Basic mechanisms of asthma.

Role of
inflammation.
C E Reed

Chest 1988;94;175-177
DOI 10.1378/chest.94.1.175
The online version of this article, along with updated information and services
can be found online on the World Wide Web at:
http://chestjournal.chestpubs.org/content/94/1/175

Chest is the official journal of the American College of Chest Physicians. It has
been published monthly since 1935. Copyright1988by the American College of
Chest Physicians, 3300 Dundee Road, Northbrook, IL 60062. All rights
reserved. No part of this article or PDF may be reproduced or distributed
without the prior written permission of the copyright holder.
(http://chestjournal.chestpubs.org/site/misc/reprints.xhtml) ISSN:0012-3692

Downloaded from chestjournal.chestpubs.org by guest on February 5, 2011

© 1988 American College of Chest Physicians
 Basic Mechanisms of Asthma
Role of Inflammation
Charles E. Reed, M.D. , F. C. C.P.

It is now recognized that the basic reason for airway tion is not possible. When chronic asthma is mild, aerosol
obstruction in asthma is chronic airway inflammation. The gI ucocorticoids or cromolyn suffice. Acute exacerbations
hyperresponsiveness and “bronchospasm” are, in part at that do not respond fully to bronchodilator drugs usually
least, a consequence of the inflammation. Optimum patient should be treated by a course of oral glucocorticoids. A few
care needs to focus on preventing inflammation when patients with severe disease require oral glucocorticoid
possible and using anti-inflammatory drugs when preven- therapy indefinitely.

E ifective treatment of an individual patient with mucosal inflammation of a special kind, chronic des-
asthma requires both an understanding of the quamating eosinophilic bronchitis. Clinicians can in-
pathogenesis of the disease and a knowledge of the tegrate all of these definitions and apply them to
outcome of therapeutic trials conducted in a series of individual patients.
patients. Understanding the pathogenesis is especially
ANATOMIC BASIS OF OBSTRUCTION
important because, by the nature of their design,
clinical trials provide conclusions about the average There are two main components of the obstruction:
outcome ofa selected group ofpatients. Any particular bronchospasm and inflammation. Bronchospasm,
patient may respond differently from the average for a acute changes in airway caliber, can be recognized by
variety of reasons. More importantly, the severity and abrupt changes in symptoms on exposure to allergens,
pathogenesis of the disease varies in the same patient irritant fumes or dusts, or changes in FEy, after
from time to time. Ofall the diseases physicians treat, bronchodilatation. Airway hyperresponsiveness can be
asthma may have the most complex pathogenesis. recognized by provocation tests with exercise, cold air,
Study ofthe pathogenesis has been hampered because histamine, or methacholine. Airway inflammation can
the definition of asthma has been controversial. This be recognized by increased numbers of eosinophils in
controversy arises because the “cause” is not known blood or sputum, by bits of desquamated epithelium
(indeed, there may not be a single “cause”), and in sputum (creola bodies),’ and by lack of immediate
operational definitions are, therefore, necessary. Epi- response of the FEy, to bronchodilators, but instead
demiologists need a definition that can be applied in slow response to glucocorticoids over several days.
large scale surveys. Usually such an epidemiologic
definition relies on answers to specific items on a Histopathology

questionnaire. Physiologists use a definition based on Histopathology shows typical changes. The submu-
variability and reversibility of airflow obstruction. cosa is infiltrated with lymphocytes, monocytes, and
Pathologists have had relatively less say in the defini- eosinophils, and blood vessels are dilated. The epithe-
tion because biopsies are not feasible, but autopsies hum is particularly damaged, cilia absent, and the
have contributed essential information about the in- epithelium is infiltrated with inflammatory cells, es-
flammatory component of airway obstruction. Immu- pecially lymphocytes, and is vacuolated and in places
nologists and allergists studying the pathogenesis of has been completely sloughed off leaving a bare
IgE-mediated allergic asthma have learned a good basement membrane thickened by collagen deposi-
deal about the mechanisms of acute changes in airway tion. This inflammation and desquamation are not
caliber, airway hyperresponsiveness, and bronchial uniform but are patchy. There is also increase in
*professor of Internal Medicine, Mayo Medical School; Consultant mucosal goblet cells, bronchial mucus glands, and
in Internal Medicine and Allergic Disease, Mayo Clinic, Rochester, smooth muscle. Because of inflammatory exudate and
Minnesota. excess mucus secretion there is increased sputum.
Reprint requests: Dr Reed, Mayo Clinic, Rochester, Minnesota
55905 Damage of the epithelium with loss of the ciliated es-

