Respiratory Physiology & Neurobiology 187 (2013) 5257

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Respiratory Physiology & Neurobiology

journal homepage: www.elsevier.com/locate/resphysiol

Anti-inammatory treatment of meconium aspiration syndrome: Benets and

risks
Daniela Mokra a, , Juraj Mokry b , Ingrid Tonhajzerova a
a
b

Department of Physiology, Jessenius Faculty of Medicine, Comenius University, Martin, Slovakia

Department of Pharmacology, Jessenius Faculty of Medicine, Comenius University, Martin, Slovakia

a r t i c l e

i n f o

Article history:
Accepted 22 February 2013
Keywords:
Meconium aspiration syndrome
Inammation
Anti-inammatory drugs
Newborn
Animal model

a b s t r a c t
Meconium aspiration syndrome (MAS) is a major cause of respiratory insufciency in the term and postterm newborns. There are several pathomechanisms participating in this disorder, particularly the airway
obstruction, surfactant dysfunction, inammation, lung edema, pulmonary vasoconstriction and bronchoconstriction. Inammatory changes resulting from meconium aspiration cause severe impairment of
lung parenchyma and surfactant, and inuence the reactivity of both vascular and airway smooth muscle.
Therefore, anti-inammatory drugs may be of benet in the management of MAS. This article reviews
the pharmacological actions and side effects of various anti-inammatory drugs used up to now in the
experimental models of MAS and in the treatment of newborns with meconium aspiration.
2013 Published by Elsevier B.V.

1. Introduction
Meconium aspiration syndrome (MAS) is a serious disease
occurring in the term and post-term newborns, but may be rarely
seen also in preterm newborns. There are several mechanisms participating in the pathogenesis of MAS. Firstly, aspirated meconium
causes obstruction of airways that may subsequently lead to alveolar atelectasis and to air-trapping. As meconium moves distally,
it inactivates pulmonary surfactant and triggers the development
of inammation, pulmonary edema, vasoconstriction, and bronchoconstriction.
Inammation plays an essential role in the pathogenesis of MAS,
thus various anti-inammatory drugs have been used for therapy.
This article reviews the inammatory changes in MAS as a rationale
for the anti-inammatory treatment and introduces several groups
of anti-inammatory medicaments used to treat MAS, with their
therapeutical actions and side effects.
2. Inammation in MAS
Meconium is a source of pro-inammatory cytokines, such the
tumor necrosis factor (TNF) or interleukines (IL-1, IL-6, IL-8)
(de Beaufort et al., 2003). These substances may injure the lung

This paper is part of a special issue entitled Immunopathology Respiratory

System, guest-edited by Mietek Pokorski.
Corresponding author at: Jessenius Faculty of Medicine, Comenius University,
Mala Hora 4, SK-03601 Martin, Slovakia. Tel.: +421 43 2633 454.
E-mail addresses: mokra@jfmed.uniba.sk (D. Mokra), mokry@jfmed.uniba.sk
(J. Mokry), tonhajzerova@jfmed.uniba.sk (I. Tonhajzerova).
1569-9048/$ see front matter 2013 Published by Elsevier B.V.
http://dx.doi.org/10.1016/j.resp.2013.02.025

tissue directly or indirectly through the cytokines and mediators produced by neutrophils (Soukka et al., 2002), macrophages
(Craig et al., 2005), and epithelial cells. Neutrophils are activated by macrophages and cytokines, which stimulate adhesion
of neutrophils to the endothelium. Meconium also potentiates
chemotactic activity of neutrophils. Within several hours, instillation of meconium causes an accumulation of neutrophils in
the lungs, while their number in the peripheral blood decreases
(Holopainen et al., 2001; Mokry et al., 2006).
Activated neutrophils and macrophages may damage the lungs
by different pathways. Production of pro-inammatory substances
(TNF, interleukins, prostaglandins, and leukotrienes), activation
of complement, activation of coagulation cascade, production of
platelet activating factor (PAF), and of vasoactive substances may
lead to destruction of capillary endothelium and basement membranes. An injury to alveolocapillary membrane results into a leak
of liquid, plasma proteins, and cells into the interstitium and alveolar spaces. Together with other substances, proteolytic enzymes
are released from the neutrophilic granules. Proteases, e.g. elastase, may damage the membranes and surfactant proteins, and
stimulate the synthesis of bioactive substances, which increases
the endothelial permeability. In addition, activated leukocytes
generate reactive nitrogen and oxygen species (RONS) with cytotoxic effects. Peroxidation of unsaturated free fatty acids causes a
loss of functional integrity of membranes and increases capillary
permeability. Oxidation stress nally results in vasoconstriction,
bronchoconstriction, platelet aggregation, accelerated cellular apoptosis (Zagariya et al., 2006), and injury of distant structures, e.g. in
the brain (Aaltonen et al., 2005).
Activated cells produce phospholipase A2 (PLA2 ). Furthermore, meconium itself contains high amounts of pancreatic PLA2 ,

