INVITED REVIEW
Antioxidant responses to oxidant-mediated lung diseases
Suzy A. A.
Comhair and
Serpil C.
Erzurum
Departments of Pulmonary and Critical Care Medicine and
Cancer Biology, Lerner Research Institute, Cleveland Clinic
Foundation, Cleveland, Ohio 44195
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ABSTRACT |
Reactive oxygen species (ROS) and reactive
nitrogen species (RNS) are generated throughout the human body.
Enzymatic and nonenzymatic antioxidants detoxify ROS and RNS and
minimize damage to biomolecules. An imbalance between the production of
ROS and RNS and antioxidant capacity leads to a state of "oxidative
stress" that contributes to the pathogenesis of a number of human
diseases by damaging lipids, protein, and DNA. In general, lung
diseases are related to inflammatory processes that generate increased
ROS and RNS. The susceptibility of the lung to oxidative injury depends
largely on its ability to upregulate protective ROS and RNS scavenging systems. Unfortunately, the primary intracellular antioxidants are
expressed at low levels in the human lung and are not acutely induced
when exposed to oxidative stresses such as cigarette smoke and
hyperoxia. However, the response of extracellular antioxidant enzymes,
the critical primary defense against exogenous oxidative stress,
increases rapidly and in proportion to oxidative stress. In this paper,
we review how antioxidants in the lung respond to oxidative stress in
several lung diseases and focus on the mechanisms that upregulate
extracellular glutathione peroxidase.
redox; reactive oxygen species; reactive nitrogen species
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INTRODUCTION |
OXYGEN IS ONE OF THE MOST abundant
elements in our world, constituting 21% of the air we breathe
(20, 122). It is essential for the oxidation of organic
compounds, which is the process by which mammalian cells generate the
energy needed to sustain life. However, oxygen may also damage the
lung. Inhaled ozone and nitric oxide may induce toxic processes that
impair lung function (20, 38, 82, 119, 122). Under normal
conditions, potentially toxic oxygen metabolites are generated at a low
level in lung cells by the transfer of a single electron during aerobic
metabolism (25, 33, 46). The resulting reactive oxygen
species (ROS), which include hydroxyl radicals, superoxide
(O
·), and hydrogen peroxide
(H2O2), play an integral role in the modulation of several physiological functions but can also be destructive if
produced in excessive amounts (31, 38, 82, 99, 104, 107).
Similarly, reactive nitrogen species (RNS) such as nitric oxide,
nitrite, and peroxynitrite (ONOO
) are both
physiologically necessary and potentially destructive.
Another oxygen-mediated mechanism of damage is inflammation, during
which leukocytes, macrophages, and mast cells release mediators that
may cause bronchoconstriction and edema as observed during an asthmatic
reaction (15, 38, 64). Lung tissue can also be destroyed
during reperfusion after an ischemic period such as that
produced by surgery (42, 94, 99, 104, 107, 134). All these
mechanisms have one thing in common: damage is at least partly mediated
by oxidants and nitrogen species.
To minimize oxidant damage to biological molecules, the human lung is
endowed with an integrated antioxidant system of enzymatic and
expendable soluble antioxidants. This system includes several antioxidant defense mechanisms that detoxify reactive products or
convert them to products that are quenched by other antioxidants (47, 58). If the oxidant burden is sufficiently great, the reactive species may overwhelm or inactivate the antioxidant system. The resulting excess oxygen species can damage major cellular components, including membrane lipids, protein, carbohydrates, and DNA.
The pathophysiological consequences of this injury are inflammation and
widespread tissue damage (46).
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OXYGEN AND REACTIVE OXYGEN SPECIES |
More than 90% of all the oxygen we breathe undergoes a concerted
tetravalent reduction to produce water in a reaction catalyzed by
cytochrome oxidase in the mitochondrial electron transport chain.
