evaluate the actions of drugs as well as their potential by direct observation, or from videoed records. Acoustic
therapeutic applicability in allergic rhinitis (Mizutani et al., recordings made electronically are also possible. Sneezing and
1999; Nabe et al., 2001; Yamasaki et al., 2001; Fukuda et al., nose rubbing are counted immediately after allergen provoca-
2003; Zhao et al., 2005). In addition, BALB/c mice have been tion and 10–60 min thereafter (Kaise et al., 1998; Nabe et al.,
utilized, mostly for immunological studies in allergic rhinitis 2001; Yamasaki et al., 2001; Mizutani et al., 2003; Fukuda
(Saito et al., 2002; Murasugi et al., 2005). Brown Norway rats et al., 2003; Zhao et al., 2005).
are also used for studying drugs effects on symptoms of Nasal blockade (decreased nasal patency) occurs as a result
experimental rhinitis (Shimizu et al., 2000; Sugimoto et al., of swelling of the nasal mucosa via vasodilatation of vascular
2000b; Fu et al., 2003). Dogs and pigs have been occassionally cavernous tissue plus increased glandular secretions. Such
used for studies of mucus secretions and nasal congestion after changes are biphasic in time since they occur in both the acute
allergen challenge (Revington et al., 1997; Szelenyi et al., 2000; and late phases. In sensitized guinea pigs, both phases of nasal
Malis et al., 2001; Tiniakov et al., 2003). congestion have been detected, with the acute phase occurring
Allergic rhinitis can be induced in laboratory animals using during the first 30 min, and a later phase 4–6 hr after exposure
different allergens. The process of induction of allergy requires to allergen. The patency in the nasal cavity can be measured in
an initial sensitization dose of allergen, followed by repeated both conscious and anaesthetized guinea pigs. In conscious
booster doses, and finally a challenge dose. Responses that can guinea pigs, a 2-chambered double-flow plethysmograph has
be evoked and measured following allergen challenge include been used to measure air flow through the nasal cavity. In this
sneezing, nose rubbing, rhinorrhea, vascular permeability technique, a guinea pig is placed with its neck extending
(exudation) and nasal congestion. In addition, biochemical through the partition of a 2-chambered box (Albert et al., 1998;
and cellular changes can be quantified and evaluated after Fujita et al., 1999; Mizutani et al., 1999; Imai et al., 2000; Nabe
challenge. et al., 2001; Yamasaki et al., 2002; Fukuda et al., 2003;
Ovalbumin and Japanese cedar pollen are 2 commonly used Mizutani et al., 2003). It is reported that nasal air flow is
allergens. The techniques used for sensitization range from inversely proportional to nasal blockade. This plethysmograph-
injection (intraperitoneal, with or without, adjuvant), bolus ic method has been used extensively but its use has been
instillation (intranasal) or steady-state inhalation exposures over criticized by Swedish researchers who consider that changes in
short, or long, periods of time with different concentrations of resistance measured in the plethysmograph originate at or below
allergen and adjuvant. In the purely nasal route for sensitization, the larynx (Finney & Forsberg, 1994). Recently, respiratory rate
4% lidocaine is insufflated over a period of 5 min followed by has been used in conscious guinea pigs to reflect resistance
intranasal doses of allergen absorbed onto aluminum hydroxide changes in the upper airway (Zhao et al., 2005).
Y.M. Al Suleimani, M.J.A. Walker / Pharmacology & Therapeutics 114 (2007) 233–260 247

In anaesthetized guinea pigs, nasal blockade can be mea- saline from the tracheal side (Shizawa et al., 1997; Yamasaki
sured using various methods, including a ventilator flow meth- et al., 1997; Imai et al., 2000; Kaise et al., 2001a; Elovsson
od (Mizuno et al., 1991; Shizawa et al., 1997; Yamasaki et al., et al., 2005). Alternatively, saline can be instilled into one
1997; Albert et al., 1998; Fukuda et al., 2003; Sakairi et al., nostril and simultaneously sucked out of the other nostril by
2005), a forced oscillation method (Narita et al., 1997; McLeod applying a negative pressure (Mizutani et al., 2001; Yamasaki
et al., 2002), and acoustic rhinometry (Kaise et al., 1998; Kaise et al., 2001, 2002; Zhao et al., 2005). The recovered nasal
et al., 2001a, 2001b). In the ventilator flow method, pulsatile air lavage is centrifuged and the resulting supernant for used for
(4–10 mL/stroke and 50–70 strokes/min) is forced through the measurement of mediators (e.g., thromboxanes, leukotrienes,
nasal cavity from the tracheal side. Any change in air flow EPO, NO2− , NO3− , histamine) by way of ELISA or radioim-
resistance is reflected as a nasal patency change. munoassay. The nasal lavage can be assessed for its total
In the forced oscillation method (also know as the flow/ leukocyte count using hemocytometers or semiautomated
pressure method), one side of nasal cavity is cannulated and the haematology analyzers, and for differential cell count using
flow of humidified air is restricted from cannulated side through cytospin followed by staining.
the other side of the nasal cavity, and out the nostril. Changes in All of the above techniques have been used in basic studies
nasal patency change air flow. into allergic rhinitis in experimental animals. However, many of
Acoustic rhinometry is used to measure the volume of the the techniques have been applied to humans.
nasal cavity. In guinea pigs, an ultrasonic transducer/probe can
measure changes in the nasal cavity within 2 cm of the nostrils. 4. Treatments for allergic rhinitis
The volume of the nasal cavity decreases when nasal blockade
increases, and vice versa. The following section considers the whole spectrum of
Rhinorrhea is a particularly troublesome symptom in allergic treatments that have been developed and used in the treatment
rhinitis. Watery nasal secretions appear in sensitized guinea pigs of allergic rhinitis. It is reasonable to conclude that no one
after allergen provocation although in most cases its production treatment is totally effective and that the different treatments
is not of a sufficient volume for it to be measured easily. Nasal target the different symptoms and signs of the disease. Some
secretions can be measured gravimetrically. For example, cotton provide immediate relief from symptoms and others modify the
thread, dyed with flourescein, can be inserted into the anterior underlying immunological mechanisms as exemplified by nasal
naris of guinea pigs for 1 min. The intensity of color is application of glucocorticoid steroids.
proportional to fluid volume, whereas any increase in weight of
the thread is due to absorbed nasal secretions (Namimatsu et al., 4.1. Currently used drugs for
1991). Alternatively, a preweighed swab can be used to absorb allergic rhinitis and limitations to their use
the secretions appearing at the anterior nares (Fujita et al., 1999;
Fukuda et al., 2003). An alternative is to use filter paper strips The 2 major classes of drugs used to treat symptoms of
inserted into the nares so as to absorb secretions over a timed allergic rhinitis are oral H1 antihistamines and intranasal
period (Zhao et al., 2005). corticosteroids. These drugs may be used as monotherapy, or
Exudation occurs as a result of increases in vascular in combination, depending on the predominant symptoms, and
permeability. In sensitized guinea pigs it can be measured using the patient's response to therapy. Alternative drugs, such as
dyes. Different dyes have been used including Evan's blue cromoglycate, may be appropriate in some patients.
(Mizuno et al., 1991; Mizutani et al., 1999, 2001), pontamine sky The first-generation antihistamines include bromphenira-
blue, (Yamasaki et al., 1997; Kaise et al., 1998) and brilliant blue mine, chlorpheniramine, and diphenhydramine. Although these
(Shizawa et al., 1997). A dye, at concentrations that vary from one drugs relieve the sneezing and rhinorrhea in allergic rhinitis,
study to another (1–10%), is administered intravenously before they easily cross the blood–brain barrier and efficacious doses
allergen challenge in anaesthetized guinea pigs. After allergen are always associated with drowsiness and impaired mental
provocation, nasal cavities are perfused with saline at a rate of performance.
0.2–0.25 mL/min for 10–20 min. Dye concentration in the The so-called second-generation antihistamines produce
collected perfusate is quantified by spectrophotometer using the none, or considerably less, sedation than the first-generation
absorbance at 620 nm. Dye concentration is proportional to drugs. The first of these terfenadine and astemizole could,
vascular permeability (exudation). rarely, produce a potentially dangerous (fatal) cardiac arrhyth-
Instead of using dye, intravenously administered 125I- mias in some patients (Day, 1999) due to an ancillary
labelled human serum albumin can be recovered from nasal pharmacological action, blockade of an important cardiac
cavities as a measure of serum protein in the cavity and hence a potassium channel. These first drugs have been taken off the
reflection of serum protein exudation (Elovsson et al., 2005). market and replaced by other newer second-generation
Since allergic rhinitis is basically an inflammatory reaction antihistamines (acrivastine, cetirizine, fexofenadine, deslorata-
of the nasal mucosa this is reflected in the presence of dine, loratadine) that are not associated with this arrhythmia
inflammatory cells and their mediators in nasal lavages. In (Kay, 2000). Fexofenadine, loratadine, and desloratadine are
sensitized guinea pigs, both cells and mediators can be detected not considered nonsedating antihistamines although this is
in nasal lavage during both the acute and chronic phases. Nasal arguable. Acrivastine may be sedating in some patients.
lavage can be achieved by perfusion of the nasal cavities with Cetirizine is considered low sedating.
248 Y.M. Al Suleimani, M.J.A. Walker / Pharmacology & Therapeutics 114 (2007) 233–260

Oral antihistamines are also first-line therapy for allergic Immunotherapy is appropriate in some patients with severe
rhinitis in children (Dykewicz et al., 1998). All members of this symptoms where their allergen is one for which potent extracts
class of these drugs have demonstrated effectiveness in the are available, and who do not respond to pharmacotherapy
relief of the seasonal and perennial rhinitis by reducing the (Dykewicz et al., 1998). Age and concomitant illnesses are
symptoms of sneezing, itching, and nasal discharge. They have factors that help determine whether immunotherapy is appro-
also been found to reduce ocular symptoms of the allergic priate. For example, immunotherapy is rarely appropriate in
conjunctivitis that frequently occurs in conjunction with allergic preschool children, the elderly and in those with severe
rhinitis. Their mechanism of action in producing relief derives pulmonary or cardiovascular disease. In general, effective
for most of this class of drugs from their being antagonist at H1 immunotherapy requires 3–5 years of treatment.
receptors although for some, for example, cetrizine, other Due to the redundancy, synergy and pleiotropism that exists
actions are involved. for the mediators of allergic rhinitis there are limitations to the
H1 antihistamines are generally not considered effective for currently available drugs in terms of their effectiveness.
nasal congestion (Dykewicz et al., 1998). Therefore, in patients Antihistamines (H1) provide symptomatic relief only. Steroids
with this symptom, combination therapy with an oral do not provide acute relief of symptoms and they are
antihistamine plus a decongestant can be helpful. Such nonselective; unsuitable for some patients (especially young
combinations are available at fixed dose ratios that can be children); may cause nasal irritation, bleeding, and in rare cases
taken once daily. The usual decongestants used, for example, even systemic side effects.
pseudoephedrine and phenylpropanolamine, can have unwant- Timing of treatment is critical with anti IgE and immu-
ed effects, such as insomnia, loss or stimulation of appetite, and notherapy needs identification of allergen and multiple injec-
should be used with caution in patients with conditions such as tions. Moreover, anticholinergics (muscarinic antagonists) are
arrhythmias or angina. Furthermore, prolonged and excessive useful only in reducing rhinorrhea.
use of decongestants, which are agonists on α1 adrenoceptors
induce vasoconstriction, is associated with paradoxical rhinor- 4.2. Possible novel targets for treating allergic rhinitis
rhea and even mucosal ulceration.
Intranasal H1 antihistamines, such as azelastine and An improved understanding of the cellular and molecular
levocabastine, are also useful in mild-to-moderate allergic mechanisms occurring in allergic rhinitis has resulted in the
rhinitis (Dykewicz et al., 1998). These topical antihistamines identification of potential novel therapies. In theory, inhibition
are administered twice daily, and have a rapid onset of action. at critical points in the upstream pathway of the allergic cascade
Both azelastine and levocabastine have been shown to improve (e.g., dendritic cells or TH2 cells) should be more effective than
symptoms in patients with seasonal or perennial allergic rhinitis the inhibition of a single downstream mediator (Holgate &
(Bousquet et al., 2001), and seem to have the potential to reduce Broide, 2003).
nasal congestion.
Intranasal corticosteroids are considered first-line treatment 4.2.1. Mediator receptor antagonists
for more severe allergic rhinitis (Dykewicz et al., 1998; As discussed above, targeting the mediator receptors with
Bousquet et al., 2001). The most effective of this class in appropriate antagonists is limited because of the large number
controlling allergic rhinitis are nasally inhaled corticosteroids of possible mediators. However, improvements can be expected
including beclomethasone, budesonide, flunisolide, mometa- in terms of the available antagonists in terms of pharmacoki-
sone, and triamcinolone (Corren, 2000; Kaszuba et al., 2001). netic profile and therapeutic utility as well as antagonists acting
Corticosteroids target the inflammatory mechanisms. Thus, on more than on type of mediator receptor.
intranasal steroids are particularly effective in ameliorating
nasal congestion, which is often the main complaint in chronic 4.2.1.1. Antihistamines. The new generation H1 antihista-
allergic rhinitis, but they also relieve other symptoms of rhinitis, mines show improved effectiveness and safety, particularly
such as rhinorrhea, sneezing, and nasal itching. Most are those which also act as inverse agonists. Inverse agonists
administered once or twice daily for extended periods. To obtain stabilize the inactive conformation of the receptor thereby
optimal benefit therapy should begin before the onset of reducing the proportion of the receptor in their active con-
symptoms (for example, before the expected pollen season). formation (Oppenheimer & Casale, 2002). A number of
The onset of action of intranasal corticosteroids is slow with antihistamines (e.g., fexofenadine, a metabolite of terfenadine
maximum benefit occurring over days or even weeks. Systemic without the potential for causing torsade) are also claimed to
side effects are minimal in adults receiving intranasal have anti-inflammatory actions (Baroody & Naclerio, 2000).
corticosteroids. Nose bleeding or irritation may occur and The recent discovery of the H4 receptor expressed on mast cells,
these tend to diminish over time although, in rare cases, septal basophils and eosinophils has generated renewed interest in hista-
perforation has occurred (Cervin & Andersson, 1998). mine because H4 receptors mediate Ca2+ signaling and chemotaxis
Intranasal cromolyn relieves allergic rhinitis symptoms in (Hofstra et al., 2003). It is possible that selective H4 antagonists
some patients. Treatment is preferably begun before the onset of could have antiinflammatory actions in allergic disease.
symptoms and does not improve symptoms once they occur. It
may need to be administered up to 4 times daily (Ratner et al., 4.2.1.2. Leukotrienes inhibitors. CysLT released from mast
2002). cells, basophils, eosinophils, and macrophages are particularly
Y.M. Al Suleimani, M.J.A. Walker / Pharmacology & Therapeutics 114 (2007) 233–260 249

