TRANSATLANTIC AIRWAY CONFERENCE

Oxidative Stress in Airway Diseases

Fernando Holguin1
1
Asthma Institute, Division of Pulmonary, Allergy and Critical Care, University of Pittsburgh, Pittsburgh, Pennsylvania

Abstract diminish response to steroids. Although oxidative stress has been

Airway oxidative stress is broadly defined as an imbalance between
prooxidative and antioxidative processes in the airway. Given its
direct exposure to the environment, the lung has several mechanisms
to prevent an excessive degree of oxidative stress. Both enzymatic and
nonenzymatic systems can buffer a wide range of reactive oxidative
species and other compounds with oxidative potential. In diseases
like asthma and chronic obstructive lung disease, airway oxidative
stress can occur from a number of sources, including greater exposure
to environmental prooxidants, airway infiltration of inflammatory
cells, metabolic deregulation, and reduced levels of antioxidants.
Airway oxidative stress has been associated with worse disease
severity, reduced lung function, and epigenetic changes that can
linked to a wide range of adverse biological effects, it has also been
associated with adaptive responses and with resolution of
inflammation. Therefore, more than being an imbalance with
a predictable threshold after which disease or injury ensues, oxidative
stress is a dynamic and continuous process. This might explain why
supplementing antioxidants has largely failed to improve diseases
such as asthma and chronic obstructive pulmonary disease. However,
the therapeutic potential of antioxidants could be greatly improved
by taking an approach that considers individual and environmental
risk factors, instead of treating oxidative airway stress broadly.
Keywords: oxidative stress; asthma; chronic obstructive
pulmonary disease

(Received in original form May 10, 2013; accepted in final form July 3, 2013 )
Correspondence and requests for reprints should be addressed to Fernando Holguin, M.D., M.P.H., Division of Pediatric Pulmonology, 3705 Fifth Avenue,
Pittsburgh, PA 15213. E-mail: holguinf@upmc.edu
Ann Am Thorac Soc Vol 10, Supplement, pp S150–S157, Dec 2013
Copyright © 2013 by the American Thoracic Society
DOI: 10.1513/AnnalsATS.201305-116AW
Internet address: www.atsjournals.org

Oxidative Stress:
A Continuum Spectrum
Oxidative stress is defined as an imbalance
between increased oxidative sources and
reduced or defective antioxidant
mechanisms. Although conceptually this is
adequate, it offers poor insight into how
dynamic and highly complicated this
process really is. This definition lends itself
to the notion that a particular balance does
in fact exist and that deviations from this
point can affect homeostasis and potentially
cause or worsen disease. As such, many
research projects have attempted to restore
this “balance” by providing antioxidants,
which for the most part have ended with
disappointing results. This lack of
therapeutic effectiveness probably stems
from several factors, including our inability
to distinguish when, in a given disease
process, oxidative stress is a disease driver
or merely an epiphenomenon; even worse,
treating with antioxidants may prevent
some lower degree of oxidative stress from
occurring, which could play an important
role in controlling inflammation and
cellular adaptive responses. Nowhere are
these complexities of oxidative stress more
evident than in the airways, which are
constantly exposed externally to oxidative
compounds and internally to recruited and
activated inflammatory cells. Given the lack
of adequate standardization in the many
biomarkers used to define airway oxidative
stress, it is difficult to fully gauge their
overall contribution to the development or
progression of airway diseases. Therefore,
instead of presenting a summary of
oxidative stress studies, this review
proposes a conceptual framework that
captures the dynamic interplay among the
many oxidative sources and the antioxidant
mechanisms; how these balancing forces
exist in a continuum spectrum that can
vary in the same individual across time
and exposures, between persons, and
between different types of airway diseases.
This framework, shown in Figure 1,
encompasses the major sources of airway
oxidative stress and some of the major
determinants of antioxidant mechanisms,
and Table 1 highlights the heterogeneity
in oxidative stress between asthma and
chronic obstructive pulmonary disease
(COPD). By no means is this intended to be
a comprehensive review of the
pathophysiology of airway oxidative stress.
Sources of Oxidative Stress,
Broadly Understood
Perhaps one of the best understood sources
for increased airway oxidative stress is
the recruitment of inflammatory cells into
the airway after exposure to trigger factors;
these activated cells can generate anion

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Figure 1. Conceptual overview of airway oxidative stress sources and mechanisms in asthma.