D. Mokra et al. / Respiratory Physiology & Neurobiology 187 (2013) 5257

which may directly or through the stimulation of arachidonic acid

metabolites injure the lung epithelium, endothelium, and surfactant, and may participate in intensied apoptosis (Holopainen
et al., 1999). Arachidonic acid released from membrane lipids
under stimulation of PLA2 acts as a precursor for synthesis of both
cyclooxygenase (COX) and lipooxygenase products, e.g. for thromboxan A2 (TXA2 ) that increases pulmonary vascular resistance
(Soukka et al., 1998), or for leukotrienes that cause bronchoconstriction (Wu et al., 1999), all of which enhances microvascular
permeability in MAS. PLA2 stimulates the production of PAF
which participates in pulmonary hypertension, increased capillary
permeability, bronchoconstriction, and in aggregation and degranulation of neutrophils, macrophages, and platelets (Berdeli et al.,
2004).
In addition, cytokines enhance the expression of inducible NO
synthase (iNOS) (Li et al., 2001; Kytola et al., 2003) and the production of nitric oxide (NO) (Khan et al., 2002a). Excessive amounts
of NO increase the formation of reactive nitrogen species (e.g.
peroxynitrite) and nally amplify the permeability of the alveolocapillary membrane and lung injury. Furthermore, cytokines
elevate endothelin-1 (ET-1), a potent vasoconstrictor stimulating
proliferation of smooth muscle (Kuo and Chen, 1999). Inammation
and release of bronchoactive substances (e.g. leukotrienes, PAF) are
probably responsible for increased airway reactivity in MAS (Mokry
et al., 2006).
3. Anti-inammatory drugs in the treatment of MAS
Regarding the role of inammation in the pathogenesis of
MAS, several anti-inammatory drugs have been administered in
the experimental models of MAS and in the treatment of newborns with meconium aspiration. Pharmacological action of these
medicaments and their effects in MAS are reviewed in the further
subsections.
3.1. Exogenous surfactant
It is known that besides the surface active properties, pulmonary
surfactant protects the lungs from inammation modulating
peroxidation, formation of nitric oxide, PLA2 , arachidonic acid
metabolites, and cytokines (Wright, 2003). Similar effects may be
observed also with exogenous surfactants, particularly those containing surfactant proteins (Mittal and Sanyal, 2009; Goto et al.,
2010). However, considering other favorable effects of surfactant,
its anti-inammatory properties seem to be of minor importance.
3.2. Glucocorticoids
Potent anti-inammatory activity of glucocorticoids (GCs)
results from reducing the migration and activation of neutrophils,
eosinophils, mononuclears, and other cells (endothelial, epithelial) and from modulation of chemotaxia and action of mediators
released from the activated cells. In addition, by stabilization of
cell membranes and by decreased production of pro-inammatory
and vasoactive substances, GCs reduce the microvascular permeability. Furthermore, directly modulating pulmonary vasomotoric
tone, GCs diminish pulmonary vasoconstriction and inhibit brogenesis (Czock et al., 2005).
GCs possess both genomic and non-genomic mechanisms of
action. In the genomic action, GCs penetrating into the cytoplasm interact with the glucocorticoid receptor (GR). The activated
complex moves into the nucleus and binds to a specic nuclear
sequence of DNA (glucocorticoid responsive element, GRE). When
GCGR complex interacts with a negative responsive element
(GRE ), inhibition of transcription factors, including the nuclear