Oxygen (O2) can also be reduced via a nonenzymatic pathway through four successive one-electron (e
) reductions
(6, 34) (Eq. 1).
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(1)
|
Cytochrome oxidase is the terminal electron acceptor in the
respiratory chain and must donate its reducing equivalents to oxygen to
allow continued electron transport. Otherwise, ATP production cannot
continue. Thus the major role for oxygen in all aerobic organisms is
simply to act as a sink or dumping ground for electrons (34). The tetravalent reduction of oxygen by the
mitochondrial electron-transport chain is considered a relatively safe
process. Nonetheless, the electron carriers catalyze alternating
one-electron oxidant-reduction reactions, and they can react with
oxygen to generate ROS such as O
· (47, 96, 97). Mitochondria are the major intracellular sites of
O
· generation under physiological conditions
(53). One other potentially major source for the
generation of O
· is the NADPH oxidase enzymatic
system, which is found in neutrophils, monocytes, macrophages,
cytochrome P-450, monoamine oxidase, and lipooxygenase
(4, 22, 31, 34). O
· is also generated
by other mechanisms such as molybdenum hydroxylase reactions (including
the xanthine, sulfite, and aldehyde oxidases) and arachidonic acid metabolism.
O
· is relatively unstable, with a half-life of
only milliseconds. Because it is charged, it does not easily cross cell
membranes (6). O
· will react,
however, with proteins that contain transition metal prosthetic groups,
such as heme moieties or iron-sulfur clusters. These reactions may
damage amino acids or cause protein/enzyme function to be lost
(50, 138). Most of the O
· generated
in vivo undergoes a nonenzymatic or superoxide dismutase (SOD)-catalyzed reaction, resulting in the nonradical
H2O2 (Eq. 2) (79).
H2O2 can also be directly produced by several
oxidase enzymes, including xanthine oxidase, monoamine, and amino acid oxidase (24).
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(2)
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H2O2 can be oxidized by
eosinophil-specific peroxidase (EPO) and neutrophil-specific peroxidase
(MPO) using halides (X
) as a cosubstrate to form the
potent oxidant hypohalous acids (HOX) and other reactive halogenating
species (Eq. 3) (44, 56, 70, 130).
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(3)
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Much of the damage done by O
· and
H2O2 in vivo is due to their production of
hydroxyl radicals (·OH) in a series of reactions catalyzed by traces
of transition ions. One such example is the iron-catalyzed Haber-Weiss
reaction in which Fe3+ is reduced to Fe2+,
followed by the Fenton reaction in which the Fe2+ catalyzes
the transformation of H2O2 into (·OH)
(Eq. 4) (54).
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(4)
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An alternative pathway for ·OH formation in vivo may involve MPO
and EPO. Under physiological concentrations of halides, MPO produces
hypochlorous acid (HOCl), and EPO produces hypobromous acid (HOBr).
Studies of ·OH with spin-trapping agents (41, 124) and
chemical traps (57, 95) have demonstrated that hypohalous acids can generate ·OH after reacting with O
· (Eq. 5). ·OH can react with different molecules such as
protein (16), DNA, and lipids (49).
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(5)
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 |
RNS |
The discovery that nitric oxide (NO) is endogenously formed
throughout the human body has led to intense interest in the variety of
roles this unique molecule plays in vivo. NO is involved in a wide
variety of regulatory mechanisms. In addition, NO is also a cytotoxic
agent present in environmental pollutants and cigarette smoke
(109). NO is formed from the semiessential amino acid
L-arginine by the action of nitric oxide synthase (NOS;
Fig. 1) (5, 90). Several
forms of NOS have now been characterized, and several distinct
NOS genes have been identified (73). The NOS are
classified as either constitutive or inducible (76, 89,
131). The constitutive forms (NOS I and NOS III) are cytosolic
and originally described and cloned from neuronal and endothelial
cells, respectively. They are dependent on Ca2+ and
calmodulin and release low amounts of NO for short periods in response
to receptor and physical stimulation (89). The inducible form (NOS II) is independent of Ca2+. Once expressed, NOS
II generates NO in large amounts for long periods (131).