The figure captures the conceptual framework related to airway oxidative mechanisms throughout the
paper. ADMA = asymmetric dimethylarginine; GSH = reduced glutathione; GSSG = oxidized
glutathione; HDAC2 = histone deacetylase–2; NADPH = nicotinamide adenine dinucleotide
phosphate; NF-kB = nuclear factor kB; Nrf2 = nuclear factor (erythroid-derived 2)-like 2; PM2.5 =
particulate matter , 2.5 mm; SOD = superoxide dismutase.
superoxide (O2.2) through reduced
nicotinamide adenine dinucleotide
phosphate (NADPH) oxidase pathway.
Mitochondrial dysfunction in airway
epithelial cells, which occurs in response to
mechanical and environmental stimuli, can
also contribute to the formation of anion
superoxide and airway oxidative stress (1).
Anion superoxide is rapidly dismutated to
hydrogen peroxide (H2O2) by superoxide
dismutase enzymes (SOD). From here,
H2O2 can react with transition metals
to generate hydroxyl radicals (dOH) or,
through the action of eosinophil or
neutrophil peroxidases, interact with
halides to respectively form hypobromous
acid (HOBr) or hypochlorous acid (HOCl)
(2, 3). In addition to formation of these
hypohalides, increased levels of nitric oxide
(NO) are formed by the up-regulation
of the epithelial inducible nitric oxide
synthase (iNOS). In the presence of reactive
oxygen species (ROS), NO rapidly forms
reactive nitrogen species (RNS), such
as peroxynitrite (4). There has been
considerable progress in understanding the
downstream effects and clinical correlates
related to these compounds. Hypohalides
can brominate, chlorinate, or nitrate
tyrosine residues affecting protein structure
and function. Chloro-, bromo-, and
nitrotyrosine compounds have been
identified in a number of disease processes.
Holguin: Oxidative Stress in Airway Diseases
In asthma, these compounds have been
shown to amplify the oxidative and
inflammatory airway process and have been
associated with poor control (5–8). For
example, using proteomic analysis,
researchers have experimentally identified
and confirmed in humans that oxidative
modification by nitro- and chlorotyrosine
reduces catalase activity, thereby allowing
more H2O2 to accumulate and further
propagate oxidative reactions (9). This
finding may also partly explain why,
when compared with normal subjects,
subjects with asthma have greater systemic
and airway increased oxidative stress, which
is associated with worse asthma severity
(10, 11).
As with asthma, subjects with COPD
have increased airway oxidative stress and
nitrosative stress (12). Patients with COPD
have a greater degree of immunostaining
for nitrotyrosine in the airway epithelium
and inflammatory cells in sputum (13).
Given the predominant neutrophilic
airway inflammation, it is possible that
the nitration of tyrosine residues results
predominantly from myeloperoxidase
(MPO)-induced oxidation of NO22 by
H2O2 or through the formation of
RNS from the interaction of NO and
ROS (13). However, unlike asthma, there
are considerably fewer data linking
nitrotyrosine measurements with
increase disease severity or risk of
exacerbation.