important in causing nasal blockade (Higashi et al., 2003). cell-dependent early- and late-phase allergen-provoked inflamma-
Clinical trials of montelukast and zafirlukast (CysLT1 receptor tory reaction in the airways of guinea pigs so providing some proof
antagonists) show that an effectiveness that is less overall than of the therapeutic potential for selective inhibitors of the protein
that of topical nasal corticosteroids (Pullerits et al., 2002; Philip kinases that are linked to mast-cell activation (Duan et al., 2003).
et al., 2002; Topuz & Ogmen, 2003). The recent discovery of In addition, mast cells also express receptors that inhibit IgE-
both CysLT1 and LT2 receptors on eosinophils, which differ in dependent degranulation through the activation of immunor-
their binding to the leukotrienes LTD4 and LTC4, highlights the eceptor tyrosine-based inhibitory motifs (ITIMS). Molecules
potential proinflammatory role of leukotrienes and the possible associated with FcεR1 inhibitory receptors, such as immuno-
for antagonists with simultaneously actions on both receptors globulin-like transcripts (ILT) and leukocyte immunoglobulin-
(Evans, 2002). like receptors (LIR), influence IgE signaling by triggering
phosphorylation of ITIM sequences on the gamma-chains of
4.2.1.3. Prostaglandin receptor antagonists. Among the FcεR1. At present, 13 LIR are known. LIR 1, 2, 3, 5 and 8 have
prostaglandins PGD2, a mast-cell-derived eicosanoid has potent inhibitory effects. LIR5 (gp49A and gp49B) is highly expressed
vasodilator properties mediated by the DP1 receptor. DP1 by mast cells (Katz et al., 1996). Although no natural ligands for
receptor antagonists could therefore possibly provide another these receptors have yet been identified, they offer targets at
therapy where nasal congestion is problematic. A second PGD2 which to direct novel inhibitory agents.
receptor, DP2 has been identified as a TH2 marker but is also The processes of differentiation, optimal secretion, and even
expressed on eosinophils and basophils where it serves a survival in mast cells are dependent on stem-cell factor (SCF;
chemotactic function whose antagonism could result in anti- Costa et al., 1996). In disorders such as mastocytosis, blockade
inflammatory responses (Arimura et al., 2001; Holgate & of SCF Src kinase activity by the selective inhibitor PP1 has a
Broide, 2003; Sugimoto et al., 2003). marked effect in suppressing mast-cell proliferation (Tatton et
al., 2003). It appears obvious that the ablation of the mast cells
4.2.1.4. Tryptase antagonists. Mast-cell granules contain high in nasal mucosa would produce benefit in allergic rhinitis,
concentrations of the protease tryptase. Tryptase can initiate a where the mucosal mast-cell population is inappropriately
range of inflammatory responses and these have been markedly increased. The implications of ablating the mast cells
implicated in chronic tissue injury and tissue remodeling in non-nasal tissue are not known.
possibly involving coagulation factor II receptor-like 1 found
on epithelial cells, fibroblasts and smooth muscle. A number of 4.2.2.3. Ion channels blocking drugs. The activity of many cell
tryptase inhibitors have been described and some efficacy in types is inextricably linked with maintenance of their transmem-
nasal allergy models (Newhouse, 2002). brane potential by Na and K and other voltage and ligand sensitive
ion channels, ion pumps and ion transporters. Similarly, both
4.2.1.5. Nitric oxide synthase inhibitors. Allergic rhinitis is secretion as well as metabolism, in its broadest sense, is regulated
associated with increased levels of NO production in allergic by intracellular calcium regulated via Ca channels, pumps and
rhinitis. NO causes vasodilation and glandular secretion transporters. These ion-related systems are therefore obvious
(Baraniuk, 1997). NOS inhibitors have been shown to reduce targets for new drugs designed to stabilize cells and preventing
nasal blockade in perennial allergic rhinitis, and plasma them secreting or manufacturing mediators. Selective blockers of
exudates in seasonal allergic rhinitis (Dear et al., 1996). inwardly rectifying and Ca2+-activated K+ channels, and Ca2+-
However, NOS inhibitors, administered intranasally to humans, independent Cl− channels linked to IgE-dependent activation,
were associated to the development of upper airway hyperre- expressed in mast cells, may also offer promise for a new
activity and significant eosinophilia (Turner et al., 2000). generation of anti-allergic drugs (Duffy et al., 2001).

4.2.2. Mast cell stabilizers 4.2.3. Inhibitors of neuronal pathways


Allergic rhinitis is associated with local neural activity, such as
4.2.2.1. Cromones. Cromolyn, and its successor nedocromil, itching, sneezing and reflex-mediated secretion (Baraniuk, 1992;
are thought to act as mast cell stabilizers, but their precise Barnes, 2001) making such neural activity a suitable target for
mechanism(s) of action is not known. They have been shown to drugs. Although SP induces eosinophilia in allergic rhinitis (Fajac
be effective in reducing immediate phase symptoms in allergic et al., 1995), inhibition of its receptors (neurokinin 1 and 2) has so
rhinitis (Kunkel et al., 1987). far proved disappointing when tested clinically.
BK is a potent releaser of neuropeptides. The effectiveness of a
4.2.2.2. Protein kinase inhibitors. Activation of Syk kinase, a B2 BK agonist was reported in nasal allergen challenge (Austin
transducer of signalling through the Fcε receptor of mast cells, via et al., 1994) but subsequent Phase III clinical trials proved disap-
binding to IgE which itself is bound to the IgE receptor leads to an pointing. Other neuropeptides also provide interesting targets,
array of responses including degranulation and neosynthesis of including CGRP in chronic vasodilation (Uddman et al., 1999) and
proinflammatory mediators. Clinically, an inhibitor of Syk kinase secretoneurin, which is present in cholinergic, adrenergic and
(R112) has been shown to be effective in relieving the symptoms of sensory nerves (Korsgren et al., 2003), and which exerts a
allergic rhinitis (Meltzer et al., 2005). Moreover, genistein, a potent proinflammatory effect on eosinophils (Dunzendorfer et al., 1998).
inhibitor of tyrosine kinase, has anti-inflammatory actions on mast- If suitable antagonists for these mediators are discovered and
250 Y.M. Al Suleimani, M.J.A. Walker / Pharmacology & Therapeutics 114 (2007) 233–260

developed they possibly could be effective in chronic forms of exerting direct effects on T lymphocytes. Studies with TLR9-
allergic rhinitis in which nasal blockade dominates. deficient mice have demonstrated that these aspects of the
innate immune response are essential in mediating the
4.2.4. Immunotherapy immunostimulatory activity of CpG DNA, which is character-
Certain strategies have been used in immunotherapy of allergies. ized by production of IL-12, IL-18, interferon gamma, IL-6 and
These include the use of allergen-specific immunotherapy (ASIT), IL-10 (Roman et al., 1997; Hemmi et al., 2000).
allergen peptide-based immunotherapy, and DNA immunotherapy. The cytokine environment induced by CpG DNA is highly
effective at reducing the levels of expression of TH2 cytokine
4.2.4.1. Allergen-specific immunotherapy. The goal of ASIT receptors (for example, the IL-4 receptor; Horner et al., 2001b).
is to modulate immune responses to allergen, and thereby In a mouse model of allergic rhinitis, CpG DNA administration
reduce the symptoms of allergic rhinitis. ASIT is administered prevented both the development of nasal symptoms and
as a series of subcutaneous or sublingually injections of highly eosinophilic inflammation (Hussain et al., 2002).
purified airborne allergen(s) with doses of 6–24 μg to patients
with allergic rhinitis who are specifically sensitized to identified 4.2.5. IgE targeting
allergen(s). ASIT is effective in reducing symptoms of allergic To avoid the problem of sensitization to foreign proteins, a
rhinitis, as evidenced by the inhibition of both early- and late- humanized monoclonal antibody containing 95% human IgG1
phase nasal responses. In children sensitized to a single allergen, and 5% murine IgE-binding epitope has been constructed
a reduced risk of subsequent development of sensitization to (Presta et al., 1993). This antibody recognizes IgE selectively
further allergens was seen (Pajno et al., 2001; Malling, 2002; and inhibits the binding of IgE to both FcεR1 and FcεR2,
Moller et al., 2002). The mechanisms by which ASIT produces thereby inhibiting mast-cell and basophil activation. By this
its beneficial clinical effects are becoming clearer (Canonica & mechanism, omalizumab therapy markedly reduces inflamma-
Passalacqua, 2003). ASIT reduces clinical symptoms by tory leukocytes and the expression of FcεR1. The latter when
inhibiting allergen-specific TH2 cells in favor of a TH1 response not occupied by IgE becomes internalized (Plewako et al.,
(immune deviation; Wachholz et al., 2002), and inducing 2002). When administered as 2-weekly, or 1-monthly subcuta-
regulatory lymphocytes carrying the CD4 and CD25 antigens neous injections, omalizumab decreases circulating free IgE by
and CD4+ CD25− TH3 (immune tolerance; McHugh & N 90% by forming small (1000 kDa), non-complement-fixing
Shevach, 2002). Specific immunotherapy also increases complexes that are eliminated by the reticuloendothelial system
allergen-specific ‘blocking’ IgG1 and IgG4 antibodies, a without causing side effects. In clinical trials of seasonal allergic
variable decline in allergen-specific IgE, and reduces both the rhinitis, omalizumab has shown efficacy (Adelroth et al., 2000;
number and activation state of mucosal mast cells, basophils Casale et al., 2001). Furthermore, in children with allergic
and eosinophils (Ebner, 1999). rhinitis, a combination of SIT with anti-IgE for 24 weeks was
Although SIT is effective in some cases, its administration more efficacious than when either treatment was given alone
can be associated with local and systemic allergic reactions, and (Kuehr et al., 2002).
so a variety of strategies have been followed in an attempt to
improve effectiveness and reduce adverse effects. 4.2.6. Cytokines and chemokines inhibitors
One of the difficulties in deciding which cytokines or
4.2.4.2. Peptide-based immunotherapy. The rationale for chemokines to target for the treatment of allergic rhinitis is the
using short peptides in ASIT is to reduce the potential for large variety of them that are expressed at sites of allergic
allergic side effects, while retaining the beneficial effect of those inflammation, as well as their overlapping functions. In allergic
peptide epitopes recognized by T cells in modifying their inflammation, research has focused particularly on individual
response to allergens. This approach relies on peptides being TH2 cytokines (for example, IL-4, IL-5, IL-9 and IL-13) and
unable to crosslink FcεR1-bound IgE on mast cells and chemokines that attract cells to sites of allergic inflammation
basophils (Holgate & Broide, 2003). (Kay, 2001).
The safety and efficacy of peptides has been taken advantage To date, there are no published studies of cytokines antagonists
of in the treatment of cat allergy using several overlapping in humans with allergic rhinitis. However, animal studies and
peptides derived from chain 1 or 2 of the major cat allergen Fel cytokine challenges in humans help illustrate their effect in nasal
d1. Weekly subcutaneous immunization with 27-amino acid allergy. The therapeutic potential of a recombinant soluble IL-4
peptides derived from Fel d1 reduced symptoms of rhinitis receptor as an inhibitor of IL-4 has produced improvements in
provoked by exposure to cats (Norman et al., 1996). asthmatics (Borish et al., 2001). Monoclonal anti-IL-4 antibodies
inhibit IgE production in mice (Zhou et al., 1997). Allergen
4.2.4.3. DNA immunotherapy. Immunostimulatory DNA challenge increases the level of expression of IL-13 in the nasal
sequences containing CpG motifs are strong inducers of a TH1 mucosa in vivo, whereas, in vitro, IL-13 increases the number of
immune response to antigen, and have therefore been secretory cells in human nasal epithelial cells (Wills-Karp et al.,
investigated in the treatment of TH2-mediated diseases such as 1998; Skowron et al., 2003). Targeting IL-13 has been
allergic rhinitis and asthma (Horner et al., 2001a). CpG DNA investigated in allergic inflammation with mouse models of
inhibits TH2 responses to antigen indirectly by influencing the asthma. Its antagonism inhibits the allergic inflammatory
function of cells of the innate immune system, rather than response in the lower airways (Wynn, 2003).
Y.M. Al Suleimani, M.J.A. Walker / Pharmacology & Therapeutics 114 (2007) 233–260 251