The biochemical effect of NO is largely defined by the concentration of
NO. The paramagnetic NO molecule contains an odd number of electrons,
which explains its highly reactive and radical nature (Fig. 1)
(65, 113). Autooxidation of NO with O2 results
in the formation of nitrite (NO
). However, at
physiological concentrations of NO and O2, this reaction may be too slow to be important in vivo (8, 66).
NO
is also a substrate for hemeperoxidases such as
MPO and EPO, which catalyze peroxidase-mediated oxidation and
chlorination of biological targets (40, 41, 66, 124, 130, 135,
136). Moreover, peroxidase-catalyzed oxidation of
NO
results in the formation of a nitrogen dioxide
radical (NO2·) or related molecules. These substances
can contribute to the nitration of phenolic compounds such as tyrosine
to form dimerized (dityrosine) and nitrated (3-nitrotyrosine) products,
which are stable (40, 41, 66, 124, 130, 135, 136).

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Fig. 1.
Reactive nitrogen species (RNS) synthesis. NO, nitric
oxide; NO , nitrate; NO nitrite;
HbO2, oxyhemoglobin; Hb3+, methemoglobin;
ONOOH, peroxynitrous acid; MPO, myeloperoxidase; HOCl, hypochlorous
acid; SNO: S-nitrosothiol; NOS II, nitric oxide synthase
II.
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Although NO
is a major end product of NO, it does
not accumulate in vivo but is rapidly oxidized to nitrate
(NO
) (91, 131). NO is also rapidly
oxidized by oxyhemoglobin (HbO2), which results in the
formation of methemoglobin (Hb3+) and NO
(1, 14, 51). The oxidative metabolism of NO may also lead
to the formation of carcinogenic nitrosoamines (72, 75)
and the rapid loss of NO's smooth muscle relaxant activity (59,
117).
The rapid reaction of NO with free radicals (radical-radical reaction)
has emerged as one of the major routes to the formation of RNS. At
present, the best understood of these reactions is the reaction with
O
· to form ONOO
(91), a
strong oxidant (113). Although ONOO
is
relatively stable, it can be protonated to yield peroxynitrous acid
(ONOOH) (31), which then rapidly decomposes to
NO
via the intermediate formation of ·OH and
NO2-like species (31). ONOOH is very
unstable, highly reactive, and capable of both oxidizing and nitrating
reactions. For instance, irreversible ONOOH modifications include
nitration of aromatic amino acids, lipids, or DNA bases (127). The amino acid tyrosine appears to be particularly
susceptible to nitration, and the formation of free or
protein-associated 3-nitrotyrosine has recently attracted interest as a
potential biomarker for the generation of RNS in vivo (101,
125).
Reactions with thiol residues leading to the formation of
S-nitrosothiols (SNO) have been proposed as a mechanism
whereby NO groups are transported and targeted to specific effector
sites, a potentially unique signaling mechanism induced by nitrosative stress (77, 85, 92). The exact mechanism by which
S-nitrosation occurs in vivo is still unclear, but it
involves the formation of NO-derived intermediates with the redox
equivalence of NO+ (the primary candidates are
N2O3 and ONOOH) and (di)nitrosyl iron complex
(52, 60, 66, 126, 132). Nitrosation of amines by these
reactive nitrogen intermediates has been implicated in the mutagenic
properties of NO, presumably through nitrosative deamination of DNA
bases (125). It is also of interest that SNO such as
S-nitroso-L-glutathione (GSNO) may inhibit
enzymes associated with the response to oxidative stress in eukaryotic
cells, including glutathione peroxidase (GPx), glutathione reductase
(7), glutathione-S-transferase (24), and
-glutamyl cysteine synthase
(55).