Environmental exposures as
contributors to airway oxidative stress. The
lung is exposed to several thousand liters of
air per day. Every breath carries with it
a very large number of compounds with
oxidative potential, including air pollution,
pollen, and particulate matter. Although
larger particles are efficiently cleared by the
nose and upper airways, fine particles
can easily access the lower airways and
promote increased airway oxidation and
inflammation (14, 15). Air pollutants can
cause oxidative stress through a variety of
mechanisms, such as direct oxidative injury
by gas phase pollutants like ozone or
nitrogen oxides, or by promoting airway
inflammation in the airways (16, 17). For
example, fine particulate matter (PM2.5,
diameter , 2.5 mm) can react with the
respiratory epithelium and promote nuclear
translocation of transcription factors with
subsequent release of inflammatory
cytokines (18). The airway oxidative stress
associated with air pollutants is evident
even after short-term exposures,
particularly among subjects with asthma or
other airway diseases. In a study of
otherwise healthy subjects with controlled
asthma, those taking a 2-hour planned walk
through Oxford Street in London (more
highly exposed to diesel emissions) had
transient decrements in FEV1 and greater
levels of MPO, IL-8, and neutrophil count
in sputum, when compared with those of
similar severity walking through Hyde Park
(19). Epidemiological studies have also
shown close temporal and exposure
associations in children between sulfur
dioxide emissions with increased
thiobarbituric acid–reactive substances
(TBARS) and between fine particulate
matter, exhaled NO, and sputum IL-8
levels (20, 21). Other nonpollutant
environmental sources can contribute to
airway oxidative stress. One interesting
example is pollen and subpollen grains,
which have been shown to have intrinsic
NADPH oxidases and to induce
mitochondrial dysfunction in airway
epithelial cells; in addition to releasing
ROS in the airway epithelium, these
particles can activate dendritic cells (DC)
(22, 23). Depending on the degree of
pollen-induced oxidative stress, the DC
response may range from adaptive (at
lower concentration) to proinflammatory
(at higher concentrations). This dual
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Table 1. Similarities and differences in airway oxidative stress sources and antioxidant allergic airway inflammation. In fact,
mechanisms between asthma and COPD rather paradoxically, among subjects with
asthma, increasing body mass index (BMI)
Asthma COPD has been associated with fewer airway
eosinophils and lower exhaled NO levels
Airway Oxidative Sources (33, 34). Some studies have shown that with
Inflammatory airway cells Inflammatory airway cells increasing BMI, there are greater levels
Predominantly eosinophilic (eosinophil Predominantly neutrophilic of airway oxidative stress biomarkers
peroxidase, bromo- and nitrotyrosine (myeloperoxidase, nitro- and that are also associated with reduced
compounds) chlorotyrosine compounds)
Mitochondrial dysfunction in airway Mitochondrial dysfunction in airway corticosteroid response in vitro (35, 36).
epithelial cells epithelial cells Airway oxidative stress in obese patients
Air pollution (ozone, PM, NO2) Air pollution (ozone, PM, NO2) with asthma may be explained by the
Pollen, subpollen particles Pollen, subpollen particles enhanced inflammatory response
Tobacco (1)* Tobacco (111)
Biomass smoke exposure Biomass smoke exposure
associated with leptin. Experimentally,
Metabolic dysregulation in obesity Airway leptin leptin increases the number of
(higher airway leptin, higher ADMA, Oxidative stress–mediated dysfunction inflammatory cells and cytokines in the
lower L-arginine), high-fat meals in HDAC airways (37). In humans, obese subjects
(transient increase in neutrophilic with asthma have the greatest levels of
airway inflammation)
airway leptin and have been shown to
Antioxidant Airway Mechanisms
release proinflammatory cytokines from
Higher GSH at baseline; may be lower Higher GSH at baseline; lower GSH levels activated alveolar macrophages (38, 39).
during exacerbation or with increased with exacerbations; tobacco depletes Another source of oxidative stress may be
severity GSH by forming aldehyde derivatives. the formation of hypochlorous acid from
Reduced SOD and catalase activity Higher levels of extracellular SOD in sputum; MPO in the setting of airway neutrophilia,
greater bronchial epithelium expression
of Mn-SOD which has been described in association
Lower levels of nonenzymatic antioxidants, Variable results in nonpulmonary, systemic with obesity and to occur after a high-fat
associated with lower lung function and indices of SOD and catalase meal diet (40, 41). Yet another more
respiratory symptoms recently proposed source for airway
Lipoxin and other electrophilic fatty acids Lower levels of antioxidants associated
play a role in the resolution of airway with lower lung function and respiratory
oxidative stress in obesity is related to the
inflammation symptoms generation of anion superoxide from airway
iNOS. During NOS uncoupling, this
Definition of abbreviations: ADMA = asymmetric dimethyl arginine; GSH = glutathione; HDAC = enzyme produces anion superoxide instead
histone deacetylase; Mn-SOD = manganese superoxide dismutase; NO2 = nitrogen dioxide; PM = of NO, with the dual effect of contributing
particulate matter; SOD = superoxide dismutase.