CHEST I 94 I 1 I JULY, 1988 175

Downloaded from chestjournal.chestpubs.org by guest on February 5, 2011

© 1988 American College of Chest Physicians
calator contributes to mucus stasis and mucus “plugs.” late upon stimulation of the IgE receptors. Most
eosinophils in tissues and bronchoalveolar lavage fluids
EPITHELIAL DESQUAMATION AND EoSINoPHIu
appear to be of the low density type. There is some
What is the basis for the shedding ofthe epithelium? evidence that an endothelial-derived factor can change
Gleich and colleagues2 have uncovered considerable eosinophils to the low density type.
evidence that it is the immediate result of toxic
proteins from eosinophil granules, particularly the BRONCHIAL HYPERRESPONSIVENESS AND
major basic protein and eosinophil peroxidase. The INFLAMMATION
evidence is as follows: first, the lesions occur at sites
Bronchial hyperresponsiveness, a feature character-
of eosinophil accumulation and especially at sites of
istic of asthma, is linked to inflammation. Epithelial
extracellular deposition of large amounts of the eosm-
damage by ozone enhances bronchial response to
ophil major basic protein. Second, sputum from pa-
provocation tests.6 Cartier et al found that patients
tients admitted for treatment ofasthma contains major
who had a late response to allergen inhalation had
basic protein at a concentration of 1 to 100 pg/ml.
increased bronchial response to histamine that in some
Doubtless, the concentration is much higher at the
cases lasted several days.7 The late phase is associated
site of deposition than in expectorate sputum. And
with eosinophils and eosinophilic granular proteins in
third, purified major basic protein added to explants
bronchoalveolar lavage fluid (see below). It is, there-
of guinea pig trachea damages cilia in low concentra-
fore, of considerable significance that in vitro studies
tions and causes epithelial desquamation at concentra-
show that stripping epithelim away from airway en-
tions of 10 to 100 pg/ml. These concentrations of
hances bronchoconstriction. There is a factor from
major basic protein also kill shistosomules in vitro and
normal epithelium that relaxes bronchial smooth mus-
damage many kinds ofmammalian tissue culture cells.
cle.8 Incubating excised bronchial tissue with MBP at
Also, eosinophil major basic protein occurs at the site
concentrations found in sputum of asthmatic patients
of the lesions in many other diseases associated with
similarly enhances bronchial contractility (NA Flana-
eosinophilia.
han, GJ Gleich, personal communication).
Eosinophilia
inflammation and Late Phase Allergic Reaction
Logically, this damage by toxic proteins from eosin-
ophils involves a sequence of at least three discrete Although eosinophilia is by no means limited to
steps: 1) stimulation of eosinophil growth in bone patients with allergic asthma (indeed, patients with
marrow; 2) localization of eosinophils in the bronchi nonallergic asthma may have more intense eosino-
by chemotactic factors; and 3) degranulation in situ.3 phiia), much of what is known about airway inflam-
Information about eosinophilcolony stimulating factors mation comes from study of IgE-mediated mecha-
and growth factors from lymphocytes is accumulating nisms. In the past 20 years there has been growing
There are several candidates for the specific eosino- interest in the “late phase” of immediate hypersensi-
philic chemotactic factor including peptides and pro- tivity After inhalation of allergen in a bronchial
teins, leukotriene B4, and platelet activating factor, provocation test there is an immediate bronchocon-
but as yet their roles have not been defined. Many of stricture reaction that lasts for 30 to 60 minutes and
them attract neutrophils as well as eosinophils. Though subsides. In some patients, a second wave of obstruc-
at times neutrophils are found in the late phase of IgE tion develops that peaks at four to 12 hours. Occasion-
reactions in the nose and bronchi and do occur ally, nocturnal asthma recurs for several days, probably
sporadically in the lesions, neutrophils are far outnum- another reflection ofairway hyperresponsiveness. Sim-
bered by eosinophils. Similarly, there are several ilar late responses occur in the skin and nose. IgE
stimuli for eosinophil degranulation, but their role in antibody is both necessary and sufficient to transfer
asthma has not been clarified. Circulating eosinophils the late phase to nonallergic recipients. It is generally
can be divided into at least two categories by their assumed that the initial reaction between allergen and
density. Circulating eosinophils from normal subjects IgE antibody occurs with antibody bound to high
have a density of about 1.088. Eosinophils from affinity receptors in mast cell membranes. Bridging of
subjects with the hypereosinophilic syndrome have a two antibody molecules initiates a chain of biochemical
density of 1.078. The eosinophils ofasthmatic subjects reactions that results in release of histamine and other
are distributed into these two populations. The in- mediators. The initial allergen IgE reaction in asthma
creased numbers appear to be mainly the low density probably takes place on mast cells lying free in the
type.4 These low density cells have smaller granules, lumen and on others situated between epithelial cells.
are more easily stimulated to degranulate, and are Both in rodents and in man, mast cells are heteroge-
more toxic to worms. They have more low affinity IgE neous with two major types, mucosal and connective
receptors, and only low-density eosinophils degranu- tissue. These types differ not only in their distribution,