53

factor kappaB (NF-B) and the protein activator (AP-1), attenuates the expression of pro-inammatory cytokines (IL-1, IL-6, IL-8,
and TNF), enzymes (PLA2 , COX-2, iNOS), and other biologically
active substances, such as PAF or ET-1. On the other hand, interaction of GCGR complex with a positive responsive element of DNA
(GRE+ ) increases transcription of lipocortine-1 in leukocytes, which
inhibits the activity of PLA2 , and thereby decreases the production
of arachidonic acid and its metabolites, and of PAF (Czock et al.,
2005).
GCs act also through the nongenomically-mediated mechanisms, which are responsible for their rapid action until the effects
mediated by genomic mechanisms set in. GCs may exert different
effects on various cells, modulating hormone secretion, neuronal
excitability, ion cycling, saccharide metabolism, and other processes within seconds or minutes (Czock et al., 2005; Lee et al.,
2012). Non-genomic effects of GCs are presumably responsible for
rapidly improved respiratory parameters (Mokra et al., 2007a,b),
and for acute cardiovascular changes (Mokra et al., 2008c), which
were observed in animals with MAS shortly after GCs administration.
In in vitro studies, GCs suppressed the meconium-induced
expression of COX-2 and iNOS in macrophages, epithelial and
endothelial cells (Li et al., 2001; Kytola et al., 2003), and the production of NO and TXA2 in epithelial cells (Khan et al., 2002a,b). In
animals with MAS, GCs inhibited expression of PLA2 in the lungs
(Holopainen et al., 1999, 2001). An interruption of the cytokine
cascade and inhibition of chemotaxia by GCs resulted in reduced
neutrophil inux into the lungs, with a simultaneous increase in
the blood leukocyte count (Soukka et al., 1997; Holopainen et al.,
2001; Mokry et al., 2006). Administration of methylprednisolone
(Soukka et al., 1997) and prednisolone (Kirimi et al., 2003) effectively improved the lung functions. Similarly, pretreatment and
early treatment with dexamethasone reduced pulmonary vasoconstriction and improved oxygenation (Holopainen et al., 2001;
Khan et al., 1999). In newborns with MAS, dexamethasone reduced
the number of leukocytes in the tracheal aspirate, decreased the
levels of several cytokines, improved lung functions, and facilitated weaning from the ventilator (Wu et al., 1999; da Costa et al.,
2001).
Taken together, neonates with severe MAS may benet from
systemic administration of GCs. However, the timing of administration is critical for an ideal response, as the changes associated
with meconium aspiration become severe very early on. Comparing
prophylactic and early (1 h after the meconium instillation) dexamethasone administration in piglets with MAS, Holopainen et al.
(2001) found higher effectiveness of the prophylactic treatment
and a weak response when the drug was given 1 h after meconium. Nevertheless, an earlier use of dexamethasone (30 min after
the meconium instillation) signicantly enhanced gas exchange,
reduced ventilatory pressures, decreased the number of neutrophils in the bronchoalveolar lavage uid, reduced edema
formation and oxidative lung injury, and alleviated meconiuminduced airway hyper responsiveness to histamine in rabbits
(Mokry et al., 2006; Mokra et al., 2007a).
The effectiveness of treatment may be increased by repetitive
administration of GCs. Dexamethasone in two doses enhanced gas
exchange and reduced oxygen requirements in piglets with MAS
(Wu et al., 1999). In a rabbit model of MAS, two doses of dexamethasone improved gas exchange and respiratory parameters and
reduced the inammation and oxidation stress more effectively
than a single dose (Mokra et al., 2007a). In newborns with MAS,
dexamethasone given for several days in a dose tapering schedule improved the lung function and facilitated weaning from the
ventilator (da Costa et al., 2001). Thus, it seems that GCs might be
effective in well-established MAS, but repetitive doses should be
used.

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D. Mokra et al. / Respiratory Physiology & Neurobiology 187 (2013) 5257