The C-C chemokines, including eotaxin, RANTES and tions. Anti-inflammatory and antiallergic properties of heparin
monocyte chemoattractant proteins 1 and 3 are particularly have been demonstrated both in vitro and in vivo (Matzner
relevant to allergic inflammation, since increased levels of these et al., 1984; Lider et al., 1990). Despite these positive effects
chemokines are detected in the nasal mucosa following allergen very little research has been undertaken over the past years to
challenge and all interact with the CCR3 receptor on systematically investigate heparin in the treatment of allergic
eosinophils, basophils and mast cells (Terada et al., 2001). rhinitis. In one clinical study, intranasal heparin significantly
Activation of CCR3 receptors by application of eotaxin to nasal reduced symptom scores 10 min after antigen challenge. In
mucosa induces an influx of eosinophils (Gorski et al., 2002). addition, eosinophil influx in airway mucosa, and ECP con-
Studies demonstrating that an 11-amino-acid synthetic peptide centratons in nasal lavage fluids were reduced (Vancheri et al.,
inhibits the nasal influx of neutrophils and protein exudation as 2001). Moreover, heparin prevents the nasal mucosa mast cell
induced by nasal challenge with IL-8 in normal subjects degranulation induced by adenosine monophosphate (Zeng
indicate the potential for inhibiting chemokine actions in the et al., 2004).
nasal mucosa (Cooper et al., 2001). Given such evidence it is
not surprising that the 3 chemokine receptors CCR3, CCR4 and 4.2.10. Phototherapy
CCR8 that are preferentially expressed by Th2 cells, mast cells Ultraviolet (UV) light has been shown to exert both local and
and eosinophils represent therapeutic targets in allergy. systemic immunosuppression (Salo et al., 2000; Duthie et al.,
2000) and has been widely used for decades in the therapy of
4.2.7. Adhesion molecules inhibitors various skin diseases. The major mechanisms for UV
Adhesion molecules expressed on leukocytes and endothe- irradiation-induced immunosuppression involves induction of
lial cells are important for inflammatory cell recruitment during apoptosis in infiltrating T cells, reductions in the number of
allergic inflammation. At present, there are no published studies dendritic cells and their function, and induction of immuno-
of antiadhesion therapy in allergic rhinitis. However, the suppressive cytokines such as IL-10 in the skin (Garssen & van
targeting of such molecules on leukocyte or endothelial cell Loveren, 2001; Nghiem et al., 2002). In addition, UV irradiation
surfaces has been studied as an approach to inhibiting aller- inhibits histamine release from mast cells in vitro and in vivo
gic inflammation. One of the adhesion molecules is endothelial (Gollhausen et al., 1985; Danno et al., 1988). Recently, the
P-selectin which is highly expressed in nasal mucosa and has immunosuppressive action of UV radiation has been investi-
been shown to stimulate eosinophil recruitment in mouse gated in allergic rhinitis. In a clinical study, intranasal irradiation
models of allergic inflammation (Symon et al., 1994). with the 308 nm xenon chloride (XeCl) ultraviolet-B laser and
Subsequent to endothelial tethering, eosinophils firmly adhere irradiation with a combination of ultraviolet-B (UVB),
to either ICAM-1 or VCAM-1. Blockade of such molecules in ultraviolet-A (UVA) and visible light (VIS) had a beneficial
allergic mouse with inflammation, or in those with inhibition of therapeutic effect in allergic rhinitis (Csoma et al., 2004; Koreck
eosinophilic tissue recruitment in ICAM-1-deficient mice, et al., 2005). Furthermore, intranasal therapy with 8-methox-
resulted in marked inhibition of the adhesion of eosinophils to ypsoralen (8-MOP), plus UVA radiation therapy for 3 weeks
endothelium (Broide et al., 1998). Furthermore, eosinophils, inhibited the symptoms of allergic rhinitis (sneezing, rhinor-
basophils, monocytes and T cells, but not neutrophils, express rhea, itching and congestion; Csoma et al., 2006). These results
high levels of very late antigen-4 (VLA-4), the ligand for suggest that intranasal phototherapy is effective in the treatment
VCAM-1 (Jackson, 2002). Binding of VLA-4 to the CS-1 of allergic rhinitis.
region of fibronectin also induces eosinophil activation (Anwar
et al., 1993), such that by targeting VLA-4, cell activation such 5. Drugs effects in animal models of allergic rhinitis
cell recruitment might be inhibited.
The actions of various putative mediators of the various
4.2.8. Selective phosphodiesterase 4 inhibitors responses seen in allergic rhinitis have been tested on different
One promising development is the use of selective phos- animals with allergic rhinitis including guinea pigs, rats, mice,
phodiesterase 4 (PDE4) inhibitors which exert anti-inflammatory dogs and pigs. Among the mediators that have been tested,
actions by blocking the breakdown (hydrolysis) of cyclic 3′5′- histamine, leukotrienes (LTB4, LTC4 and LTD4), cytokines,
AMP (cAMP) in lymphocytes, eosinophils, neutrophils and NO, thromboxane (TXA2 and TXB2) and kinins have mostly
monocytes. Reduced cAMP attenuates release of mediators and been studied. These mediators and their antagonists have been
cytokines (Giembycz, 2000). Although known to be effective in applied to mimic or block either acute, late or both phases of
the treatment of asthma, and chronic obstructive pulmonary allergic rhinitis. Analogous studies have been performed in
disease, oral once-daily therapy with the PDE4 inhibitor humans and generally there is reasonable concordance between
roflumilast in patients with allergic rhinitis subjected to repeated the effects seen in laboratory animals and those seen in humans.
allergen exposure proved to be efficacious, especially on nasal Thus the various mediators found to be involved in producing
blockade (Sorbera et al., 2000; Schmidt et al., 2001). allergic rhinitis symptoms in the animals mimic the situation
found in humans. Table 1 summaries the effects of various
4.2.9. Heparin drugs and the roles of inflammatory mediators involved in
The anticoagulant, heparin, a straight-chain, highly sulfated allergic signs and symptoms in different experimental animals.
glycosaminoglycan, is present in mast cells at high concentra- The actions of these mediators have been deduced either from
252
Table 1
The effects of various drugs on nasal allergic responses in different animal models of allergic rhinitis

Drug Mediator (targeted by the drug) Effect (alleviated by the drug) Reference

Guinea pig
Mepyramine, pranlukast histamine (H1), CysLT sneezing, nasal obstruction Mizutani et al., 2003
LY303870 (NK1 receptor antagonist), SR48968 (NK2 receptor antagonist), neuropeptides (SP, NK-A, CGRP) sneezing , nasal obstruction Kaise et al., 2001a
CGRP(8-37) (CGRP-1 receptor antagonist
Oxatomide histamine (H1), pLTs sneezing, nose rubbing, vascular permeability, Kaise et al., 1998
nasal obstruction

Y.M. Al Suleimani, M.J.A. Walker / Pharmacology & Therapeutics 114 (2007) 233–260
ABT-491 (PAF antagonist) PAF nasal obstruction Albert et al., 1998
Mepyramine, naphazoline (α-adrenergic) histamine (H1), α-adrenoceptor nasal obstruction Mizutani et al., 1999
Flutropium histamine (H1) + other allergy mediators vascular permeability Mizuno et al., 1991
Olopatadine tachykinins sneezing Kaise et al., 2001b
Seratrodast, azelastine TXA2, histamine (H1) vascular permeability, nasal obstruction Yamasaki et al., 1997
TMK688 (5-lipoxygenase inhibitor) LT (B4, C4) exudation, nasal obstruction Shizawa et al., 1997
Mepyramine histamine (H1) sneezing Nabe et al., 2001
Mepyramine, chlorpheniramine histamine (H1) nasal obstruction McLeod et al., 2002
Pranlukast CysLT nasal obstruction Fujita et al., 1999
EPO nasal obstruction, edema, epithelial disruption Imai et al., 2000
TXB2, pLTs, eNOS, histamine sneezing, nose rubbing, rhinorrhea, nasal obstruction Zhao et al., 2005
Fexofenadine, terfenadine thromboxane, histamine (H1) nasal obstruction Sakairi et al., 2005
Pranlukast, naphazoline, L-NAME LTD4, NO nasal obstruction Mizutani et al., 2001
Chlorpheniramine, diphenhydramine, NG-nitro-L-arginine histamine, NO nasal obstruction Bockman and Zeng, 2002
Terfenadine, seratrodast, pranlukast, dexamethasone histamine (H1), TXA2, pLTs sneezing, nasal obstruction Yamasaki et al., 2001
L-NAME, naphazoline constitutively produced NO nasal obstruction Imai et al., 2001

Rat
Mometasone fluticasone Cytokines sneezing, nose rubbing Sugimoto et al., 2000a
Hlorpheniramine, ketotifen, astemizole, epinastine histamine (H1) sneezing, nose rubbing Sugimoto et al., 2000b
Dexamethasone CysLT mucus production Shimizu et al., 2000
ABT-491 (PAF antagonist), mepyramine, methysergide, PAF, histamine, serotonin, LTs vascular permeability Albert et al., 1998
A-79175 (5-lipoxiginase inhibitor)

Mouse
T cell epitope (P2-246-259) cytokines (IFN-gamma, IL-2, IL-4) sneezing, vascular permeability Murasugi et al., 2005
TNF-α sneezing, nose rubbing, increase expression of Iwasaki et al., 2003
adhesion molecules, eosinophil infiltration
Cetirizine, epinastine, ramatroban, zafirlukast histamine (H1), TXA2, LTs eosinophil infiltration Kayasuga et al., 2003
IL-5 eosinophilopoiesis Saito et al., 2002
Mediators from basophils, eosinophils, sneezing, nose rubbing, AHR Saito et al., 2001
CD4 + cells, IL4 and IL5 cells

Dog
Zileuton LTB4 neutrophilia, nasal secretion Cardell et al., 2000
Phenylephrine, D-pseudoephedrine histamine (H1) nasal obstruction Tiniakov et al., 2003
NPY 24-36 (selective NPY Y2 receptor agonist) NPY nasal secretion, vasodilatation Revington et al., 1997
D-pseudoephedrine, chlorpheniramine histamine (H1) nasal obstruction Rudolph et al., 2003

Pig
CGRP mediates BK and histamine induced nasal obstruction Malis et al., 2001
Azelastine, levocabastine, beclomethasone, ipratropium histamine (H1), cytokines, pLTs, ACh watery secretion Szelenyi et al., 2000

CysLTs: cysteinyl leukotrienes; pLTs, peptidyl leukotrienes; PAF: platelet activating factor; TXA2, thromboxane A2; LT, leukotriene; EPO: eosinophil peroxidase; TXB2, thromboxane B2; eNOS, endothelial nitric oxide synthase; NO: nitric oxide; IFN-gamma, interferon gamma; IL:
interleukin; TNF-α: tumor necrosis factor alpha; AHR: airway hyperresponsiveness; NPY: neuropeptide Y; CGRP: calcitonin gene related peptide.
Y.M. Al Suleimani, M.J.A. Walker / Pharmacology & Therapeutics 114 (2007) 233–260 253

their direct application, or via the action of the appropriate Anwar, A. R., Moqbel, R., Walsh, G. M., Kay, A. B., & Wardlaw, A. J. (1993).
mediator antagonists. Adhesion to fibronectin prolongs eosinophil survival. J Exp Med 177(3),
839−843.
It is clear from such findings that the guinea pig has been the Ariizumi, K., Shen, G. L., Shikano, S., Xu, S., Ritter, R., Kumamoto, T., et al.
most used species. In this species the symptoms of allergic (2000). Identification of a novel, dendritic cell-associated molecule, dectin-1,
rhinitis appear to be alleviated by those drugs that also alleviate by subtractive cDNA cloning. J Biol Chem 275(26), 20157−20167.
the same symptoms seen in humans suffering from allergic Arimura, A., Yasui, K., Kishino, J., Asanuma, F., Hasegawa, H., Kakudo, S., et al.
(2001). Prevention of allergic inflammation by a novel prostaglandin receptor
rhinitis. Thus H1 antihistamines, leukotriene antagonists and
antagonist, S-5751. J Pharmacol Exp Ther 298(2), 411−419.
steroids all alleviate allergic rhinitis in humans and guinea pigs. Austin, C. E., Foreman, J. C., & Scadding, G. K. (1994). Reduction by Hoe 140,
Alpha adrenoceptor agonists are used routinely to alleviate the the B2 kinin receptor antagonist, of antigen-induced nasal blockage. Br J
nasal congestion of rhinitis in humans but such drugs have Pharmacol 111(4), 969−971.
rarely been investigated for such actions in laboratory animals, Bachert, C., Wagenmann, M., & Holtappels, G. (1998). Cytokines and adhesion
even in guinea pigs. molecules in allergic rhinitis. Am J Rhinol 12(1), 3−8.
Bakker, R. A., Timmerman, H., & Leurus, R. (2000). Histamine receptors: specific
While there is a respectable body of evidence from many ligands, receptor biochemistry, and signal transduction. In F. E. R. Simon (Ed.),
studies in guinea pigs, the number of analogous studies in other Histamine and H1-antihistamines in allergic disease (pp. 27−64). New York:
laboratory species is limited. Thus there are insufficient studies in Marcel Dekker Inc.
rats, mice, dogs and pigs to warrant comparing the profile of Banchereau, J., Briere, F., Caux, C., Davoust, J., Lebecque, S., Liu, Y. J., et al.
actions of the drugs used in man to treat allergic rhinitis with their (2000). Immunobiology of dendritic cells. Annu Rev Immunol 18, 767−811.
Baraniuk, J. N. (1992). Sensory, parasympathetic, and sympathetic neural
actions in these species. As a result of all of the work conducted in influences in the nasal mucosa. J Allergy Clin Immunol 90(6 Pt 2), 1045−1050.
guinea pigs, compared with the body of work in other species, it is Baraniuk, J. N. (1997). Pathogenesis of allergic rhinitis. J Allergy Clin Immunol
probably best to assume that, until further evidence refutes such 99(2), S763−S772.
an assumption, the actions of drugs in allergic rhinitis in guinea Baraniuk, J. N. (1998). Neuropeptides. Am J Rhinol 12(1), 9−16.
pigs best represents the situation in humans. Baraniuk, J. N. (2000). Mechanisms of rhinitis. In M. V. Lasley & L. C. Altman
(Eds.), Rhinitis immunology and allergy clinics of North America (pp. 245−264).
In conclusion, despite our understanding of allergic rhinitis Philadelphia: W.B. Saunders.
we are still some way from understanding all of the mechanisms Baraniuk, J. N., & Kaliner, M. (1991). Neuropeptides and nasal secretion. Am J
involved in all of the various stages of the disease, from the Physiol 261(4 Pt 1), L223−L235.
mechanisms that result in hypersensitivity, to the mechanisms Barnes, P. J. (2001). Neurogenic inflammation in the airways. Respir Physiol
involved in the all the associated pathological changes. It is not 125(1-2), 145−154.
Barnes, P. J., & Liew, F. Y. (1995). Nitric oxide and asthmatic inflammation.
surprising therefore that the ideal drug treatment for this disease Immunol Today 16(3), 128−130.
has yet to be discovered. There are many possible molecular Barnes, P. J., Chung, K. F., & Page, C. P. (1998). Inflammatory mediators of
sites at which to theoretically attack the underlying pathology asthma: an update. Pharmacol Rev 50(4), 515−596.
but the very existence of such a large number of sites argues for Baroody, F. M. (1997). Anatomy and physiology. In R. M. Naclerio, S. R.
Durham, & N. Mydind (Eds.), Allergic and nonallergic rhinitis. Copenha-
the necessity for simultaneous actions at a number of sites. In
gen: Munksgaard.
the absence of a single molecular mechanism being responsible Baroody, F. M., & Naclerio, R. M. (2000). Antiallergic effects of H1-receptor
for the condition, we have to be content to try and identify the antagonists. Allergy 55(Suppl 64), 17−27.
most critical sites. Baroody, F. M., Ford, S., Lichtenstein, L. M., Kagey-Sobotka, A., & Naclerio,
R. M. (1994). Physiologic responses and histamine release after nasal
antigen challenge. Effect of atropine. Am J Respir Crit Care Med 149(6),
References 1457−1465.
Bascom, R., Wachs, M., Naclerio, R. M., Pipkorn, U., Galli, S. J., &
Adamko, D. J., Odemuyiwa, S. O., Vethanayagam, D., & Moqbel, R. (2005). Lichtenstein, L. M. (1988a). Basophil influx occurs after nasal antigen
The rise of the phoenix: the expanding role of the eosinophil in health and challenge: effects of topical corticosteroid pretreatment. J Allergy Clin
disease. Allergy 60(1), 13−22. Immunol 81(3), 580−589.
Adelroth, E., Rak, S., Haahtela, T., Aasand, G., Rosenhall, L., Zetterstrom, O., et al. Bascom, R., Pipkorn, U., Lichtenstein, L. M., & Naclerio, R. M. (1988b). The
(2000). Recombinant humanized mAb-E25, an anti-IgE mAb, in birch pollen- influx of inflammatory cells into nasal washings during the late response to
induced seasonal allergic rhinitis. J Allergy Clin Immunol 106(2), 253−259. antigen challenge. Effect of systemic steroid pretreatment. Am Rev Respir
Akdis, C. A., & Blaser, K. (2003). Histamine in the immune regulation of Dis 138(2), 406−412.
allergic inflammation. J Allergy Clin Immunol 112(1), 15−22. Bentley, A. M., Jacobson, M. R., Cumberworth, V., Barkans, J. R., Moqbel, R.,
Albert, D. H., Malo, P. E., Tapang, P., Shaughnessy, T. K., Morgan, D. W., Schwartz, L. B., et al. (1992). Immunohistology of the nasal mucosa in
Wegner, C. D., et al. (1998). The role of platelet-activating factor (PAF) and seasonal allergic rhinitis: increases in activated eosinophils and epithelial
the efficacy of ABT-491, a highly potent and selective PAF antagonist, in mast cells. J Allergy Clin Immunol 89(4), 877−883.
experimental allergic rhinitis. J Pharmacol Exp Ther 284(1), 83−88. Black, M. J., & Revison, K. A. (1980). CMA J, 881−884.
Andersen, I. B., Lundqvist, G. R., Jensen, P. L., & Proctor, D. F. (1974). Human Bockman, C. S., & Zeng, W. (2002). Histamine receptor type coupled to nitric
response to controlled levels of sulfur dioxide. Arch Environ Health 28(1), oxide-induced relaxation of guinea-pig nasal mucosa. Auton Autacoid
31−39. Pharmacol 22(5-6), 269−276.
Andersson, M., & Pipkorn, U. (1988). The effect of platelet activating factor on Boey, H., Rosenbaum, R., Castracane, J., & Borish, L. (1989). Interleukin-4 is a
nasal hypersensitivity. Eur J Clin Pharmacol 35(3), 231−235. neutrophil activator. J Allergy Clin Immunol 83(5), 978−984.
Anggard, A. (1974). Capillary and shunt blood flow in the nasal mucosa of the Borish, L. C., Nelson, H. S., Corren, J., Bensch, G., Busse, W. W., Whitmore, J. B.,
cat. Acta Oto-laryngol 78(5-6), 418−422. et al. (2001). Efficacy of soluble IL-4 receptor for the treatment of adults with
Anggard, A., Lundberg, J. M., & Lundblad, L. (1983). Nasal autonomic asthma. J Allergy Clin Immunol 107(6), 963−970.
innervation with special reference to peptidergic nerves. Eur J Respir Dis Bousquet, J. (1998). Antihistamines in severe/chronic rhinitis. Clin Exp Allergy
Suppl 128(Pt 1), 143−149. 28(Suppl 6), 49−53.
254 Y.M. Al Suleimani, M.J.A. Walker / Pharmacology & Therapeutics 114 (2007) 233–260