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ANTIOXIDANTS |
ROS and RNS play important physiological functions and yet they
can also cause extensive damage. The balance between physiological functions and damage is determined by the relative rates of formation and the removal of ROS and RNS.
Normally, ROS and RNS are removed rapidly before they cause cellular
dysfunction and eventual cell death. All aerobic organisms use a series
of primary antioxidant defenses to protect against oxidative damage.
Furthermore, numerous repair enzymes remove and/or repair damaged
molecules. However, an antioxidant cannot distinguish between radicals
that play a physiological role and those that cause damage
(6). Moreover, some antioxidant compounds also have
prooxidant actions (6). This section will review the
enzymatic and nonenzymatic primary antioxidant defenses.
Enzymatic antioxidants.
SOD (EC 1.15.1.11) is an ubiquitous enzyme with an essential function
in protecting aerobic cells against oxidative stress (79).
It catalyzes O
· radicals to H2O2. There are three forms of SOD. The
copper-zinc SOD is located in the cytosol, the manganese SOD is
primarily a mitochondrial enzyme, and extracellular SOD is usually
found on the outside of the plasma membrane (43).
Catalase (EC 1.11.1.6) is a tetrameric hemoprotein that undergoes
alternate divalent oxidation and reduction at its active site in the
presence of H2O2 and catalyzes the dismutation
reaction (22, 36, 102). As a result, catalase has
appreciable reductive activity for small molecules such as
H2O2 and methyl or ethyl hydroperoxide. It does
not metabolize large molecular peroxides such as lipid hydroperoxide
products of lipid peroxidation (129). Catalase is most
effective in the presence of high H2O2
concentrations. However, in the presence of low concentrations of
either H2O2 or other peroxides, the glutathione
system plays a critical role (20).
The glutathione system is a central mechanism for reducing
H2O2. It complements catalase as a reducing
system for H2O2 but exceeds catalase in its
capacity to eliminate additional varieties of toxic peroxides
(105). Other metabolized substrate species include large
molecule lipid peroxides, formed by free radical attack on
polyunsaturated lipid membranes and products of lipooxygenase-catalyzed reactions (58). The key enzyme in the redox cycle
responsible for the reduction of H2O2 is GPx.
This reaction specifically requires reduced glutathione (GSH) to serve
as the electron donor. The glutathione disulfide (GSSG) formed in the
course of the reaction is subsequently reduced back to GSH by
glutathione reductase, which uses NADPH generated from the hexose
monophosphate shunt system as an electron donor (37, 80).
Healthy, nonstressed cells maintain a high intracellular GSH:GSSG ratio
to ensure the availability of GSH and thereby promote active reduction
of H2O2 through the glutathione system
(37, 80). In a role unrelated to its role in the GSH
system, free GSH can also function as a water-soluble antioxidant by
interacting directly with radical intermediates in nonenzymatic
catalyzed reactions. Scavenging of O
· by GSH leads
to the formation of thiyl radicals (GS · ) and
H2O2 via several steps, which is a radical
propagation reaction. This reaction leads to the formation of
GS · and H2O2 and can occur in
physiologically relevant concentrations. Hence, a substance that is
generally accepted to be an antioxidant may possess prooxidant activity
under certain conditions (6, 38).
Four GPx have been described, all selenium enzymes: 1) the
classic cytosolic form, found in all cells (9);
2) a membrane-associated GPx phospholipid
H2O2 (39); 3) another
cytoplasmic enzyme, gastrointestinal GPx, which was first found in
cells of the gastrointestinal tract (23); and
4) an extracellular GPx (eGPx), first identified as a
distinct enzyme in human plasma (137). All members of this family of enzymes can be oxidized by organic hydroperoxides,
hydroperoxide, or both, and can subsequently be reduced by glutathione
(137). The existence of multiple forms of GPx is due to
the expression of different genes (103). All GPx contain a
selenium atom in the active site in the form of selenocysteine.
Nonenzymatic antioxidants.