*Plus signs represent more or less intensity of tobacco exposure playing a role in airway oxidative to oxidative stress while reducing NO
stress. bioavailability (42). Uncoupling has been
shown to occur when there is less enzyme
substrate (L-arginine) and/or when the
response in DC to oxidative stress may lead peroxides, peroxynitrate, and NO. Tar levels of endogenous NOS inhibitors are
to different T-cell phenotypes; depending phase compounds include semiquinone, increased. Asymmetric dimethyl arginine
on when the DC-naive T-cell interaction dOH, and H O radicals. Active smokers
2 2 (ADMA) is derived from the post-
occurs, it may explain why diesel have greater levels of airway and systemic translational methylation of L-arginine and
exhaust particle–mediated oxidative stress biomarkers of oxidative stress (28). These is one of three NOS inhibitors that can
has been shown to be an adjuvant toward biomarkers are increased during COPD uncouple all NOS isoforms (43). Subjects
allergic sensitization (24). Thus, air exacerbations and are associated with with asthma, particularly those with more
pollution–mediated oxidative stress may bronchitic symptoms, air trapping, and loss severe disease, have been shown to have
not only increase the risk of developing of lung function (29, 30). Biomass exposure lower L-arginine levels (44). In addition,
allergic airway diseases (25) but also is a major public health burden in obesity and the metabolic syndrome have been
potentially contribute to other well-known developing countries and one that is also associated with greater ADMA levels (45).
long-term health effects of air pollution, shown to cause systemic and airway Cross-sectionally, plasma L-arginine/
such as reduced lung growth, steeper lung oxidative stress that may play an important ADMA is inversely related to BMI in
function decline, and reduced response to role in the development of biomass-related subjects with asthma, and lower ratios have
asthma medications (26, 27). obstructive lung disease and bronchitis been linked with increased frequency of
Both active and passive tobacco smoke (31, 32). respiratory symptoms (46). Furthermore,
constitute one of the most significant Metabolic dysregulation as a source the L-arginine/ADMA balance may
exposures to airway oxidative stress sources of airway oxidative stress. There is growing potentially determine why BMI is inversely
in humans. It is estimated that a single puff evidence that obesity is a significant associated with exhaled NO. ADMA has
contains 1014 oxygen radicals, which exist comorbidity that can worsen asthma been found to be higher in the airways of
in gas and tar phases. Gas phase radicals severity and reduce control by mechanisms subjects with asthma and to be inversely
include, among many other ROS, epoxides, that are not determined by increased related to exhaled NO. In murine models

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of airway sensitization, pretreatment of
animals with ADMA can augment the
airway inflammatory response (42).
Therefore, based on these studies, the
L-arginine/ADMA balance could be an
important determinant of airway oxidative
stress and reduced NO bioavailability. The
clinical relevance of this pathway could
be potentially determined in further studies
by supplementing either L-arginine or
L-citrulline to obese subjects with asthma,
which can block NOS uncoupling and
reduce airway oxidative stress (47). This
supplementation would be particularly
beneficial for those with asthma onset after
the age of 12 years, for whom this pathway
seems to be more relevant (46).
Antioxidants mechanisms in the lung,
broadly understood. The lung is equipped
with enzymatic (SOD, catalase, glutathione
peroxidase) and nonenzymatic antioxidant
systems (ceruloplasmin, ferritin, ascorbic
acid, uric acid, thionine, and carotene),
which allow the lung to function while
constantly buffering a wide range of
environmental oxidants. Having inadequate
antioxidant levels or mechanisms is
a hallmark of airway oxidative stress that is
well established and the subject of excellent
reviews (48–50). The goal of this section
is therefore not to review each pathway
but rather to discuss these antioxidants as
a dynamic component of oxidative stress
with clinical and redox signaling
repercussions.
Glutathione (GSH) is a tripeptide
thiol concentrated in the alveolar
epithelial lining fluid that reduces organic
hydroperoxides and protects against airway
lipid peroxidation. During oxidative
reactions, GSH is converted to glutathione
disulfide or GSSG, which under normal
circumstances is mostly in the form of GSH,
and less than 5% is GSSG (51). Compared
with healthy control subjects, adults
with asthma have higher GSH airway
concentrations, which may reflect an
adaptive response to increased baseline
production of ROS (52). However, children
with severe symptomatic asthma have been
shown to have significantly lower airway
GSH levels and a greater proportion of
GSSG, when compared with subjects
with mild to moderate asthma or healthy
control subjects (53). These children
also had the greatest airway levels of H2O2,
malondialdehyde, and 8-isoprostanes,
which correlated with the degree of
oxidized glutathione, suggesting that
Holguin: Oxidative Stress in Airway Diseases
greater oxidative burden in subjects with
severe asthma leads to a more oxidized
thiol redox potential. Yet, interestingly,
a reduced airway GSH/GSSG ratio is not
only a biomarker of oxidative stress but also
may propagate inflammation, skew the
inflammatory response toward a Th2
phenotype, and impair redox signaling.