Bousquet, J., Vignola, A. M., Campbell, A. M., & Michel, F. B. (1996). Ciprandi, G., Cirillo, I., Vizzaccaro, A., Milanese, M., & Tosca, M. A. (2004).
Pathophysiology of allergic rhinitis. Int Arch Allergy Immunol 110(3), Airway function and nasal inflammation in seasonal allergic rhinitis and
207−218. asthma. Clin Exp Allergy 34(6), 891−896.
Bousquet, J., Van Cauwenberge, P., & Khaltaev, N. (2001). Allergic rhinitis and Cochand, L., Isler, P., Songeon, F., & Nicod, L. P. (1999). Human lung dendritic
its impact on asthma. J Allergy Clin Immunol 108(5 Suppl), S147−S334. cells have an immature phenotype with efficient mannose receptors. Am J
Bradding, P., Feather, I. H., Wilson, S., Bardin, P. G., Heusser, C. H., Holgate, S. T., Respir Cell Mol Biol 21(5), 547−554.
et al. (1993). Immunolocalization of cytokines in the nasal mucosa of normal Cole, P. (1982). Upper respiratory airflow. In D. F. Proctor & I. Andersen (Eds.), The
and perennial rhinitic subjects. The mast cell as a source of IL-4, IL-5, and IL-6 nose. Upper airway physiology and the atmospheric environment (pp. 99−139).
in human allergic mucosal inflammation. J Immunol 151(7), 3853−3865. Amsterdam: Elsevier Biomedical Press.
Bradding, P., Mediwake, R., Feather, I. H., Madden, J., Church, M. K., Holgate, Cooper Jr. J.A., Ridgeway, A. L., Pearson, J., & Culbreth, R. R. (2001).
S. T., et al. (1995). TNF alpha is localized to nasal mucosal mast cells and is Attenuation of interleukin 8-induced nasal inflammation by an inhibitor
released in acute allergic rhinitis. Clin Exp Allergy 25(5), 406−415. peptide. Am J Respir Crit Care Med 163(5), 1198−1205.
Brofeldt, S., Ingstrup, M. H., Niebur-Jorgensen, M., Katholm, N., Mygind, J., Corren, J. (2000). Allergic rhinitis: treating the adult. J Allergy Clin Immunol
Widdicombe, C., et al. (1979). Biochemical and biophysical properties of 105(6 Pt 2), S610−S615.
nasal secretions sampled separately from the anterior and the posterior Costa, J. J., Matossian, K., Resnick, M. B., Beil, W. J., Wong, D. T., Gordon, J. R.,
parts of the human nose. et al. (1993). Human eosinophils can express the cytokines tumor necrosis factor-
Broide, D. H., Sullivan, S., Gifford, T., & Sriramarao, P. (1998). Inhibition of alpha and macrophage inflammatory protein-1 alpha. J Clin Invest 91(6),
pulmonary eosinophilia in P-selectin- and ICAM-1-deficient mice. Am J 2673−2684.
Respir Cell Mol Biol 18(2), 218−225. Costa, J. J., Demetri, G. D., Harrist, T. J., Dvorak, A. M., Hayes, D. F., Merica,
Brostoff, J. (1986). IgE receptors on inflammatory cells: the role of IgE E. A., et al. (1996). Recombinant human stem cell factor (kit ligand)
complexes in food allergy. Ann Inst Pausteur Immunol 137D(1), 131−136. promotes human mast cell and melanocyte hyperplasia and functional
Broms, P. (1982). Rhinomanometry: III. Procedures and criteria for distinction activation in vivo. J Exp Med 183(6), 2681−2686.
between skeletal stenosis and mucosal swelling. Acta Otolaryngol 94(3-4), Creticos, P. S., Peter, S. P., Adkinson, N. F., Naclerio, R. M., Hayes, E. C.,
361−370. Norman, P. S., et al. (1984). Peptide leukotriene release after antigen
Calderon, M. A., Lozewicz, S., Prior, A., Jordan, S., Trigg, C. J., & Davies, R. J. challenge in patients sensitive to ragweed. N Engl J Med 310(25),
(1994). Lymphocyte infiltration and thickness of the nasal mucous 1626−1630.
membrane in perennial and seasonal allergic rhinitis. J Allergy Clin Csoma, Z., Ignacz, F., Bor, Z., Szabo, G., Bodai, L., Dobozy, A., et al. (2004).
Immunol 93(3), 635−643. Intranasal irradiation with the xenon chloride ultraviolet B laser improves
Calderon, M. A., Devalia, J. L., Prior, A. J., Sapsford, R. J., & Davies, R. J. allergic rhinitis. J Photochem Photobiol B Biol 75(3), 137−144.
(1997). A comparison of cytokine release from epithelial cells cultured from Csoma, Z., Koreck, A., Ignacz, F., Bor, Z., Szabo, G., Bodai, L., et al. (2006).
nasal biopsy specimens of atopic patients with and without rhinitis and PUVA treatment of the nasal cavity improves the clinical symptoms of
nonatopic subjects without rhinitis. J Allergy Clin Immunol 99(1 Pt 1), allergic rhinitis and inhibits the immediate-type hypersensitivity reaction in
65−76. the skin. J Photochem Photobiol B Biol 83(1), 21−26.
Calliet, R. (1992). Head and face pain syndromes. Philadelphia: F.A. Davis. Cuss, F. M. (1999). Beyond the histamine receptor: effect of antihistamines on
Canonica, G. W., & Passalacqua, G. (2003). Noninjection routes for mast cells. Clin Exp Allergy 29(Suppl 3), 54−59.
immunotherapy. J Allergy Clin Immunol 111(3), 437−448 (quiz 449). Dahl, R., & Mygind, N. (1998). Anatomy, physiology and function of the nasal
Cardell, L. O., Agusti, C., & Nadel, J. A. (2000). Nasal secretion in ragweed- cavities in health and disease. Adv Drug Deliv Rev 29(1-2), 3−12.
sensitized dogs: effect of leukotriene synthesis inhibition. Acta Otolaryngol Danno, K., Fujii, K., Tachibana, T., Toda, K., & Horio, T. (1988). Suppressed
120(6), 757−760. histamine release from rat peritoneal mast cells by ultraviolet B irradiation:
Casale, T. B., Condemi, J., LaForce, C., Nayak, A., Rowe, M., Watrous, M., et al. decreased diacylglycerol formation as a possible mechanism. J Invest
(2001). Effect of omalizumab on symptoms of seasonal allergic rhinitis: a Dermatol 90(6), 806−809.
randomized controlled trial. JAMA 286(23), 2956−2967. Day, J. (1999). Pros and cons of the use of antihistamines in managing allergic
Castells, M. C., Irani, A. M., & Schwartz, L. B. (1987). Evaluation of human rhinitis. J Allergy Clin Immunol 103(3 Pt 2), S395−S399.
peripheral blood leukocytes for mast cell tryptase. J Immunol 138(7), de Baey, A., & Lanzavecchia, A. (2000). The role of aquaporins in dendritic cell
2184−2189. macropinocytosis. J Exp Med 191(4), 743−748.
Cauna, N. (1970). The fine structure of the arteriovenous anastomosis and its de Graaf-in t Veld, C., Garrelds, I. M., Koenders, S., & Gerth van Wijk, R.
nerve supply in the human nasal respiratory mucosa. Anat Rec 168(1), (1996). Relationship between nasal hyperreactivity, mediators and eosino-
9−21. phils in patients with perennial allergic rhinitis and controls. Clin Exp
Cauna, N., & Hinderer, K. H. (1969). Fine structure of blood vessels of Allergy 26(8), 903−908.
the human nasal respiratory mucosa. Ann Otol Rhinol Laryngol 78(4), Dear, J. W., Ghali, S., & Foreman, J. C. (1996). Attenuation of human nasal
865−879. airway responses to bradykinin and histamine by inhibitors of nitric oxide
Cella, M., Engering, A., Pinet, V., Pieters, J., & Lanzavecchia, A. (1997). synthase. Br J Pharmacol 118(5), 1177−1182.
Inflammatory stimuli induce accumulation of MHC class II complexes on Devillier, P., Advenier, C., Drapeau, G., Marsac, J., & Regoli, D. (1988).
dendritic cells. Nature 388(6644), 782−787. Comparison of the effects of epithelium removal and of an enkephalinase
Cervin, A., & Andersson, M. (1998). Intranasal steroids and septum perforation- inhibitor on the neurokinin-induced contractions of guinea-pig isolated
an overlooked complication? A description of the course of events and a trachea. Br J Pharmacol 94(3), 675−684.
discussion of the causes. Rhinology 36(3), 128−132. Doyle, W. J., Boehm, S., & Skoner, D. P. (1990). Physiologic responses to
Chang, T. W. (2000). The pharmacological basis of anti-IgE therapy. Nat intranasal dose-response challenges with histamine, methacholine, bradyki-
Biotechnol 18(2), 157−162. nin, and prostaglandin in adult volunteers with and without nasal allergy.
Chatelain, C., Pochon, N., & Lacroix, J. S. (1995). Functional effects of J Allergy Clin Immunol 86(6 Pt 1), 924−935.
phosphoramidon and captopril on exogenous neuropeptides in human nasal Drettner, B., & Aust, R. (1974). Plethysmographic studies of the blood flow in
mucosa. Eur Arch Otorhinolaryngol 252(2), 83−85. the mucosa of the human maxillary sinus. Acta Otolaryngol 78(3-4),
Christiansen, S. C., Eddleston, J., Woessner, K. M., Chambers, S. S., Ye, R., 259−263.
Pan, Z. K., et al. (2002). Up-regulation of functional kinin B1 receptors in Druce, H. M., Wright, R. H., Kossoff, D., & Kaliner, M. A. (1985). Cholinergic
allergic airway inflammation. J Immunol 169(4), 2054−2060. nasal hyperreactivity in atopic subjects. J Allergy Clin Immunol 76(3),
Christie, P. E., Hawksworth, R., Spur, B. W., & Lee, T. H. (1992). Effect of 445−452.
indomethacin on leukotriene4-induced histamine hyperresponsiveness in Duan, W., Kuo, I. C., Selvarajan, S., Chua, K. Y., Bay, B. H., & Wong, W. S.
asthmatic subjects. Am Rev Respir Dis 146(6), 1506−1510. (2003). Antiinflammatory effects of genistein, a tyrosine kinase inhibitor,
Y.M. Al Suleimani, M.J.A. Walker / Pharmacology & Therapeutics 114 (2007) 233–260 255