Cells use nonenzymatic antioxidant compounds to react directly with
oxidizing agents and disarm them. Such antioxidants are said to be
"scavengers"; their roles are unavoidably suicidal. For example,
vitamin E (
-tocopherol) is a membrane-bound antioxidant that
terminates the chain reaction of lipid peroxidase by scavenging lipid
peroxyl radicals (LOO · ) (6, 34, 123). In this
reaction, vitamin E becomes a radical, but it is much less reactive
than LOO · (123). However, at high concentrations,
the radical form of vitamin E may function as a prooxidant
(6). Vitamin C can also directly scavenge
O
· and ·OH by forming the semidehydroascorbate
free radical that is subsequently reduced by GSH (78).
Vitamin C, however, is usually not considered a major antioxidant
because it also has prooxidant properties. It is probably the only
cellular reducing agent other than O
· capable of
converting Fe3+ to Fe2+, which then reacts with
H2O2 to form ·OH (106). Whether
the prooxidant or antioxidant properties of vitamin C prevail in any particular tissue is determined by the extent of available iron stores;
iron overload favors excess oxidant generation (6, 106).
Other nonenzymatic antioxidants include
-carotene (scavenger of
O
· anions and peroxyl radicals), uric acid
(hydroxyl radical, O
·, peroxyl radical scavenger),
glucose (hydroxyl radical scavenger), bilirubin (LOO · scavenger), taurine (hypochlorous acid quencher), albumin (transition metal binding), and cysteine and cysteamine (donators of
sulfhydryl groups).
 |
ANTIOXIDANTS IN THE LUNG |
Lungs are unique because they have a large epithelial surface area
that is at risk for oxidant-mediated attack. The tracheobronchial tree
and the alveolar space are exposed to reactive oxidizing species in the
form of inhaled airborne pollutants, tobacco smoke, and products of
inflammation. The lung, therefore, requires additional antioxidant
resources to prevent airway-borne oxidant injury (58). The
major airways contain high-molecular-weight mucopolypeptide glycoproteins, which are synthesized by the epithelial cells and glands
that increase mucus production in the presence of inflammation (58). The lung contains intracellular antioxidant enzymes
to maintain a normal redox state. The alveolar space can recruit additional antioxidant activity from the epithelial lining fluid (ELF).
This fluid contains large amounts of GSH (100-fold higher than in
plasma), 90% of which is in the reduced form (19, 27, 35, 114,
115). The ELF also contains catalase, SOD, and GPx (19,
27, 114, 115). Additional antioxidants contained in ELF include
ceruloplasmin, transferrin, ascorbate, vitamin E, ferritin, other serum
proteins, and small molecules such as bilirubin (58). The
multiplicity of the antioxidant systems available to the lung and their
overlapping specific activities suggest that to maintain normal
pulmonary cellular function, it is critically important for the lung to
adequately control redox balance. Disequilibrium, either through
increased oxidant stress or decreased antioxidant resources, can result
in a series of pathophysiological events in the lung that culminate in
cellular death and pulmonary dysfunction (58). A partial
list of major lung diseases associated with oxidants is
presented in Table 1.
 |
EXTRACELLULAR ANTIOXIDANT RESPONSE IN LUNGS EXPOSED TO OXIDATIVE
STRESS |
Normally, the homeostasis of cellular functions during oxidative
stress depends on the rapid induction of protective antioxidant enzymes. Naturally occurring antioxidants exist to protect cells and
tissue against the continuous production of ROS/RNS during normal
metabolism (58). Tissues and cells respond to mild
oxidative stress by increasing antioxidant defenses (119).
However, high levels of ROS/RNS may overwhelm antioxidant defenses,
resulting in oxidant-mediated injury or cell death (4,
20).