On the other hand, systemic administration of GCs may be

associated with various adverse effects almost mediated via the
genomic mechanisms, such as increased risk of infection, aggravation of diabetes mellitus, induction of arterial hypertension,
osteoporosis, cataract formation, glaucoma, and growth retardation in children, where the severity of deterioration depends on
the time and dose of a glucocorticoid derivative (Czock et al.,
2005). In our experiments, several acute side effects presumably
mediated by the non-genomic mechanisms were observed, such
as increased blood pressure, decreased heart rate, increased heart
rate variability, and increased incidence of cardiac arrhythmia in
meconium-instilled rabbits already during and immediately after
intravenous administration of dexamethasone, whereas changes in
some cardiovascular variables were evident for several hours after
the treatment delivery (Mokra et al., 2008c).
Nevertheless, occurrence of adverse effects of GCs depends
also on the properties of the individual GCs and on the route of
administration. For example, local administration may enhance the
therapeutic effect and eliminate side effects of systemic GCs. In the
studies by Basu et al. (2007) and Tripathi and Saili (2007), both
nebulized (budecort) and systemic (methylprednisolone) administration of GCs led to comparable results on lung function, duration
of oxygenotherapy, and hospitalization, without an increased incidence of sepsis in newborns with MAS. In the meconium-instilled
rabbits, budesonide administered into the jet of a ventilator during
inpulsion regime of high-frequency jet ventilation (inspiration time
20%) signicantly improved oxygenation and decreased pulmonary
shunting, edema formation, neutrophil count in the lungs and several markers of oxidative injury compared with the non-treated
group (Mokra et al., 2007b), with less cardiovascular side effects
than previously observed in systemic administration of dexamethasone (Mokra et al., 2008c). As the locally administered GCs may
target lung inammation, edema, vaso- and bronchoconstriction
more effectively than those systemically administered, intrapulmonary delivery of GCs might be advantageous particularly in the
diseases with a diffuse injury to the lungs, such as MAS. However,
local instillation may affect the pharyngeal mucosa and may attenuate local immunity in the upper airways (Rizzo and Sol, 2006). In
addition, intratracheally given glucocorticoids may interfere with
the surface activity of pulmonary surfactant and with exogenous
surfactant delivered as a therapy (Zhang et al., 2012). This effect
seems to depend on the concentrations of both glucocorticoid and
surfactant, and on the content of cholesterol in exogenous surfactant, as cholesterol-free preparations (Curosurf and Survanta) may
be more suitable as carriers of glucocorticoids (Zhang et al., 2012).
In addition, adverse effects of GCs may be reduced when combined with medicaments with similar or additive effects, e.g.
with methylxanthines or antioxidants. Both GCs and methylxanthines (such as theophylline) inuence the transcription of
inammatory genes in the cell nucleus, but via different mechanisms. Theophylline may restore the responsiveness of GCs reduced
due to oxidative stress and acute cytokine-mediated inammation (Barnes, 2005). In our experiments, intratracheal budesonide
followed by intravenous low-dose aminophylline reduced lung
edema, intrapulmonary shunts, the number of lung neutrophils,
and improved gas exchange more effectively than aminophylline
(Mokra et al., 2008a). In addition, no signicant cardiovascular effects were observed with the combined treatment, while
aminophylline alone increased the blood pressure and heart rate
(unpublished observation).
3.3. Inhibitors of phosphodiesterase
Phosphodiesterases (PDE), a superfamily of enzymes, degrade
cAMP and cGMP. Each type of cells is able to produce several
subtypes of phosphodiesterases. Thus, their origin is considered