on a guinea pig model of asthma. Am J Respir Crit Care Med 167(2), airway resistance of antigen-induced rhinitis in guinea pigs. Eur J Pharmacol
185−192. 369(3), 349−356.
Duffy, S. M., Lawley, W. J., Conley, E. C., & Bradding, P. (2001). Resting and Fukuda, S., Midoro, K., Gyoten, M., Kawano, Y., Ashida, Y., Nabe, T., et al.
activation-dependent ion channels in human mast cells. J Immunol 167(8), (2003). Effects of TAK-427 on acute nasal symptoms and nasal obstruction in
4261−4270. guinea pig model of experimental allergic rhinitis. Eur J Pharmacol 476(3),
Dunzendorfer, S., Schratzberger, P., Reinisch, N., Kahler, C. M., & 239−247.
Wiedermann, C. J. (1998). Secretoneurin, a novel neuropeptide, is a potent Galli, S. J., Gordon, J. R., & Wershil, B. K. (1994). Mast cell and eosinophil
chemoattractant for human eosinophils. Blood 91(5), 1527−1532. cytokinesin allergy and inflammation. In G. J. Gleich & A.B. Kay (Eds.),
Durham, S. R., Ying, S., Varney, V. A., Jacobson, M. R., Sudderick, R. M., Eosinophils in allergy and inflammation (pp. 255−280). New York: Marcel
Mackay, I. S., et al. (1992). Cytokine messenger RNA expression for IL-3, Dekker.
IL-4, IL-5, and granulocyte/macrophage-colony-stimulating factor in the Garrelds, I. M., van Amsterdam, J. G., de Graaf-in't Veld, C., Gerth van Wijk,
nasal mucosa after local allergen provocation: relationship to tissue R., & Zijlstra, F. J. (1995). Nitric oxide metabolites in nasal lavage fluid of
eosinophilia. J Immunol 148(8), 2390−2394. patients with house dust mite allergy. Thorax 50(3), 275−279.
Duthie, M. S., Kimber, I., Dearman, R. J., & Norval, M. (2000). Differential Garssen, J., & van Loveren, H. (2001). Effects of ultraviolet exposure on the
effects of UVA1 and UVB radiation on Langerhans cell migration in mice. immune system. Crit Rev Immunol 21(4), 359−397.
J Photochem Photobiol B Biol 57(2-3), 123−131. Geijtenbeek, T. B., Torensma, R., van Vliet, S. J., van Duijnhoven, G. C.,
Dykewicz, M. S., Fineman, S., Skoner, D. P., Nicklas, R., Lee, R., Blessing- Adema, G. J., van Kooyk, Y., et al. (2000). Identification of DC-SIGN, a
Moore, J., et al. (1998). Diagnosis and management of rhinitis: complete novel dendritic cell-specific ICAM-3 receptor that supports primary immune
guidelines of the Joint Task Force on Practice Parameters in Allergy, Asthma responses. Cell 100(5), 575−585.
and Immunology. American Academy of Allergy, Asthma, and Immunol- Geppetti, P., Tramontana, M., Santicioli, P., Del Bianco, E., Giuliani, S., &
ogy. Ann Allergy Asthma Immunol 81(5 Pt 2), 478−518. Maggi, C. A. (1990). Bradykinin-induced release of calcitonin gene-related
Ebner, C. (1999). Immunological mechanisms operative in allergen-specific peptide from capsaicin-sensitive nerves in guinea-pig atria: mechanism of
immunotherapy. Int Arch Allergy Immunol 119(1), 1−5. action and calcium requirements. Neuroscience 38(3), 687−692.
Eddleston, J., Christiansen, S. C., Jenkins, G. R., Koziol, J. A., & Zuraw, B. L. Gerth van Wijk, R. G., de Graaf-in 't Veld, C., & Garrelds, I. M. (1999). Nasal
(2003). Bradykinin increases the in vivo expression of the CXC chemokine hyperreactivity. Rhinology 37(2), 50−55.
receptors CXCR1 and CXCR2 in patients with allergic rhinitis. J Allergy Giembycz, M. A. (2000). Phosphodiesterase 4 inhibitors and the treatment of
Clin Immunol 111(1), 106−112. asthma: where are we now and where do we go from here? Drugs 59(2),
Eiserich, J. P., Hristova, M., Cross, C. E., Jones, A. D., Freeman, B. A., 193−212.
Halliwell, B., et al. (1998). Formation of nitric oxide-derived Gleich, G. J., Abu-Ghazaleh, R. A., & Glitz, D. G. (1994). Eosinophil granule
inflammatory oxidants by myeloperoxidase in neutrophils. Nature 391 proteins-structure and function. In G. J. Gleich & A. B. Kay (Eds.), Eosi-
(6665), 393−397. nophils in allergy and inflammation (pp. 1−18). New York: Marcel Dekker.
Elovsson, S., Smailagic, A., Erjefalt, I., Zackrisson, C., Eriksson, C., & Wang, Gollhausen, R., Kaidbey, K., & Schechter, N. (1985). UV suppression of mast
X. (2005). Evaluation of nasal barrier dysfunction at acute- and late-phase cell-mediated wealing in human skin. Photodermatology 2(2), 58−67.
reactions in a guinea pig model of allergic rhinitis. Vascul Pharmacol 43(4), Gorski, P., Wittczak, T., Walusiak, J., Palczynski, C., Ruta, U., Kuna, P., et al.
267−276. (2002). Eotaxin but not MCP-3 induces eosinophil influx into nasal fluid in
Enerback, L., Pipkorn, U., & Granerus, G. (1986). Intraepithelial migration of allergic patients. Allergy 57(6), 519−528.
nasal mucosal mast cells in hay fever. Int Arch Allergy Appl Immunol 80(1), Gosset, P., Malaquin, F., Delneste, Y., Wallaert, B., Capron, A., Joseph, M., et al.
44−51. (1993). Interleukin-6 and interleukin-1 alpha production is associated
Evans, J. F. (2002). Cysteinyl leukotriene receptors. Prostaglandins Other Lipid with antigen-induced late nasal response. J Allergy Clin Immunol 92(6),
Mediat 68-69, 587−597. 878−890.
Evans, M. J., & Plopper, C. G. (1988). The role of basal cells in adhesion of columnar Gosset, P., Tillie-Leblond, I., Malaquin, F., Durieu, J., Wallaert, B., & Tonnel, A. B.
epithelium to airway basement membrane. Am Rev Respir Dis 138(2), (1997). Interleukin-8 secretion in patients with allergic rhinitis after an allergen
481−483. challenge: interleukin-8 is not the main chemotactic factor present in nasal
Fajac, I., Braunstein, G., Ickovic, M. R., Lacronique, J., & Frossard, N. (1995). lavages. Clin Exp Allergy 27(4), 379−388.
Selective recruitment of eosinophils by substance P after repeated allergen Grevers, G., & Kastenbauer, E. (1996). Functional morphology of nasal blood
exposure in allergic rhinitis. Allergy 50(12), 970−975. vessels in humans. Acta Otolaryngol 116(2), 312−315.
Feldberg, W., & Kellaway, C. H. (1938). Liberation of histamine and formation Groneberg, D. A., Folkerts, G., Peiser, C., Chung, K. F., & Fischer, A. (2004).
of lyscithin-like substances by cobra venom. J Physiol 94, 187−226. Neuropeptide Y (NPY). Pulm Pharmacol Ther 17(4), 173−180.
Ferreira, S. H., Lorenzetti, B. B., & Poole, S. (1993). Bradykinin initiates Halama, A. R., Decreton, S., Bijloos, J. M., & Clement, P. A. (1990). Density of
cytokine-mediated inflammatory hyperalgesia. Br J Pharmacol 110(3), epithelial cells in the normal human nose and the paranasal sinus mucosa. A
1227−1231. scanning electron microscopic study. Rhinology 28(1), 25−32.
Figueroa, J. M., Mansilla, E., & Suburo, A. M. (1998). Innervation of nasal Hamid, Q., Barkans, J., Meng, Q., Ying, S., Abrams, J. S., Kay, A. B., et al.
turbinate blood vessels in rhinitic and nonrhinitic children. Am J Respir Crit (1992). Human eosinophils synthesize and secrete interleukin-6, in vitro.
Care Med 157(6 Pt 1), 1959−1966. Blood 80(6), 1496−1501.
Finney, M. J., & Forsberg, K. I. (1994). Quantification of nasal involvement in a Hanif, J., Jawad, S. S. M., & Eccles, R. (2000). The nasal cycle in health and
guinea pig plethysmograph. J Appl Physiol 76(4), 1432−1438. disease. Clin Otolaryngol Allied Sci 25(6), 461−467.
Fox, A. J., Lalloo, U. G., Belvisi, M. G., Bernareggi, M., Chung, K. F., & Hauser-Kronberger, C., Hacker, G. W., Muss, W., Saria, A., & Albegger, K.
Barnes, P. J. (1996). Bradykinin-evoked sensitization of airway sensory (1993). Autonomic and peptidergic innervation of human nasal mucosa.
nerves: a mechanism for ACE-inhibitor cough. Nat Med 2(7), 814−817. Acta Otolaryngol 113(3), 387−393.
Fu, L. J., Dai, Y., Wang, Z. T., & Zhang, M. (2003). Inhibition of experimental Hellquist, H. B., & Karlsson, M. G. (1992). Nasal memory T lymphocytes
allergic rhinitis by the n-butanol fraction from the anomalous fruits of capable of producing IL-4 in the allergic reaction. Allergy 47(4 Pt 1),
Gleditsia sinensis. Biol Pharm Bull 26(7), 974−977. 334−336.
Fujikura, T., Shimosawa, T., & Yakuo, I. (2001). Regulatory effect of histamine Hemmi, H., Takeuchi, O., Kawai, T., Kaisho, T., Sato, S., Sanjo, H., et al.
H1 receptor antagonist on the expression of messenger RNA encoding CC (2000). A Toll-like receptor recognizes bacterial DNA. Nature 408(6813),
chemokines in the human nasal mucosa. J Allergy Clin Immunol 107(1), 740−745.
123−128. Heppt, W., Dinh, Q. T., Cryer, A., Zweng, M., Noga, O., Peiser, C., et al. (2004).
Fujita, M., Yonetomi, Y., Shimouchi, K., Takeda, H., Aze, Y., Kawabata, K., et al. Phenotypic alteration of neuropeptide-containing nerve fibres in seasonal
(1999). Involvement of cysteinyl leukotrienes in biphasic increase of nasal intermittent allergic rhinitis. Clin Exp Allergy 34(7), 1105−1110.
256 Y.M. Al Suleimani, M.J.A. Walker / Pharmacology & Therapeutics 114 (2007) 233–260

Higashi, N., Taniguchi, M., Mita, H., Ishii, T., & Akiyama, K. (2003). Nasal Kaszuba, S. M., Baroody, F. M., deTineo, M., Haney, L., Blair, C., & Naclerio,
blockage and urinary leukotriene E4 concentration in patients with seasonal R. M. (2001). Superiority of an intranasal corticosteroid compared with an
allergic rhinitis. Allergy 58(6), 476−480. oral antihistamine in the as-needed treatment of seasonal allergic rhinitis.
Hilberg, O., Grymer, L. F., & Pedersen, O. F. (1995). Nasal histamine challenge Arch Intern Med 161(21), 2581−2587.
in nonallergic and allergic subjects evaluated by acoustic rhinometry. Katz, H. R., Vivier, E., Castells, M. C., McCormick, M. J., Chambers, J. M., &
Allergy 50(2), 166−173. Austen, K. F. (1996). Mouse mast cell gp49B1 contains two immunor-
Hilding, A. C. (1963). Phagocytosis, mucous flow, and ciliary action. Arch eceptor tyrosine-based inhibition motifs and suppresses mast cell activation
Environ Health 6, 61−71. when coligated with the high-affinity Fc receptor for IgE. Proc Natl Acad
Hirata, N., Takeuchi, K., Ukai, K., Jin, C., Yoshida, T., & Sakakura, Y. (1999). Sci U S A 93(20), 10809−10814.
Expression and localization of histamine H2 receptor messenger RNA in Kay, G. G. (2000). The effects of antihistamines on cognition and performance.
human nasal mucosa. J Allergy Clin Immunol 103(5 Pt 1), 944−949. J Allergy Clin Immunol 105(6 Pt 2), S622−S627.
Hofstra, C. L., Desai, P. J., Thurmond, R. L., & Fung-Leung, W. P. (2003). Kay, A. B. (2001). Allergy and allergic diseases. Second of two parts. N Engl J
Histamine H4 receptor mediates chemotaxis and calcium mobilization of Med 344(2), 109−113.
mast cells. J Pharmacol Exp Ther 305(3), 1212−1221. Kayasuga, R., Iba, Y., Hossen, M. A., Watanabe, T., & Kamei, C. (2003). The
Hogan, S. P., & Foster, P. S. (1997). Cytokines as targets for the inhibition of role of chemical mediators in eosinophil infiltration in allergic rhinitis in
eosinophilic inflammation. Pharmacol Ther 74(3), 259−283. mice. Int Immunopharmacol 3(4), 469−473.
Holgate, S. T., & Broide, D. (2003). New targets for allergic rhinitis-a disease of Kellaway, C. H., & Trethewie, E. R. (1940). The liberation of a slow reacting
civilization. Nat Rev Drug Discov 2(11), 902−914. smooth-muscle stimulating substance in anaphylaxis. J Exp Physiol 30,
Honda, Z., Ishii, S., & Shimizu, T. (2002). Platelet-activating factor receptor. 121−145.
J Biochem (Tokyo) 131(6), 773−779. Kelso, A. (1995). Th1 and Th2 subsets: paradigms lost? Immunol Today 16(8),
Horiguchi, S., & Okamoto, Y. (2005). Role of T cells in allergic rhinitis. Clin Exp 374−379.
Allergy 5(2), 64−67. Kharitonov, S. A., Rajakulasingam, K., O'Connor, B., Durham, S. R., & Barnes,
Horner, A. A., Van Uden, J. H., Zubeldia, J. M., Broide, D., & Raz, E. (2001a). DNA- P. J. (1997). Nasal nitric oxide is increased in patients with asthma and
based immunotherapeutics for the treatment of allergic disease. Immunol Rev allergic rhinitis and may be modulated by nasal glucocorticoids. J Allergy
179, 102−118. Clin Immunol 99(1 Pt 1), 58−64.
Horner, A. A., Widhopf, G. F., Burger, J. A., Takabayashi, K., Cinman, N., Knani, J., Campbell, A., Enander, I., Peterson, C. G., Michel, F. B., &
Ronaghy, A., et al. (2001b). Immunostimulatory DNA inhibits IL-4-de- Bousquet, J. (1992). Indirect evidence of nasal inflammation assessed
pendent IgE synthesis by human B cells. J Allergy Clin Immunol 108(3), by titration of inflammatory mediators and enumeration of cells in
417−423. nasal secretions of patients with chronic rhinitis. J Allergy Clin Immunol
Howarth, P. H. (1995). The cellular basis for allergic rhinitis. Allergy 50(23 90(6 Pt 1), 880−889.
Suppl), 6−10. Knapp, H. R. (1990). Reduced allergen-induced nasal congestion and
Howarth, P. H., & Holgate, S. T. (1990). Basic aspects of allergic reactions. In C. leukotriene synthesis with an orally active 5-lipoxygenase inhibitor.
Naspitzs & D. G. Tinkelman (Eds.), Childhood rhinitis and sinusitis: N Engl J Med 323(25), 1745−1748.
Pathophysiology and Treatment (pp. 1−35). New York: Marcel Dekker. Knipping, S., Riederer, A., Agha-Mir-Salim, P., Holzhausen, H. J., & Berghaus, A.
Howarth, P. H., Salagean, M., & Dokic, D. (2000). Allergic rhinitis: not purely a (2001). Basic classical, peptidergic and nitrergic innervation pattern of
histamine-related disease. Allergy 55(Suppl 64), 7−16. human nasal glands-a histochemical and immunohistochemical study.
Hussain, I., Jain, V. V., Kitagaki, K., Businga, T. R., O'Shaughnessy, P., & Kline, Laryngorhinootologie 80(12), 697−703.
J. N. (2002). Modulation of murine allergic rhinosinusitis by CpG Knowles, M., Clark, C. E., Fischer, N. D., et al. (1987). Nasal secretions: Role of
oligodeoxynucleotides. Laryngoscope 112(10), 1819−1826. epithelial ion transport. In N. Mygind & U. Pipkorn (Eds.), Allergic and
Imai, N., Miyahara, A., Yamazaki, Y., Homma, R., Ino, Y., & Kurumi, M. vasomotor rhinitis: Pathophysiological aspects (pp. 77−90). Copenhagen:
(2000). Involvement of eosinophils in the early-phase allergic reaction in a Munksgaard.
guinea pig rhinitis model. Int Arch Allergy Immunol 122(4), 270−278. Koga, Y., Satoh, S., Sodeyama, N., Hashimoto, Y., Yanagisawa, T., & Hirshman,
Imai, A., Nabe, T., Mizutani, N., Sakarai, H., Takenaka, H., & Kohno, S. (2001). C. A. (1992). Role of acetylcholinesterase in airway epithelium-mediated
Involvement of nitric oxide in pollen-induced biphasic nasal blockage in inhibition of acetylcholine-induced contraction of guinea-pig isolated
sensitised guinea pigs. Eur J Pharmacol 423(1), 63−70. trachea. Eur J Pharmacol 220(2-3), 141−146.
Iriyoshi, N., Takeuchi, K., Yuta, A., Ukai, K., & Sakakura, Y. (1996). Increased Koreck, A. I., Csoma, Z., Bodai, L., Ignacz, F., Kenderessy, A. S., Kadocsa, E.,
expression of histamine H1 receptor mRNA in allergic rhinitis. Clin Exp et al. (2005). Rhinophototherapy: a new therapeutic tool for the management
Allergy 26(4), 379−385. of allergic rhinitis. J Allergy Clin Immunol 115(3), 541−547.
Iwasaki, M., Saito, K., Takemura, M., Sekikawa, K., Fujii, H., Yamada, Y., et al. Korsgren, M., Erjefalt, J. S., Hinterholzl, J., Fischer-Colbrie, R., Emanuelsson,
(2003). TNF-alpha contributes to the development of allergic rhinitis in C. A., Andersson, M., et al. (2003). Neural expression and increased lavage
mice. J Allergy Clin Immunol 112(1), 134−140. fluid levels of secretoneurin in seasonal allergic rhinitis. Am J Respir Crit
Jackson, D. Y. (2002). Alpha 4 integrin antagonists. Curr Pharm Des 8(14), Care Med 167(11), 1504−1508.
1229−1253. Krouse, J. H. (2002). Seasonal and perennial rhinitis. In J. H. Krouse, S. J.
Juliusson, S., Aldenborg, F., & Enerback, L. (1995). Proteinase content of mast Chadwick, B. R. Gordon, & M. J. Derebery (Eds.), Allergy and
cells of nasal mucosa; effects of natural allergen exposure and of local immunology (pp. 209−220). Philadelphia, USA: Lippincott Williams &
corticosteroid treatment. Allergy 50(1), 15−22. Wilkins.
Kaise, T., Akamatsu, Y., & Ohmori, K. (1998). Effect of oxatomide on Krump, E., & Borgeat, P. (1999). Adenosine. An endogenous inhibitor of
experimental allergic rhinitis in guinea pigs. Jpn J Pharmacol 76(2), arachidonic acid release and leukotriene biosynthesis in human neutrophils.
223−226. Adv Exp Med Biol 447, 107−115.
Kaise, T., Akamatsu, Y., Ikemura, T., Ohmori, K., Ishii, A., & Karasawa, A. Kuehr, J., Brauburger, J., Zielen, S., Schauer, U., Kamin, W., Von Berg, A., et al.
(2001a). Involvement of neuropeptides in the allergic nasal obstruction in (2002). Efficacy of combination treatment with anti-IgE plus specific
guinea pigs. Jpn J Pharmacol 86(2), 196−202. immunotherapy in polysensitized children and adolescents with seasonal
Kaise, T., Akamatsu, Y., Ohmori, K., Ishii, A., & Karasawa, A. (2001b). allergic rhinitis. J Allergy Clin Immunol 109(2), 274−280.
Inhibitory effect of olopatadine hydrochloride on the sneezing response Kuna, P., Alam, R., Ruta, U., & Gorski, P. (1998). RANTES induces nasal
induced by intranasal capsaicin challenge in guinea pigs. Jpn J Pharmacol mucosal inflammation rich in eosinophils, basophils, and lymphocytes in
86(2), 258−261. vivo. Am J Respir Crit Care Med 157(3 Pt 1), 873−879.
Kaliner, M. A. (1994). The mediators of the early and late phases of allergic Kunkel, G., Mygind, N., Okuda, N., & Van Cauwenberge, P. (1987). Sodium
rhinitis. Adv Prostaglandin Thromboxane Leukotriene Res 22, 271−278. cromoglycate. Allerg Vasomotor Rhinitis Clin Asp, 159−164.
Y.M. Al Suleimani, M.J.A. Walker / Pharmacology & Therapeutics 114 (2007) 233–260 257