Indeed, it has been shown that among
children with severe asthma with
impaired thiol redox balance, there is
a corresponding increased expression of
Nrf2 (nuclear factor [erythroid-derived 2]-
like 2), yet this is was highly dysfunctional
as it did not increase some of the
antioxidant response elements (ARE),
including key enzymes involved in
glutathione synthesis and conjugation (54).
A significant imbalance in the airway
thiol metabolism has also been described
for patients with COPD, which may
be associated with downstream redox
transcription changes and proinflammatory
events (55). Similar to subjects with asthma,
those with COPD have higher airway
GSH levels; however, these levels can be
reduced by active smoking and during
COPD exacerbations (30). Reduced GSH
levels in acute exacerbations may reflect
an insufficient response to oxidative stress
in the form of reduced g-glutamyl cysteine
synthetase activity or might result from
direct depletion by an overwhelming
oxidative burden from ROS released by
activated airway neutrophils. In addition,
tobacco smoke may deplete GSH by
forming glutathione aldehyde derivatives,
which cannot be converted to GSSG (56).
Regardless of the underlying mechanisms,
a thiol airway redox imbalance in COPD
causes an impaired antioxidant response,
allowing ROS and RNS to produce redox
transcription changes that further
propagate inflammation and worsen
oxidative stress. These changes may partly
occur through nuclear factor (NF)-kB
activation and subsequent release of
proinflammatory cytokines. Also,
inhibition of histone deacetylase-2
(HDCA2) can secondarily reduce Nrf2
activity, thereby further impairing the
antioxidant response (57).
SOD and catalase are also vulnerable
targets to the downstream effects of
increased airway nitrosative and oxidative
stress, which can cause enzymatic
modification resulting in loss of activity.
Oxidation and nitration of Mn-SOD
is present in the asthmatic airway and
correlates with disease severity (58). Also, in
subjects with asthma, lower serum SOD
activity is significantly related to the degree
of airflow obstruction and is inversely
associated with 3-bromotyrosine levels (59).
The activity of catalase, a major H2O2
scavenger, is also reduced in asthma.
Compared with healthy control subjects,
subjects with asthma have reduced catalase
activity in the bronchoalveolar lavage. The
recovered catalase from the airways of
subjects with asthma has increased markers
of protein oxidation, including
nitrotyrosine and chlorination and
oxidation of sulfhydryls, linking oxidative
modification to reduced activity in vivo (9).
Although oxidative modification of SOD
or catalase has not been described to the
same extent in COPD, several studies have
shown that this condition is associated with
changes in the expression and levels of
these enzymes. Compared with healthy
control subjects, extracellular SOD is
increased in the sputum of patients with
COPD, with the highest concentrations
seen among those who are also active
smokers (60). The expression of Mn-SOD
has also been shown to be higher in the
central bronchial epithelium of smokers
with COPD and in the alveolar epithelium
of smokers without or with COPD,
when compared with nonsmokers (61).
Using plasma levels and erythrocyte
concentrations as indices of systemic
oxidative stress, the results are variable,
with some studies showing increased or
decreased levels of SOD and catalase
(62). These discrepancies may be explained
by differences in smoking behavior among
subjects.
Nonenzymatic antioxidants. In
population studies, plasma antioxidant
levels have been associated with lung
function even after adjusting for smoking
and other potential confounders. A change
in 1 SD in the serum levels of either
b-carotene or vitamin C or vitamin E or
selenium is independently associated with
changes in FEV1 ranging from 23 to 49 ml,
yet when considering the joint effect of
these antioxidants, 1 SD is associated with
as much as 94 ml; this amount of lung
volume is roughly equivalent to the
difference in FEV1 between people 4 years
apart (63). These epidemiological data
provide a convincing argument that some
antioxidants are critical to preventing
airway obstruction. Compared with healthy
control subjects, patients with asthma have
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lower plasma levels of carotenes, ascorbic
acid, and vitamin E (64). Reduced ascorbic
acid levels have been associated with
increased respiratory symptoms, higher
odds of being diagnosed with asthma, and
diminished lung function, whereas lower
plasma carotene levels have also been
associated with higher odds for asthma
diagnosis (65, 66). Reduced plasma
antioxidant levels in subjects with asthma
may be secondary to greater airway and
systemic oxidative burden known to occur
in these patients. Similarly, COPD is
characterized by low plasma antioxidant
levels. Having reduced levels of vitamin
C and b-carotene is associated with
bronchitic symptoms and lower FEV1 and
FVC in subjects with chronic airflow
obstruction, with steeper associations noted
among active smokers (66, 67).