to be the regulatory mechanism of the concentration of cyclic

nucleotides in cells. In the respiratory system and in the pathogenesis of MAS, predominantly PDE3, PDE4, PDE5, and PDE7 isoforms
may be involved due to their pro-inammatory and smooth muscle
contractile activity (Chung, 2006). Therefore, non-selective (such
as methylxantines) and selective inhibitors of PDE could be potentially used in MAS therapy.
3.3.1. Non-selective PDE inhibitors (methylxanthine derivatives)
Methylxanthines appear in several plants as natural alkaloids.
The best known of them are caffeine, with the predominant central
effects (stimulation of breathing and psychostimulation), and theophylline and theobromine, with the stronger peripheral effects,
such as bronchodilation and cardiostimulation. Because of these
properties, methylxanthines, particularly theophylline, are widely
used in the treatment of asthma and chronic obstructive pulmonary
disease (Barnes, 2005).
The mechanisms of methylxanthines action are complex
and still not fully elucidated. As non-selective PDE inhibitors,
methylxanthines increase concentrations of cAMP and cGMP
in the cells leading to bronchodilation and vasodilation. In
addition, methylxanthines decrease concentrations of calcium,
acetylcholine, and monoamines and modulate release and action
of various mediators of inammation and bronchoconstriction,
including prostaglandinds. Due to similar chemical structure,
methylxanthines compete with other purinergic substances for
a binding site on the receptors and work as the antagonists
of adenosine receptors. Since adenosine, an endogenous purine
nucleoside, evokes bronchoconstriction and chronic inammation
in the airways (through release of histamine and leukotrienes) and
modulates the action of white blood cells, competitive inhibitors
of adenosine receptors, including methylxanthines, work as bronchodilators. In addition, methylxanthines facilitate activity of
mast cells and basophils, enhance production of surfactant and
mucociliary clearance, and ameliorate scavenging of ROS (Barnes,
2005).
The action of theophylline depends on its plasma concentration.
A therapeutical theophylline plasma concentrations (1020 g/ml)
causes bronchodilation and vasodilation, decreases permeability
of the vascular wall, and has several anti-inammatory effects,
such as increased release of IL-10, inhibition of NF-B, and uptake of ROS. These effects are mediated largely by PDE inhibition
and adenosine antagonism. Toxic plasma concentrations (more
than 20 g/ml) may be associated with nausea, headache, and
adverse effects on the gastrointestinal (mediated via PDE inhibition) and cardiovascular systems (mediated predominantly via
adenosine A1 receptor antagonism). On the other hand, low plasma
concentrations (510 g/ml) may show anti-inammatory and
immunomodulatory action, which is not mediated by either PDE
inhibition or adenosine receptor antagonism, but by direct activation of histone deacetylase activity leading to reduced transcription
of inammatory genes (Barnes, 2005). The different actions of low
and high doses of theophylline were previously shown also in the
treatment of MAS in rabbits (Mokra et al., 2008b). High-dose aminophylline (a derivative of theophylline) more effectively reduced
shunting and requirements for articial ventilation, enhanced gas
exchange, decreased lung edema formation, the number of neutrophils in BAL, lipid oxidation, and tracheal reactivity to histamine.
However, low-dose aminophylline more effectively reduced the
lung reactivity to histamine and protein oxidation (Mokra et al.,
2008b).
Properties of individual methylxanthine derivatives may differ according to their ability to inuence the specic PDE families
and to the extent of an interaction with adenosine receptors. For
example, pentoxifylline inhibited degranulation of polymorphonuclears and decreased the production of TNF in in vitro incubation

D. Mokra et al. / Respiratory Physiology & Neurobiology 187 (2013) 5257

with meconium (Tegtmeyer et al., 2002). In piglets with MAS,

pentoxifylline prevented local ventilatory perturbations and an
increase in the macrophage count in BAL uid, and TNF and protein concentrations in the lungs, but had no signicant effect on
the lung neutrophil accumulation (Korhonen et al., 2004). Aminophylline, a mixture of theophylline and ethylenediamine which
enhances water-solubility of theophylline, improved gas exchange,
reduced lung edema and the number of neutrophils in the lungs,
and decreased oxidative lung injury and airway hyperreactivity to
histamine in a rabbit model of MAS (Mokra et al., 2008b).
Systemic administration of methylxanthines may be accompanied by undesirable side effects, due usually to overdosing with
plasma levels higher than 1520 g/ml. The most frequent side
effects of methylxanthines are headache, agitation, gastrointestinal signs such as nausea, vomiting, gastric pain, gastroesophageal
reux or increased secretion of the gastric HCl, and increased
diuresis. At high plasma concentrations, cardiovascular side effects,
such as arterial hypertension, tachycardia, or increased generation of arrhythmias may occur. The occurrence of side effects is
related to various mechanisms of action of methylxanthines. For
example, central nervous effects and hyper secretion of gastric
juice may be attributed to antagonism of adenosine A1 receptors,
while nausea and headache are possibly caused by inuencing
phosphodiesterases, particularly PDE4 (Barnes, 2005). In our experiments, intravenous aminophylline at both low (1 mg/kg) and high
(2 mg/kg) doses was associated with an acute increase in blood
pressure, heart rate, and heart rate variability, and more frequent
cardiac arrhytmia during and within several hours after injection in the meconium-instilled rabbits (unpublished observation).
Side effects of methylxanthine derivatives may be eliminated by
decreasing the dose, or by their suitable combination with other
drugs (e.g. glucocorticoids).
3.3.2. Selective PDE inhibitors
Systemic side effects might be reduced also by the use of selective PDE inhibitors, targeting the therapeutical effect at one subtype
of phosphodiesterase (usually specic to one type of cell or tissue). In meconium-induced inammation and pulmonary vasoand bronchoconstriction, the activities of PDE3, PDE4, PDE5, and
PDE7 may be enhanced (Chung, 2006). In piglets with MAS, PDE5
inhibitor sildenal reversed an increase in pulmonary vascular
resistance within 1 h of the treatment, without affecting the systemic hemodynamics (Shekerdemian et al., 2002). Milrinone, a
selective PDE3 inhibitor improved oxygenation and survival of
neonates with MAS (Bassler et al., 2006). In our experiments, the
PDE3 inhibitor olprinone enhanced pulmonary functions, reduced
lung edema, and diminished inammation and oxidative lung
injury in the meconium-instilled rabbits (Mokra et al., 2012). The
PDE3 and PDE5 inhibitors have been already tested, but there are no
studies on the use of PDE4 inhibitors in MAS. As the PDE4 inhibitors
have been proven benecial in asthma (Chung, 2006), their possible
benets in MAS need to be evaluated.
Nevertheless, possible side effects of selective PDE inhibitors
should be carefully considered. As previously noticed, cardiovascular side effects may be comparable in both selective and
non-selective PDE inhibitors (Barnes, 2005). This was conrmed
also in our recent study, where intravenous administration of both
aminophylline (non-selective PDE inhibitor) and olprinone (PDE3
inhibitor) caused rapid, but short-term, increase in blood pressure
and heart rate of comparable severity (unpublished observation).
3.4. Interactions with reninangiotensinaldosterone (RAA)
system
As the meconium aspiration increases apoptosis of airway
and alveolar epithelial cells, pharmacologic inhibition through