176 Symposium

Downloaded from chestjournal.chestpubs.org by guest on February 5, 2011

© 1988 American College of Chest Physicians
but also in their morphology staining characteristics, cockroaches, are frequent causes of allergic inflam-
response to various non-IgE stimuli such as compound mation. After specific identification of relevant aller-
48/80, and character of both the proteoglycans and gens, patients should make every reasonable effirt to
enzymes of the avoid them. This identification involves three compo-
Naclerio and co-workers’#{176} have used nasal challenge nents-demonstration of IgE antibody by skin tests
as a model of the allergic reaction. During the imme- or in vitro tests, knowledge that the allergen exists in
diate response to ragweed mast cell mediators, hista- the air in the patient’s environment, and correlation of
mine, prostaglandin D2 (PGD2), and tryptase appear symptoms with exposure.
in the nasal washings. During the late phase, these In choosing drug therapy, attention should be de-
same mediators reappear, except PGD2. Inasmuch as voted to controlling the inflammation. In acute, severe
PGD2 is a mediator produced only by mast cells, not asthma, systemic glucocorticoids are the only effective
basophils, and as glucocorticoids do not inhibit medi- anti-inflammatory therapy and are almost always mdi-
ator release in mast cells but do so in basophils, and cated. In chronic asthma, aerosol cromolyn or aero-
gl ucocorticoids are effective in preventing the late sol glucocorticoids usually suffice, but severe cases
phase, Nacleno and colleagues suggest that basophils require continuous therapy with oral preparations.
recruited into the arena are the source ofthe mediators Episodes of asthma both in children and adults are
in the late phase. Neutrophils and eosinophils also often provoked by viral infections. The associated
begin to appear in the nasal washings at four hours bronchial inflammation is not due to bacterial coloni-
and increase later. Eosinophil granule proteins also zation and does not respond to antibiotics. If the epi-
appear during the late phase indicating that eosinophils sode is severe, a course oforal prednisone is appropri-
have been stimulated to release their toxic proteins. ate, as it is during an exacerbation from any cause.
Similarly, first neutrophils and then eosinophils appear REFERENCES
in bronchoalveolar lavage fluids during the late phase
1 Naylor B. The shedding of the mucosa of the bronchial tree in
of the asthmatic response.” Eosinophils peak in the asthma. Thorax 1962; 17:69-71
circulation at 24 hours at a time the airway obstruction 2 GleIch CJ, Motojima 5, Frlgas E, Kephart GM, Fujisawa T,
has passed. It is not yet known how long eosinophils Kravis LP The eoslnophiic leukocyte and the pathology of fatal
persist after an antigen challenge, but in some cases bronchial asthma: evidence for pathologic heterogeneIty. J
Allergy Clinc Immunol 1987; 80:412-15
peripheral blood eosinophilia lasts at least a week. The
3 Slifman NR, Adolphson CR, Cleich GJ. Eosinophils: biochemical
peripheral blood eosinophilia correlates temporally and cellular aspects. In: Middleton et al, eds. Allergy principles
with the hyperresponsiveness. and practice, 3rd ed St. Louis: CV Mosby (In press)
Like eosinophils, some lung macrophages and some 4 Fukuda T, Dunnette SL, Reed CE, Ackerman SJ, Peters MS,
lymphocytes have low affinity IgE receptors. The role Gleich GJ. Increased numbers of hypodense eosinophlls In the
blood of patients with bronchial asthma. Am Rev Respir Dis
these cells play in generating the inflammation of
1985; 132:981-85