Oxidative Stress: A Role for
Resolution of Inflammation
It is commonly misunderstood that in
oxidative stress, oxidation reactions are
“the bad element” or the injurious
processes that propagate inflammation and
promote injury, whereas lack of adequate
antioxidants is the loss of the “good
element” that needs to be restored to
return things to a certain physiologic
homeostasis. Yet, failure of antioxidant
supplementation to successfully improve
many diseases provides convincing
evidence that the oxidative stress imbalance
is a complex phenomenon. Oxidative
stress, as mentioned earlier, is rather
a continuous process in which oxidative
reactions play a role in mitigating
inflammation and in adaptive cellular
responses. One of these oxidative reactions
is the lipid products generated by the
interaction of RNS/ROS with unsaturated
fatty acids to form nitrated fatty acids or
lipid hydroperoxides. Nitrated fatty acids
are nonenzymatically produced by the
interaction of unsaturated fatty acids with
secondary nitrogen oxidation products,
such as nitrogen dioxide, nitrite, and
peroxynitrate (68). The addition of a nitro
group to a double bond at the carbon chain
of an unsaturated fatty acid leads to an
alkenyl nitro-configuration providing
electrophilic reactivity. During conditions
of higher oxygen levels, nonenzymatic
oxidation reactions predominate, forming
lipid hydroperoxides that are also potent
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electrophiles. Both nitroalkenes and
hydroperoxides can react with other
nucleophiles, such as Cys or His residues,
by forming Michael adducts (68).
These reactions produce reversible
posttranslational modification in signaling
proteins, such as the peroxisome
proliferated activated receptors (PPAR),
and the keap1/Nrf2 pathways (68, 69). Both
nitro oleic and nitro linolenic acids are
examples of these nitrated fatty acids that
have been shown to be endogenous PPARg
ligands and to inhibit proinflammatory
cytokine production (69). These
nitroalkenes have also been shown to
induce expression of the hemeoxygenase-1
(HO-1) gene, which is part of the
antioxidant response elements targeted
by Nrf2 and is known to provide
cytoprotection against oxidative lung injury
(70, 71). In addition to induction of ARE,
nitrated fatty acids interact with the
p65 subunit if NF-kB, preventing its
nuclear translocation and release of
proinflammatory cytokines (72). Other
forms of electrophilic fatty acids that share
similar pharmacological properties are
formed enzymatically. Lipoxins are formed
in mucosal surfaces by the interaction
of leukocyte 5-lypoxygenase and epithelial
15-lipoxygenease (73). Unlike other
arachidonic acid derivatives, lipoxins are
protective against bronchial constriction
and reduce airway inflammation (73).
Cycloxygenase-2 (Cox-2) mediates the
formation of electrophilic fatty acid oxo-
derivatives, from omega-3 fatty acids
(74). These compounds, like nitrated fatty
acids, are known to be endogenous PPAR
ligands and to induce the ARE via Nrf2
activation (74). However, whether oxidative
stress plays a role in determining the
formation of enzymatically derived
electrophilic fatty acids is unclear at this time.
Autophagy is a homeostatic process
involved in adaptive responses and cell
survival, in which ROS can play an
important role. Autophagy provides
a pathway for the turnover of cytoplasmic
organelles and proteins through a lysosome-
dependent degradation process and can
be triggered by oxidative stress, among other
factors. In the lung, HO-1 has been
shown to modulate autophagic
activation, resulting in less cell death (71).
Thus, HO-1 could be a link between the
formation of electrophilic fatty acids and
autophagy, as part of an adaptive response
to oxidative stress (75).
AnnalsATS Volume 10 Supplement | December 2013
Can Airway Oxidative
Stress Be Treated?
Should It Be Treated?
In asthma, treatment with cysteine-donor
antioxidants has been problematic due to
reduced bioavailability, potential side effects
including increased airway resistance and
enhanced bronchial hyperresponsiveness,
and the inability to improve gas exchange
or lung volumes. For COPD, treatment
with cysteine-donor antioxidants such as
N-acetylcysteine (NAC) has led to more
encouraging results. In the BRONCUS
study, patients with COPD were
randomized to 600 mg/d of NAC versus
placebo for more than 3 years. Both groups
showed similar rates of lung function
decline, yet in post hoc analysis, patients on
the NAC arm showed less hyperinflation.