55

the use of apoptosis blockers might be of benet. Apoptosis of

lung cells is induced by angiotensin II, a product of angiotensinconverting enzyme (ACE). Besides local regulation of apoptosis,
angiotensin II is suggested to affect the neutrophil accumulation
in tissue (Zagariya et al., 2006). Several investigators used captopril or other ACE inhibitors to suppress the apoptotic process
and to reduce inammation in the meconium-injured lungs. In
newborn rabbits, pretreatment with captopril before meconium
instillation decreased the levels of ET-1 and pro-inammatory
cytokines and reduced apoptosis (Zagariya et al., 2006). Pretreatment with saralasin, a competitive inhibitor of angiotensin II,
prevented an increase in lung tissue myeloperoxidase activity,
endothelial monocyte-activating polypeptide, and lung epithelial
apoptosis in rats with MAS (Lukkarinen et al., 2004). Therefore,
inuencing the action of angiotensin II via inhibition of ACE or
blockade of angiotensin receptors seems to be another promising
approach in the treatment of MAS. The adverse effects of captopril
are similar to other ACE inhibitors, such as cough, rash, and taste
disturbances (metallic or loss of taste).
3.5. Antioxidants
Since the products of lipid and protein peroxidation deteriorate
the lung tissue in MAS, antioxidant substances, such as superoxide
dismutase or N-aetylcysteine, may be also of benet.
Superoxide dismutase enzymatically catalyze dismutation of
superoxide into oxygen and hydrogen peroxide, and thus, it works
in antioxidant defense in nearly all cells exposed to oxygen. At the
moment, no serious adverse effects have been described in the use
of superoxide dismutase. Intratracheal administration of recombinant human superoxide dismutase decreased myeloperoxidase
activity, NO and 8-isoprostane levels and lung injury score in the
meconium-instilled rats (Lu et al., 2005), increased oxygenation,
and reduced vasoconstriction and oxidative injury in newborn
lambs with persistent pulmonary hypertension (Lakshminrusimha
et al., 2006).
N-acetylcysteine (NAC) contains SH group, and thereby scavenges hydrogen peroxide, hydroxol radicals, and hypochlorous
acid. NAC is easily deacetylated to cysteine, a precursor of glutathione synthesis in cells, and thus stimulates the glutathione
system. In addition, NAC reduces cellular production of proinammatory mediators (e.g. TNF-alpha and IL-1). Besides potent
antioxidant and anti-inammatory action, NAC reduces viscosity
and elasticity of mucus because of its ability to reduce disulphide bonds (Gillissen and Nowak, 1998). It may promote the
expression of surfactant protein (SP)-A and improve its surface
activity (Fu et al., 2000). Thanks to low bioavailability, NAC is virtually non-toxic and is rarely associated with any adverse effects,
such as anaphylaxis, tachycardia and hypotension, or reduced
chemotaxis and increased cytotoxicity to polymorphonuclears.
These effects are limited to very high concentrations (Gillissen
and Nowak, 1998). In our recent experiments, intravenous
NAC enhanced gas exchange and effectively reduced inammation and oxidation stress in the meconium-instilled rabbits,
with negligible acute cardiovascular side effects (unpublished
observation).
3.6. Inhibitors of cyclooxygenase
As mentioned in the previous subsection, arachidonic acid is
metabolized via cyclooxygenase and lipooxygenase to various substances including prostaglandins and leukotrienes, which exhibit
potent pro-inammatory and vasoactive effects. Since constitutive COX-1 is expressed in most tissues and organs, production
of inducible COX-2 is associated with inammation and edema.
In clinical practice, inhibitors of cyclooxygenase (COX) are widely