asthma remains to be defined, but the prominence of 5 Rothenberg ME, Owen WFJ, Silberstein DS, Soberman RJ,
lymphocytes in the bronchial wall strongly suggests Austin KF, Stevens RI. Eosinophils cocultured with endothelial
they are important. cells have Increased survival and functional pmpertles Science
1987; 237:645-46
CLINICAL IMPLICATIONS 6 Golden JA, Nadel JA, Bouchey HA. Bronchial hyperfrrltability
in healthy subjects after exposure to ozone. Am Rev Respir Dis
What use can the clinician make ofthis information?
1978; 118:257-89
How does it affect patient management? Mainly by 7 Cartier A, Thompson NC, Firth PA, Roberts B, Tech M,
changing focus of treatment from “bronchospasm” to Hargreave FE. Allergen Induced Increase in bronchial respon-
“inflammation.” siveness to histamine: relationship to the late asthmatic response
change in airway caliber. J Allergy Clin Immunol
and 1982;
Prevention of exposure to allergens is an effective
70:170-75
way of preventing inflammation. Occupational expo-
8 Flavahan NA, Aarhus LL, Rimeile TJ, Vanhoutte PM. Respira-
sure accounts for as much as 5 percent ofasthma cases. tory epithellum Inhibits bronchial smooth muscle tone. J AppI
Longitudinal studies of workers exposed to western Physiol 1985; 98:834-38
red cedar or toluene diisocyanate reveal that airway 9 Befers AD, Blenenstock J, Denburg JA. Mast cell differentiation
and heterogeneity. New York: Raven Press, 1986
obstruction can persist months and years after expo-
10 Naclerlo RM, Prood D, lbgia AG, Adklnson NF Jr, Meyers DA,
sure ceases. Airway hyperresponsiveness persists even Kagey-Sobotka A, et al Inflammatory mediators in late antigen-
longer. The severity and persistence of asthma in- induced rhinitis. N EngI J Med 1985; 313:65-8
creases as exposure Although prospective 11 Wardlow AJ, Dunnette S, Gleich CJ, Collins J% Kay AB.
studies have not yet been done, it seems reasonable Eosinophils and mast cells in bronchoalveolar lavage in subjects
with mild asthma. Relationship to bronchial hyperreactlvity. Am
to extrapolate this information about occupational
Rev Respir Dis 1988; 137:62-9
asthma to environmental allergens. In children and 12 Chan-Yeung M, MacLean L, Paggioro PL. Followup study of
young adults, airborne allergens, both outdoors like 232 patients with occupational asthma caused by western red
pollens and molds and indoors like mites, pets, and cedar. (Thuja plicata)J Mlergy Clin Immunol 1987; 79:792-96

CHEST I 94 I 1 I JULY, 1988 177

Downloaded from chestjournal.chestpubs.org by guest on February 5, 2011

© 1988 American College of Chest Physicians
 Basic mechanisms of asthma. Role of inflammation.
C E Reed
Chest 1988;94; 175-177
DOI 10.1378/chest.94.1.175
This information is current as of February 5, 2011
Updated Information & Services
Updated Information and services can be found at:
http://chestjournal.chestpubs.org/content/94/1/175
Permissions & Licensing
Information about reproducing this article in parts (figures, tables) or in its entirety can be found
online at:
http://www.chestpubs.org/site/misc/reprints.xhtml
Reprints
Information about ordering reprints can be found online:
http://www.chestpubs.org/site/misc/reprints.xhtml
Citation Alerts
Receive free e-mail alerts when new articles cite this article. To sign up, select the "Services" link to
the right of the online article.
Images in PowerPoint format
Figures that appear in CHEST articles can be downloaded for teaching purposes in PowerPoint
slide format. See any online figure for directions.

Downloaded from chestjournal.chestpubs.org by guest on February 5, 2011

© 1988 American College of Chest Physicians