Labrakis-Lazanas, K., Lazanas, M., Koussissis, S., Tournis, S., & Demopoulos, Malling, H. J. (2002). Is sublingual immunotherapy clinically effective? Curr
C. A. (1988). PAF of biological fluids in disease: blood levels in allergic Opin Allergy Clin Immunol 2(6), 523−531.
rhinitis. Haematologica 73(5), 379−382. Martin, U., Bryden, K., Devoy, M., & Howarth, P. (1996). Increased levels of
Lacroix, J. S., Auberson, S., Morel, D. R., Theodorsson, E., Hokfelt, T., & exhaled nitric oxide during nasal and oral breathing in subjects with seasonal
Lundberg, J. M. (1992). Vascular control of the pig nasal mucosa: rhinitis. J Allergy Clin Immunol 97(3), 768−772.
distribution and effect of somatostatin in relation to noradrenaline and Matzner, Y., Marx, G., Drexler, R., & Eldor, A. (1984). The inhibitory effect of
neuropeptide Y. Regul Pept 40(3), 373−387. heparin and related glycosaminoglycans on neutrophil chemotaxis. Thromb
Laitinen, L. A., Heino, M., Laitinen, A., Kava, T., & Haahtela, T. (1985). Haemost 52(2), 134−137.
Damage of the airway epithelium and bronchial reactivity in patients with Mauser, P. J., Pitman, A., Witt, A., Fernandez, X., Zurcher, J., Kung, T., et al.
asthma. Am Rev Respir Dis 131(4), 599−606. (1993). Inhibitory effect of the TRFK-5 anti-IL-5 antibody in a guinea pig
Lambrecht, B. N. (2001). Allergen uptake and presentation by dendritic cells. model of asthma. Am Rev Respir Dis 148(6 Pt 1), 1623−1627.
Curr Opin Allergy Clin Immunol 1(1), 51−59. McHugh, R. S., & Shevach, E. M. (2002). The role of suppressor T cells in
Lantero, S., Sacco, O., Scala, C., Morelli, M. C., & Rossi, G. A. (1996). regulation of immune responses. J Allergy Clin Immunol 110(5), 693−702.
Eosinophil locomotion and the release of IL-3 and IL-5 by allergen- McLeod, R. L., Mingo, G. G., Herczku, C., DeGennaro-Culver, F., Kreutner, W.,
stimulated mononuclear cells are effectively downregulated in vitro by Egan, R. W., et al. (1999). Combined histamine H1 and H3 receptor
budesonide. Clin Exp Allergy 26(6), 656−664. blockade produces nasal decongestion in an experimental model of nasal
Law, A. W., Reed, S. D., Sundy, J. S., & Schulman, K. A. (2003). Direct costs of congestion. Am J Rhinol 13(5), 391−399.
allergic rhinitis in the United States: estimates from the 1996 Medical McLeod, R. L., Young, S. S., Erickson, C. H., Parra, L. E., & Hey, J. A. (2002).
Expenditure Panel Survey. J Allergy Clin Immunol 111(2), 296−300. Characterization of nasal obstruction in the allergic guinea pig using the
Leeb-Lundberg, L. M., Marceau, F., Muller-Esterl, W., Pettibone, D. J., & forced oscillation method. J Pharmacol Toxicol Methods 48(3), 153−159.
Zuraw, B. L. (2005). International union of pharmacology: XLV. Meltzer, E. O., Berkowitz, R. B., & Grossbard, E. B. (2005). An intranasal Syk-
Classification of the kinin receptor family: from molecular mechanisms to kinase inhibitor (R112) improves the symptoms of seasonal allergic rhinitis
pathophysiological consequences. Pharmacol Rev 57(1), 27−77. in a park environment. J Allergy Clin Immunol 115(4), 791−796.
Leggieri, E., Tedeschi, A., Lorini, M., Bianco, A., & Miadonna, A. (1991). Metwali, A., Blum, A. M., Ferraris, L., Klein, J. S., Fiocchi, C., & Weinstock, J. V.
Study of the effects of paf-acether on human nasal airways. Allergy 46(6), (1994). Eosinophils within the healthy or inflamed human intestine produce
466−471. substance P and vasoactive intestinal peptide. J Neuroimmunol 52(1), 69−78.
Leirisalo-Repo, M. (1994). The present knowledge of the inflammatory process Miadonna, A., Tedeschi, A., Arnoux, B., Sala, A., Zanussi, C., & Benveniste, J.
and the inflammatory mediators. Pharmacol Toxicol 75(Suppl 2), 1−3. (1989). Evidence of PAF-acether metabolic pathway activation in antigen
Lider, O., Mekori, Y. A., Miller, T., Bar-Tana, R., Vlodavsky, I., Baharav, E., challenge of upper respiratory airways. Am Rev Respir Dis 140(1), 142−147.
et al. (1990). Inhibition of T lymphocyte heparanase by heparin prevents T Miadonna, A., Milazzo, N., Lorini, M., Sala, A., & Tedeschi, A. (1996). Nasal
cell migration and T cell-mediated immunity. Eur J Immunol 20(3), neutrophilia and release of myeloperoxidase induced by nasal challenge with
493−499. platelet activating factor: different degrees of responsiveness in atopic and
Liu, A. H., & Murphy, J. R. (2003). Hygiene hypothesis: fact or fiction? nonatopic subjects. J Allergy Clin Immunol 97(4), 947−954.
J Allergy Clin Immunol 111(3), 471−478. Minshall, E. M., Cameron, L., Lavigne, F., Leung, D. Y., Hamilos, D., Garcia-
Lund, V. J. (1996). Nasal physiology: neurochemical receptors, nasal cycle, and Zepada, E. A., et al. (1997). Eotaxin mRNA and protein expression in
ciliary action. Allergy Asthma Proc 17(4), 179−184. chronic sinusitis and allergen-induced nasal responses in seasonal allergic
Lundblad, L. (1990). Neuropeptides and autonomic nervous control of the rhinitis. Am J Respir Cell Mol Biol 17(6), 683−690.
respiratory mucosa. In N. Myding, U. Pipkorn, & R. Dalh (Eds.), Rhinitis and Mizuno, H., Kawamura, Y., Iwase, N., & Ohno, H. (1991). Effects of flutropium
asthma. Similarities and differences (pp. 65−75). Copenhagen: Munksgaard. on experimental models of drug- and allergy-induced rhinitis in guinea pigs.
Lung, M. A., Phipps, R. J., Wang, J. C., & Widdicombe, J. G. (1984). Control of Jpn J Pharmacol 55(3), 321−328.
nasal vasculature and airflow resistance in the dog. J Physiol 349, 535−551. Mizutani, N., Nabe, T., Sasaki, K., Takenaka, H., & Kohno, S. (1999). Nasal
Lurie, A., Nadel, J. A., Roisman, G., Siney, H., & Dusser, D. J. (1994). Role of hyperresponsiveness to histamine induced by repetitive exposure to cedar
neutral endopeptidase and kininase II on substance P-induced increase in pollen in guinea-pigs. Eur Respir J 14(6), 1368−1375.
nasal obstruction in patients with allergic rhinitis. Am J Respir Crit Care Mizutani, N., Nabe, T., Imai, A., Sakurai, H., Takenaka, H., & Kohno, S. (2001).
Med 149(1), 113−117. Markedly increased nasal blockage by intranasal leukotriene D4 in an
Ma, R. Q., Qu, B. S., Liu, R. L., & Li, Y. W. (2000). Study on the relationship experimental allergic rhinitis model: contribution of dilated mucosal blood
between allergic rhinitis and airway hyperresponsiveness. Lin Chuang Er Bi vessels. Jpn J Pharmacol 86(2), 170−182.
Yan Hou Ke Za Zhi 14(2), 55−56. Mizutani, N., Nabe, T., Takenaka, H., & Kohno, S. (2003). Acquired nasal
Ma, R. Z., Gao, J., Meeker, N. D., Fillmore, P. D., Tung, K., Watanabe, S., et al. hyperresponsiveness aggravates antigen-induced rhinitis in the guinea pig.
(2002). Identification of Bphs, an autoimmune disease locus, as histamine J Pharmacol Sci 93(4), 437−445.
receptor H1. Science 297(5581), 620−623. Moller, C., Dreborg, S., Ferdousi, H. A., Halken, S., Host, A., Jacobsen, L., et al.
MacGlashan Jr., D. (2003). Histamine: A mediator of inflammation. J Allergy (2002). Pollen immunotherapy reduces the development of asthma in
Clin Immunol 112(4 Suppl), S53−S59. children with seasonal rhinoconjunctivitis (the PAT-study). J Allergy Clin
MacGlashan Jr., D., White, J. M., Huang, S. K., Ono, S. J., Schroeder, J. T., & Immunol 109(2), 251−256.
Lichtenstein, L. M. (1994). Secretion of IL-4 from human basophils. The Moqbel, R., Hamid, Q., Ying, S., Barkans, J., Hartnell, A., Tsicopoulos, A., et al.
relationship between IL-4 mRNA and protein in resting and stimulated (1991). Expression of mRNA and immunoreactivity for the granulocyte/
basophils. J Immunol 152(6), 3006−3016. macrophage colony-stimulating factor in activated human eosinophils.
Mahnke, K., Guo, M., Lee, S., Sepulveda, H., Swain, S. L., Nussenzweig, M., et al. J Exp Med 174(3), 749−752.
(2000). The dendritic cell receptor for endocytosis, DEC-205, can recycle and Mosimann, B. L., White, M. V., Hohman, R. J., Goldrich, M. S., Kaulbach, H. C.,
enhance antigen presentation via major histocompatibility complex class II- & Kaliner, M. A. (1993). Substance P, calcitonin gene-related peptide, and
positive lysosomal compartments. J Cell Biol 151(3), 673−684. vasoactive intestinal peptide increase in nasal secretions after allergen
Mahr, T. A., & Sheth, K. (2005). Update on allergic rhinitis. Pediatr Rev 26(8), challenge in atopic patients. J Allergy Clin Immunol 92(1 Pt 1), 95−104.
284−289. Mosmann, T. R., & Coffman, R. L. (1989). TH1 and TH2 cells: different
Malis, D. D., Rist, B., Nicoucar, K., Beck-Sickinger, A. G., Morel, D. R., & patterns of lymphokine secretion lead to different functional properties.
Lacroix, J. S. (2001). Modulatory effect of two novel CGRP receptor Annu Rev Immunol 7, 145−173.
antagonists on nasal vasodilatatory responses to exogenous CGRP, Motobayashi, Y., Imagawa, W., & Saida, K. (2001). Ramatroban (Baynas): a
capsaicin, bradykinin and histamine in anaesthetised pigs. Regul Pept 101 review of its pharmacological and clinical profile. Nippon Yakurigaku
(1-3), 101−108. Zasshi 118(6), 397−402.
258 Y.M. Al Suleimani, M.J.A. Walker / Pharmacology & Therapeutics 114 (2007) 233–260