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D. Mokra et al. / Respiratory Physiology & Neurobiology 187 (2013) 5257

used for their analgesic, antipyretic, and anti-inammatory effects.

According to their selectivity, COX inhibitors are divided to COX-2
selective and COX non-selective (such a indomethacin or acetylsalicylic acid). Indomethacin reduces the production of prostaglandins
responsible for inammation and edema formation. However, similarly to other non-selective COX inhibitors it may induce peptic
ulcers, worsen psychiatric disorders or to cause hyperkalemia and
hypernatremia. In MAS, indomethacin inhibited release of TXA2
from epithelial cells (Khan et al., 2002b), but did not inuence the
expression of COX-2 or iNOS in the lungs (Kytola et al., 2003). On
the other hand, pretreatment with acetylsalicylic acid prevented
the initial pulmonary hypertensive response and reduced release
of prostanoids in piglets with meconium aspiration (Soukka et al.,
1998). However, these results are insufcient to recommend COX
inhibitors for MAS treatment, although their adverse effect prole (especially of COX-2 selective inhibitors) is more advantageous
compared with that in GCs.
3.7. Endothelin antagonists
Considering the role of ET-1 in the meconium-induced pulmonary vasoconstriction (Kuo and Chen, 1999), administration
of endothelin receptor antagonists may partially improve the
status of meconium-injured newborns. In hypoxia-induced pulmonary hypertension in rats, oral pretreatment with bosentan,
an antagonist of ETA and ETB receptors attenuated pulmonary
hypertension, right heart hypertrophy, and remodeling of small
pulmonary arteries (Chen et al., 1995). Similarly, intravenous
administration of tezosentan, another combined antagonist of
both ETA and ETB receptors lowered pulmonary vascular resistance, and enhanced survival in piglets with MAS (Geiger et al.,
2006).
3.8. Prostacyclin analogs
Prostacyclin (PGI2 ) as a potent pulmonary vasodilator may be
benecial, particularly in the hypoxic conditions. Inhaled PGI2 may
be well combined with other drugs. For example, inhalation of PGI2
showed a synergistic effect with the PDE inhibitors in experimental pulmonary hypertension (Schermuly et al., 2001). In a model
of MAS, iloprost, a synthetic analog of PGI2 was combined with
tezosentan, a dual endothelin A and B receptor blocker (Geiger et al.,
2008). However, side effects of the two later groups of medicaments
should be evaluated in the models of MAS before recommendations
for clinicians can be made.
4. Concluding remarks
Advances in our understanding the pathogenesis of MAS
lead to the development of novel approaches focusing on pulmonary inammation and oxidative injury. A wide variety of
anti-inammatory drugs acting on different levels of inammatory
cascade may alone, or in combination with exogenous surfactant
and vasodilators, improve clinical status and survival of newborns
with MAS. Nevertheless, effects of anti-inammatory drugs, including their side effects in the meconium-induced lung injury should
be tested thoroughly in the experimental and clinical conditions
before their clinical use may be recommended.
Acknowledgments
Supported by Project Center of Excellence for Perinatology
Research No. 26220120036, co-nanced from EU sources; Grant
APVV-0435-11, and Grant VEGA Nos. 1/0057/11 and 1/0030/11.

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