In this study, NAC did not influence yearly
exacerbation rate, but the HR for
a COPD exacerbation was reduced by 22%
among those not taking inhaled steroids
(76). In a recent metaanalysis, among
723 patients from nine studies, 48.5 versus
31.2% of subjects treated with NAC had
no COPD exacerbations (relative benefit,
1.56; 95% confidence interval, 1.37–1.77);
in five studies, patients receiving NAC
reported symptom improvement (relative
benefit, 1.78; 95% confidence interval,
1.5–2.0) (77). A recent study of patients
with COPD with a median Global Initiative
for Chronic Obstructive Lung Disease score
of II evaluated the use of a high dose
NAC of 1,200 mg/d versus placebo for
1 year. NAC was associated with a lower
rate of yearly COPD exacerbations (1.71 vs.
0.9; P = 0.01) and improvements in forced
expiratory flow in the midexpiratory
phase; in addition, 53.8% in the NAC arm
versus 37.5% in the placebo remained
exacerbation-free at 1 year (78). Based on
these results, it would appear that patients
with moderate COPD might benefit from
a high dose of NAC, whereas no clinical
benefit from this type of therapy has been
demonstrated for patients with asthma.
There are several potential factors
that might explain the lack of anticipated
antioxidant therapy in airway diseases,
including (1) insufficient knowledge of the
clinical pharmacology of antioxidants
and the role and timing of antioxidants in
the pathophysiology of airway diseases
(i.e., knowing when antioxidants are needed
to reduce further inflammation or oxidative
stress vs. when would antioxidants, by
 TRANSATLANTIC AIRWAY CONFERENCE

blocking oxidative reactions, mostly impair
mechanisms involved in resolution of
inflammation), (2) insufficient dosing or
duration due to limited dose–response
studies, (3) method of antioxidant delivery,
(4) selection of unstandardized unvalidated
primary outcome indicators, and (5) lack
of surrogate biomarkers of oxidative stress
to accompany functional outcomes (51).
Should We Treat Oxidative
Stress Routinely?
Although there are no indications for the use
of antioxidant supplementation in the
treatment of airway disorders for the
aforementioned reasons, there are
situations in which, given the nature of
environmental exposures or individual
factors, supplementation of specific
antioxidants could be warranted. For
example, among children with asthma
living in highly polluted environments,
supplementation with antioxidant vitamins
prevented lung function changes associated
with ambient ozone exposure, particularly
among those with prevalent glutathione
s-transferase polymorphisms, like GSTM1
null (79, 80). Heavy smokers with low
vitamin C, and particularly those with
functional polymorphisms in the
glutamate-cysteine ligase, are at highest risk
from accelerated lung function decline; it is
therefore possible that vitamin C
supplementation in this population could
be protective (81), whereas it might not
have the same degree of efficacy in other
populations without these risks factors.
Although we are clearly far from
determining the individual characteristics
(genetic or habit-related) or the interaction
with disease and environment that would
make a person a candidate for antioxidant
supplementation, it is only through an
individualized phenotypic (including
environment) and genomic approach that
we can learn the real therapeutic potential
of antioxidant supplementation.
Summary
Airway oxidative stress is a complex
phenomenon with important physiological
and pathophysiological implications in
many airway disorders. We conceptually
understand that airway oxidative stress
occurs from an imbalance between oxidative
and antioxidative processes, yet we lack
basic understanding of when oxidative stress
is largely an epiphenomenon or when it is a
major driver of disease. Given this lack
of knowledge, coupled with an absence of
standardized biomarkers that link to clinical
or functional outcomes, it is not surprising
that antioxidant therapy for airway
diseases has largely been unsuccessful.
Airway oxidative stress should be framed in
the context of individual (phenotypical and
genetic) risk factors and environmental
exposures, to determine which specific cases
could benefit from antioxidant therapy.
Recommending treatment widely to restore
some measure of airway oxidative stress is
not recommended; not only will it not be
not beneficial for many patients but also
it has the potential to harm, if it blocks
mechanisms aimed at resolving
inflammation that depend on some low
degree of oxidative stress. n
Author disclosures are available with the text
of this article at www.atsjournals.org.

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