Mullins, R. J., Olson, L. G., & Sutherland, D. C. (1989). Nasal histamine challenges Okuda, M., Ohtsuka, H., & Kawabori, S. (1985). Studies of nasal surface
in symptomatic allergic rhinitis. J Allergy Clin Immunol 83(5), 955−959. basophilic cells. Ann Allergy 54(1), 69−71.
Munitz, A., & Levi-Schaffer, F. (2004). Eosinophils: ‘new’ roles for ‘old’ cells. Oppenheimer, J. J., & Casale, T. B. (2002). Next generation antihistamines:
Allergy 59(3), 268−275. therapeutic rationale, accomplishments and advances. Expert Opin Investig
Murasugi, T., Nakagami, Y., Yoshitomi, T., Hirahara, K., Yamashita, M., Drugs 11(6), 807−817.
Taniguchi, Y., et al. (2005). Oral administration of a T cell epitope inhibits Otsuka, H., Denburg, J., Dolovich, J., Hitch, D., Lapp, P., Rajan, R. S., et al.
symptoms and reactions of allergic rhinitis in Japanese cedar pollen allergen- (1985). Heterogeneity of metachromatic cells in human nose: significance of
sensitized mice. Eur J Pharmacol 510(1-2), 143−148. mucosal mast cells. J Allergy Clin Immunol 76(5), 695−702.
Mygind, N. (1982). Mediators of nasal allergy. J Allergy Clin Immunol 70(3), Pajno, G. B., Barberio, G., De Luca, F., Morabito, L., & Parmiani, S. (2001).
149−159. Prevention of new sensitizations in asthmatic children monosensitized to
Mygind, N., & Naclerio, R. (1993). Allergic and nonallergic rhinitis. house dust mite by specific immunotherapy. A six-year follow-up study.
Philadelphia: WB Saunders. Clin Exp Allergy 31(9), 1392−1397.
Nabe, T., Mizutani, N., Osaki, S., Sugahara, S., Takenaka, H., & Kohno, S. Paul, W., Douglas, G. J., Lawrence, L., Khawaja, A. M., Perez, A. C., Schachter, M.,
(2001). Comparison of cedar pollen-induced allergic rhinitis in passively et al. (1994). Cutaneous permeability responses to bradykinin and histamine in
and actively sensitized guinea pigs. Jpn J Pharmacol 85(4), 409−415. the guinea-pig: possible differences in their mechanism of action. Br J Pharmacol
Naclerio, R. M. (1991). Allergic rhinitis. N Engl J Med 325(12), 860−869. 111(1), 159−164.
Naclerio, R. M., Proud, D., Togias, A. G., Adkinson Jr., N.F., Meyers, D. A., Pawankar, R. (2005). Mast cells in allergic airway disease and chronic
Kagey-Sobotka, A., et al. (1985). Inflammatory mediators in late antigen- rhinosinusitis. Chem Immunol Allergy 87, 111−129.
induced rhinitis. N Engl J Med 313(2), 65−70. Pawankar, R., Yamagishi, S., & Yagi, T. (2000). Revisiting the roles of mast
Nakaya, M., Takeuchi, N., & Kondo, K. (2004). Immunohistochemical cells in allergic rhinitis and its relation to local IgE synthesis. Am J Rhinol
localization of histamine receptor subtypes in human inferior turbinates. 14(5), 309−317.
Ann Otol Rhinol Laryngol 113(7), 552−557. Philip, G., Malmstrom, K., Hampel, F. C., Weinstein, S. F., LaForce, C. F.,
Namimatsu, A., Yamaura, S., Go, K., Tanimoto, H., & Okuda, M. (1991). A new Ratner, P. H., et al. (2002). Montelukast for treating seasonal allergic rhinitis:
method of the measurement of nasal secretion in guinea pigs. Int Arch a randomized, double-blind, placebo-controlled trial performed in the
Allergy Appl Immunol 95(1), 29−34. spring. Clin Exp Allergy 32(7), 1020−1028.
Narita, S., Asakura, K., Shirasaki, H., & Kataura, A. (1997). Effects of a cysteinyl Platts-Mills, T. A., Hayden, M. L., Chapman, M. D., & Wilkins, S. R.
leukotriene antagonist, ONO-1078 (pranlukast), on total airway resistance (1987). Seasonal variation in dust mite and grass-pollen allergens in dust
after antigen challenge in sensitized guinea pigs. Inflamm Res 46(4), from the houses of patients with asthma. J Allergy Clin Immunol 79(5),
143−146. 781−791.
Nayak, A. S., & Schenkel, E. (2001). Desloratadine reduces nasal congestion in Plewako, H., Arvidsson, M., Petruson, K., Oancea, I., Holmberg, K., Adelroth, E.,
patients with intermittent allergic rhinitis. Allergy 56(11), 1077−1080. et al. (2002). The effect of omalizumab on nasal allergic inflammation.
Newhouse, B. J. (2002). Tryptase inhibitors- review of the recent patent J Allergy Clin Immunol 110(1), 68−71.
literature. IDrugs 5(7), 682−688. Presta, L. G., Lahr, S. J., Shields, R. L., Porter, J. P., Gorman, C. M., Fendly, B. M.,
Nghiem, D. X., Kazimi, N., Mitchell, D. L., Vink, A. A., Ananthaswamy, H. N., et al. (1993). Humanization of an antibody directed against IgE. J Immunol
Kripke, M. L., et al. (2002). Mechanisms underlying the suppression of 151(5), 2623−2632.
established immune responses by ultraviolet radiation. J Invest Dermatol Pullerits, T., Praks, L., Ristioja, V., & Lotvall, J. (2002). Comparison of a nasal
119(3), 600−608. glucocorticoid, antileukotriene, and a combination of antileukotriene and
Nicosia, S., Capra, V., Accomazzo, M. R., Ragnuni, D., Ravasi, S., Caiani, A., et al. antihistamine in the treatment of seasonal allergic rhinitis. J Allergy Clin
(1999). Receptors for cysteinyl-leukotrienes in human cells. Adv Exp Med Biol Immunol 109(6), 949−955.
447, 165−170. Raab, W. (1989). Practically important allergies. An overview. Wien Med
Nijman, H. W., Kleijmeer, M. J., Ossevoort, M. A., Oorschot, V. M., Vierboom, Wochenschr 139(6-7), 108−115.
M. P., van de Keur, M., et al. (1995). Antigen capture and major Rajakulasingam, K., Polosa, R., Lau, L. C., Church, M. K., Holgate, S. T., &
histocompatibility class II compartments of freshly isolated and cultured Howarth, P. H. (1993). Comparative nasal effects of bradykinin and
human blood dendritic cells. J Exp Med 182(1), 163−174. histamine: influence on nasal airways resistance and plasma protein
Nishioka, K., Ogawa, T., Saito, C., Nishioka, S., Nakagawa, F., Ohomichi, T., et al. exudation. Thorax 48(4), 324−329.
(1995). Major basic protein, eosinophil cationic protein, and arylsulfatase in Rajakulasingam, K., Hamid, Q., O'Brien, F., Shotman, E., Jose, P. J., Williams,
nasal secretions of patients with Japanese cedar pollinosis. Acta Med Okayama T. J., et al. (1997). RANTES in human allergen-induced rhinitis: cellular
49(1), 29−33. source and relation to tissue eosinophilia. Am J Respir Crit Care Med 155(2),
Noble, S. L., Forbes, R. C., & Woodbridge, H. B. (1995). Allergic rhinitis. 696−703.
Am Fam Phys 51(4), 837−846. Ramis, I., Catafau, J. R., Serra, J., Bulbena, O., Picado, C., & Gelpi, E. (1991).
Nonaka, M., Nonaka, R., Jordana, M., & Dolovich, J. (1996). GM-CSF, IL-8, In vivo release of 15-HETE and other arachidonic acid metabolites in nasal
IL-1R, TNF-alpha R, and HLA-DR in nasal epithelial cells in allergic secretions during early allergic reactions. Prostaglandins 42(5), 411−420.
rhinitis. Am J Respir Crit Care Med 153(5), 1675−1681. Raskovic, S., Bogic, M., Peric-Popadic, A., Arandjelovic, S., Jovcic, Z., &
Norman, P. S., Ohman Jr., J.L., Long, A. A., Creticos, P. S., Gefter, M. A., Tomic-Spiric, V. (1998). [The role of prostaglandins in allergic inflamma-
Shaked, Z., et al. (1996). Treatment of cat allergy with T-cell reactive tion]. Srp Arh Celok Lek 126(9-10), 388−393.
peptides. Am J Respir Crit Care Med 154(6 Pt 1), 1623−1628. Ratner, P. H., Ehrlich, P. M., Fineman, S. M., Meltzer, E. O., & Skoner, D. P.
Numata, T., Konno, A., Yamakoshi, T., Hanazawa, T., Terada, N., & Nagata, H. (2002). Use of intranasal cromolyn sodium for allergic rhinitis. Mayo Clin
(1999). Comparative role of peptide leukotrienes and histamine in the Proc 77(4), 350−354.
development of nasal mucosal swelling in nasal allergy. Ann Otol Rhinol Regoli, D., Barabe, J., & Park, W. K. (1977). Receptors for bradykinin in rabbit
Laryngol 108(5), 467−473. aortae. Can J Physiol Pharmacol 55(4), 855−867.
Oh, S. J., Min, Y. G., Kim, J. W., Lee, S. J., & Jarin, P. R. (2003). Expression of Revington, M., Lacroix, J. S., & Potter, E. K. (1997). Sympathetic and
nitric oxide synthases in nasal mucosa from a mouse model of allergic parasympathetic interaction in vascular and secretory control of the nasal
rhinitis. Ann Otol Rhinol Laryngol 112(10), 899−903. mucosa in anaesthetized dogs. J Physiol 505(Pt 3), 823−831.
Ohtoshi, T., Tsuda, T., Vancheri, C., Abrams, J. S., Gauldie, J., Dolovich, J., Riccio, M. M., & Proud, D. (1996). Evidence that enhanced nasal reactivity to
et al. (1991). Human upper airway epithelial cell-derived granulocyte- bradykinin in patients with symptomatic allergy is mediated by neural
macrophage colony-stimulating factor induces histamine-containing cell reflexes. J Allergy Clin Immunol 97(6), 1252−1263.
differentiation of human progenitor cells. Int Arch Allergy Appl Immunol Riechelmann, H. (2005). Oral second generation antihistamines in allergic
95(4), 376−384. rhinitis. Laryngo- Rhino- Otol 84(1), 30−41.
Y.M. Al Suleimani, M.J.A. Walker / Pharmacology & Therapeutics 114 (2007) 233–260 259

Riederer, A., Knipping, S., & Toleti, B. (2002). Regulation of the swelling mechanism Shakoory, B., Fitzgerald, S. M., Lee, S. A., Chi, D. S., & Krishnaswamy, G.
in the inferior turbinate of human nasal mucosa. Laryngo- Rhino- Otol 81(7), (2004). The role of human mast cell-derived cytokines in eosinophil biology.
469−475. J Interferon Cytokine Res 24(5), 271−281.
Rodriguez, A., Regnault, A., Kleijmeer, M., Ricciardi-Castagnoli, P., & Shimizu, T., Hirano, H., Majima, Y., & Sakakura, Y. (2000). A mechanism of
Amigorena, S. (1999). Selective transport of internalized antigens to the antigen-induced mucus production in nasal epithelium of sensitized rats. A
cytosol for MHC class I presentation in dendritic cells. Nat Cell Biol 1(6), comparison with lipopolysaccharide-induced mucus production. Am J
362−368. Respir Crit Care Med 161(5), 1648−1654.
Roman, M., Martin-Orozco, E., Goodman, J. S., Nguyen, M. D., Sato, Y., Shin, M. H., Averill, F. J., Hubbard, W. C., Chilton, F. H., Baroody, F. M., Liu,
Ronaghy, A., et al. (1997). Immunostimulatory DNA sequences function as M. C., et al. (1994). Nasal allergen challenge generates 1-0-hexadecyl-2-
T helper-1-promoting adjuvants. Nat Med 3(8), 849−854. lyso-sn-glycero-3-phosphocholine. Am J Respir Crit Care Med 149(3 Pt 1),
Rudolph, K., Bice, D. E., Hey, J. A., & McLeod, R. L. (2003). A model of allergic 660−666.
nasal congestion in dogs sensitized to ragweed. Am J Rhinol 17(4), 227−232. Shirasaki, H., & Asakura, K. (1990). Detection of platelet-activating factor
Sadeghi-Hashjin, G., Folkerts, G., Henricks, P. A., Verheyen, A. K., van der in nasal lavage fluid from patients with pollinosis and experimen-
Linde, H. J., van Ark, I., et al. (1996). Peroxynitrite induces airway tal animals with nasal allergy. Nippon Jibiinkoka Gakkai Kaiho 93(3),
hyperresponsiveness in guinea pigs in vitro and in vivo. Am J Respir Crit 420−427.
Care Med 153(5), 1697−1701. Shirasaki, H., Kojima, T., Asakura, K., Kataura, A., Shimamoto, K., & Iimura,
Saito, H., Howie, K., Wattie, J., Denburg, A., Ellis, R., Inman, M. D., et al. (2001). O. (1989). The pathophysiological role of kinin and chemical mediators on
Allergen-induced murine upper airway inflammation: local and systemic experimental allergic rhinitis. Adv Exp Med Biol 247A, 375−378.
changes in murine experimental allergic rhinitis. Immunology 104(2), Shizawa, T., Maeda, K., Abe, K., Ishii, T., & Kamitani, T. (1997). Effects of
226−234. TMK688, a novel anti-allergic drug, on allergic nasal obstruction and
Saito, H., Matsumoto, K., Denburg, A. E., Crawford, L., Ellis, R., Inman, M. D., exudative responses in sensitized guinea pigs. Naunyn-Schmiedeberg's Arch
et al. (2002). Pathogenesis of murine experimental allergic rhinitis: a study Pharmacol 356(6), 815−819.
of local and systemic consequences of IL-5 deficiency. J Immunol 168(6), Sim, T. C., Reece, L. M., Hilsmeier, K. A., Grant, J. A., & Alam, R. (1995).
3017−3023. Secretion of chemokines and other cytokines in allergen-induced nasal
Saito, H., Morikawa, H., Howie, K., Crawford, L., Baatjes, A. J., Denburg, E., et al. responses: inhibition by topical steroid treatment. Am J Respir Crit Care
(2004). Effects of a cysteinyl leukotriene receptor antagonist on eosinophil Med 152(3), 927−933.
recruitment in experimental allergic rhinitis. Immunology 113(2), 246−252. Sisson, J. H., Prescott, S. M., McIntyre, T. M., & Zimmerman, G. A. (1987).
Sakairi, T., Suzuki, K., Makita, S., Wajima, T., Shakuto, S., Yoshida, Y., et al. Production of platelet-activating factor by stimulated human polymorpho-
(2005). Effects of fexofenadine hydrochloride in a guinea pig model of nuclear leukocytes. Correlation of synthesis with release, functional events,
antigen-induced rhinitis. Pharmacology 75(2), 76−86. and leukotriene B4 metabolism. J Immunol 138(11), 3918−3926.
Salo, H. M., Jokinen, E. I., Markkula, S. E., Aaltonen, T. M., & Penttila, H. T. Skoner, D., Doyle, W., Boehm, S., & Fireman, P. (1988). Late phase eustachian
(2000). Comparative effects of UVA and UVB irradiation on the immune tube and nasal allergic responses associated with inflammatory mediator
system of fish. J Photochem Photobiol B Biol 56(2-3), 154−162. elaboration. Am J Rhinol 2, 155−161.
Sanderson, C. J. (1993). Interleukin-5 and the regulation of eosinophil Skowron, M., Perret, E., Marano, F., Caput, D., & Tournier, F. (2003).
production. In H. Smith & R. M. Cook (Eds.), London: Academic Press. Interleukin-13 alters mucociliary differentiation of human nasal epithelial
Sanico, A. M., Stanisz, A. M., Gleeson, T. D., Bora, S., Proud, D., Bienenstock, J., cells. Chest 123(3 Suppl), 373S−374S.
et al. (2000). Nerve growth factor expression and release in allergic in- Springer, J., Geppetti, P., Fischer, A., & Groneberg, D. A. (2003). Calcitonin
flammatory disease of the upper airways. Am J Respir Crit Care Med 161(5), gene-related peptide as inflammatory mediator. Pulm Pharmacol Ther 16(3),
1631−1635. 121−130.
Santambrogio, L., Sato, A. K., Carven, G. J., Belyanskaya, S. L., Strominger, J. L., Sorbera, L. A., Lesson, P. A., & Castaner, J. (2000). Rofumilast, BY-217. Drugs
& Stern, L. J. (1999). Extracellular antigen processing and presenta- Future 25, 1261−1264.
tion by immature dendritic cells. Proc Natl Acad Sci U S A 96(26), Strachan, D. P. (1989). Hay fever, hygiene, and household size. BMJ 299(6710),
15056−15061. 1259−1260.
Saria, A., Martling, C. R., Yan, Z., Theodorsson-Norheim, E., Gamse, R., & Sugimoto, M., Sugiyama, S., Yanagita, N., & Ozawa, T. (1994). Laser
Lundberg, J. M. (1988). Release of multiple tachykinins from capsaicin- high performance liquid chromatography determination of prostaglan-
sensitive sensory nerves in the lung by bradykinin, histamine, dimethylphe- dins in nasal lavage fluid in allergic rhinitis. Clin Exp Allergy 24(4),
nyl piperazinium, and vagal nerve stimulation. Am Rev Respir Dis 137(6), 324−329.
1330−1335. Sugimoto, Y., Ishizawa, K., Saitou, K., Suzuki, G., Tarumi, T., Nakara, H., et al.
Schmelz, M., Schmidt, R., Bickel, A., Handwerker, H. O., & Torebjork, H. E. (2000a). Effect of mometasone furoate by topical application on allergic
(1997). Specific C-receptors for itch in human skin. J Neurosci 17(20), rhinitis model in rats. Pharmacology 61(2), 91−95.
8003−8008. Sugimoto, Y., Kawamoto, E., Chen, Z., & Kamei, C. (2000b). A new model of
Schmidt, B. M., Kusma, M., Feuring, M., Timmer, W. E., Neuhauser, M., allergic rhinitis in rats by topical sensitization and evaluation of H(1)-
Bethke, T., et al. (2001). The phosphodiesterase 4 inhibitor roflumilast is receptor antagonists. Immunopharmacology 48(1), 1−7.
effective in the treatment of allergic rhinitis. J Allergy Clin Immunol 108(4), Sugimoto, H., Shichijo, M., Iino, T., Manabe, Y., Watanabe, A., Shimazaki, M.,
530−536. et al. (2003). An orally bioavailable small molecule antagonist of CRTH2,
Schneider, E., Rolli-Derkinderen, M., Arock, M., & Dy, M. (2002). Trends in ramatroban (BAY u3405), inhibits prostaglandin D2-induced eosinophil
histamine research: new functions during immune responses and hemato- migration in vitro. J Pharmacol Exp Ther 305(1), 347−352.
poiesis. Trends Immunol 23(5), 255−263. Sugimoto, Y., Iba, Y., Nakamura, Y., Kayasuga, R., & Kamei, C. (2004).
Schroeder, J. T., MacGlasha Jr., D. W., Kagey-Sobotka, A., White, J. M., & Pruritus-associated response mediated by cutaneous histamine H3 receptors.
Lichtenstein, L. M. (1994). IgE-dependent IL-4 secretion by human Clin Exp Allergy 34(3), 456−459.
basophils. The relationship between cytokine production and histamine Svensson, C., Andersson, M., Greiff, L., Alkner, U., & Persson, C. G. (1995).
release in mixed leukocyte cultures. J Immunol 153(4), 1808−1817. Exudative hyperresponsiveness of the airway microcirculation in seasonal
Schroeder, J. T., Lichtenstein, L. M., & MacDonald, S. M. (1997). Recombinant allergic rhinitis. Clin Exp Allergy 25(10), 942−950.
histamine-releasing factor enhances IgE-dependent IL-4 and IL-13 secretion Symon, F. A., Walsh, G. M., Watson, S. R., & Wardlaw, A. J. (1994). Eosinophil
by human basophils. J Immunol 159(1), 447−452. adhesion to nasal polyp endothelium is P-selectin-dependent. J Exp Med
Settipane, R. J., Hagy, G. W., & Settipane, G. A. (1994). Long-term risk factors 180(1), 371−376.
for developing asthma and allergic rhinitis: a 23-year follow-up study of Szelenyi, I., Marx, D., & Jahn, W. (2000). Animal models of allergic rhinitis.
college students. Allergy Proc 15(1), 21−25. Arzneimittelforschung 50(11), 1037−1042.
260 Y.M. Al Suleimani, M.J.A. Walker / Pharmacology & Therapeutics 114 (2007) 233–260

Tatton, L., Morley, G. M., Chopra, R., & Khwaja, A. (2003). The Src-selective membrane complement regulatory proteins. Laryngoscope 106(5 Pt 1),
kinase inhibitor PP1 also inhibits Kit and Bcr-Abl tyrosine kinases. J Biol 599−604.
Chem 278(7), 4847−4853. Wachholz, P. A., Nouri-Aria, K. T., Wilson, D. R., Walker, S. M., Verhoef, A.,
Teixeira, M. M., Gristwood, R. W., Cooper, N., & Hellewell, P. G. (1997). Till, S. J., et al. (2002). Grass pollen immunotherapy for hayfever is
Phosphodiesterase (PDE)4 inhibitors: anti-inflammatory drugs of the future? associated with increases in local nasal but not peripheral Th1:Th2 cytokine
Trends Pharmacol Sci 18(5), 164−171. ratios. Immunology 105(1), 56−62.
Terada, N., Hamano, N., Kim, W. J., Hirai, K., Nakajima, T., Yamada, H., et al. Wagenmann, M., Baroody, F. M., Desrosiers, M., Hubbard, W. C., Ford, S.,
(2001). The kinetics of allergen-induced eotaxin level in nasal lavage fluid: Lichtenstein, L. M., et al. (1996). Unilateral nasal allergen challenge leads to
its key role in eosinophil recruitment in nasal mucosa. Am J Respir Crit Care bilateral release of prostaglandin D2. Clin Exp Allergy 26(4), 371−378.
Med 164(4), 575−579. Wang, C. G., Du, T., Xu, L. J., & Martin, J. G. (1993). Role of leukotriene D4 in
Tiffany, C. W., & Burch, R. M. (1989). Bradykinin stimulates tumor necrosis allergen-induced increases in airway smooth muscle in the rat. Am Rev
factor and interleukin-1 release from macrophages. FEBS Lett 247(2), Respir Dis 148(2), 413−417.
189−192. Wells, U., & Widdicombe, J. G. (1986). Lateral nasal gland secretion in the
Tiniakov, R. L., Tiniakova, O. P., McLeod, R. L., Hey, J. A., & Yeates, D. B. anaesthetized dog. J Physiol 374, 359−374.
(2003). Canine model of nasal congestion and allergic rhinitis. J Appl White, M. V. (1993). Nasal cholinergic hyperresponsiveness in atopic subjects
Physiol 94(5), 1821−1828. studied out of season. J Allergy Clin Immunol 92(2), 278−287.
Togias, A. (2000). Unique mechanistic features of allergic rhinitis. J Allergy Widdicombe, J. G. (1986). The physiology of the nose. Clin Chest Med 7(2),
Clin Immunol 105(6 Pt 2), S599−S604. 159−170.
Togias, A., Naclerio, R. M., Proud, D., Pipkorn, U., Bascom, R., Iliopoulos, O., Widdicombe, J. G. (1990). Nasal pathophysiology. Respir Med 84(Suppl A),
et al. (1988). Studies on the allergic and nonallergic nasal inflammation. 3−9 (discussion 9-10).
J Allergy Clin Immunol 81(5 Pt 1), 782−790. Widdicombe, J. (1997). Microvascular anatomy of the nose. Allergy 52(40
Tokuyama, K., Kuo, H. P., Rohde, J. A. L., Barnes, P. J., & Rogers, D. F. (1990). Suppl), 7−11.
Neural control of goblet cell secretion in guinea pig airways. Am J Physiol Widdicombe, J. G., & Wells, U. M. (1982). Airway secretions. In D. F. Proctor
259(2 pt 1), L108−L115. & I. B. Andersen (Eds.), The nose: Upper airway physiology and the
Topuz, B., & Ogmen, G. G. (2003). Montelukast as an adjuvant to mainstay therapies atmospheric environment (pp. 215−244). Amsterdam: Elsevier.
in patients with seasonal allergic rhinitis. Clin Exp Allergy 33(6), 823−826. Wills-Karp, M., Luyimbazi, J., Xu, X., Schofield, B., Neben, T. Y., Karp, C. L.,
Tos, M. (1983). Distribution of mucus producing elements in the respiratory et al. (1998). Interleukin-13: central mediator of allergic asthma. Science
tract. Differences between upper and lower airway. Eur J Respir Dis Suppl 282(5397), 2258−2261.
128(Pt 1), 269−279. Wilson, S. J., Lau, L., & Howarth, P. H. (1998). Inflammatory mediators in
Turner, P. J., & Foreman, J. C. (1999). Hyperresponsiveness in the human nasal naturally occurring rhinitis. Clin Exp Allergy 28(2), 220−227.
airway: new targets for the treatment of allergic airway disease. Mediators Wright, A. L., Holberg, C. J., Martinez, F. D., Halonen, M., Morgan, W., &
Inflamm 8(3), 133−146. Taussig, L. M. (1994). Epidemiology of physician-diagnosed allergic
Turner, P. J., Maggs, J. R., & Foreman, J. C. (2000). Induction by inhibitors of rhinitis in childhood. Pediatrics 94(6 Pt 1), 895−901.
nitric oxide synthase of hyperresponsiveness in the human nasal airway. Br J Wynn, T. A. (2003). IL-13 effector functions. Annu Rev Immunol 21, 425−456.
Pharmacol 131(2), 363−369. Yamasaki, M., Matsumoto, T., Fukuda, S., Nakayama, T., Nagaya, H., &
Uddman, R., Anggard, A., & Widdicombe, J. G. (1987). Nerves and Ashida, Y. (1997). Involvement of thromboxane A2 and histamine in
neurotransmittors in the nose. In N. Myding & U. Pipkorn (Eds.), Allergic experimental allergic rhinitis of guinea pigs. J Pharmacol Exp Ther 280(3),
and vasomotor rhinitis. Pathophysiological aspects (pp. 50−62). Copenha- 1471−1479.
gen: Munksgaard. Yamasaki, M., Mizutani, N., Sasaki, K., Nabe, T., Matsumoto, T., Ashida, Y., et al.
Uddman, R., Cantera, L., Cardell, L. O., & Edvinnsson, L. (1999). Expression of (2001). Involvement of thromboxane A2 and peptide leukotrienes in early and
NPY Y1 and CGRP1 receptors in human nasal mucosa: implications in late phase nasal blockage in a guinea pig model of allergic rhinitis. Inflamm Res
allergic rhinitis. Ann Otol Rhinol Laryngol 108(10), 969−973. 50(9), 466−473.
Valladeau, J., Ravel, O., Dezutter-Dambuyant, C., Moore, K., Kleijmeer, M., Yamasaki, M., Mizutani, N., Sasaki, K., Nabe, T., & Kohno, S. (2002). No
Liu, Y., et al. (2000). Langerin, a novel C-type lectin specific to Langerhans involvement of interleukin-5 or eosinophils in experimental allergic rhinitis
cells, is an endocytic receptor that induces the formation of Birbeck in guinea pigs. Eur J Pharmacol 439(1-3), 159−169.
granules. Immunity 12(1), 71−81. Zeiger, R. S., Heller, S., Mellon, M. H., Forsythe, A. B., O'Connor, R. D.,
Van Oosterhout, A. J., van Ark, I., Hofman, G., Van Der Linde, H. J., Fattah, D., Hamburger, R. N., et al. (1989). Effect of combined maternal and infant food-
& Nijkamp, F. P. (1996). Role of interleukin-5 and substance P in allergen avoidance on development of atopy in early infancy: a randomized
development of airway hyperreactivity to histamine in guinea-pigs. Eur study. J Allergy Clin Immunol 84(1), 72−89.
Respir J 9(3), 493−499. Zeng, D., Prosperini, G., Russo, C., Spicuzza, L., Cacciola, R. R., Di Maria, G. U.,
Vancheri, C., Mastruzzo, C., Armato, F., Tomaselli, V., Magri, S., Pistorio, M. P., et al. (2004). Heparin attenuates symptoms and mast cell degranulation induced
et al. (2001). Intranasal heparin reduces eosinophil recruitment after nasal by AMP nasal provocation. J Allergy Clin Immunol 114(2), 316−320.
allergen challenge in patients with allergic rhinitis. J Allergy Clin Immunol Zhao, Y., Woo, J. K., Leung, P. C., Chen, G. G., Wong, Y. O., Liu, S. X., et al.
108(5), 703−708. (2005). Symptomatic and pathophysiological observations in a modified
Varney, V. A., Jacobson, M. R., Sudderick, R. M., Robinson, D. S., Irani, A. M., animal model of allergic rhinitis. Rhinology 43(1), 47−54.
Schwartz, L. B., et al. (1992). Immunohistology of the nasal mucosa Zhou, C. Y., Crocker, I. C., Koenig, G., Romero, F. A., & Townley, R. G. (1997).
following allergen-induced rhinitis. Identification of activated T lympho- Anti-interleukin-4 inhibits immunoglobulin E production in a murine model
cytes, eosinophils, and neutrophils. Am Rev Respir Dis 146(1), 170−176. of atopic asthma. J Asthma 34(3), 195−201.
Varsano, S., Frolkis, I., Shapiro, H., & Ophir, D. (1996). Human nasal
epithelium adsorbs complement C3-related fragments and expresses cell

View publication stats

You might also like