Numerous studies have revealed that oxidant stress plays a crucial role
in the initiation and progression of a wide range of diseases and in
the regulation of a number of important biological processes. Pulmonary
diseases associated with oxidative stress include asthma, hyperoxia,
sarcoidosis, and chronic beryllium disease (CBD). ROS play a key role
in the initial lung response to asbestos and silica that leads to
interstitial pulmonary fibrosis (87, 88). Interestingly,
during the development of pulmonary diseases, antioxidant responses are
different. For example, asbestosis and sarcoidosis lead to an increase
of SOD, whereas there are no changes found in silicosis or hyperoxic
lung injury (27, 62, 71). In contrast, SOD activity is
significantly lower in patients with asthma and decreases further
during an asthmatic exacerbation.
The glutathione system is altered in lung inflammatory conditions. For
instance, GSH levels are elevated in the ELF of chronic smokers and in
chronic beryllium disease, an immune-specific granulomatous inflammation (29). Levels of GSH in ELF decrease rapidly
in patients with mild asthma during an asthma exacerbation
(27). Similarly, GSH levels are decreased in ELF in
idiopathic pulmonary fibrosis (17, 74), asbestosis
(11), acute respiratory distress syndrome
(13), and in human immunodeficiency virus-positive patients (12). Levels of glutathione modulate the T helper
type 1 (Th1) vs. the Th2 immune response pattern
(93). For example, high levels of glutathione in
patients with CBD may contribute to the development and/or maintenance
of a chronic Th1 cell-mediated immune response to beryllium, whereas
the low GSH levels may contribute to the development or maintenance of
Th2 cell immune response in asthma.
Other enzymes of the glutathione system are also influenced by oxidant
stress. Some studies have shown increased GPx activity in ELF of
smokers compared with nonsmokers (29, 104), whereas others
have shown decreased GPx in smokers (81). The difference in GPx activity may be due to the difference in smoking history (19, 86). GPx activity is not altered in asthma but is
increased in lungs of CBD patients. Overall, the antioxidant response
is inconsistent across different oxidant-mediated lung diseases.
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EGPX AND ITS ROLE IN OXIDATIVE STRESS |
Expression of eGPx.
eGPx transcripts have been found in epithelial cells with
well-developed brush borders that contain lipids and alkaline
phosphatase activity, e.g., the human airways, intestine, and renal
tubules (2, 3, 68, 120). Alveolar macrophages are also
able to synthesize and secrete eGPx (2, 28, 30). The GPx
family is an important enzymatic component of the mechanisms for
detoxifying ROS in the lung and may play a significant role in
preventing pulmonary oxidant stress. eGPx gene expression is
upregulated in bronchial epithelial cells and ELF as a result of
oxidative stress occurring in individuals with asthma or CBD and in
those who have been exposed to exogenous oxidants such as cigarette smoke (Fig. 2) (2,
28-30). The upregulation of eGPx occurs rather late after
exposure (after 24 h) (28), which may explain why eGPx was not induced after 12 h of hyperoxia. In support of this, levels of eGPx mRNA and protein increase only after 72 h of
hyperoxia in a mouse model (67). Induction of eGPx mRNA in
bronchial epithelial cells is associated with elevated protein levels
in ELF, suggesting that the increase of eGPx occurs, in part, by
bronchial epithelial cell synthesis and secretion (28).
However, alveolar macrophages can also express eGPx (2,
30). It is not known whether other lung cells or inflammatory
cells upregulate eGPx gene in response to oxidative stress.

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Fig. 2.
Expression of extracellular glutathione peroxidase (eGPx)
mRNA in human airway epithelial cells (means ± SE). No
significant difference in the expression of eGPx mRNA was found in
cells from individuals with asthma, chronic beryllium disease (CBD),
and smoke exposure (P > 0.05), but in all 3 groups,
levels were significantly higher than in controls (P < 0.05). GAPDH, glyceraldehyde-3-phosphate dehydrogenase.
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Bronchial epithelial cells significantly increase eGPx mRNA expression
in response to increased intracellular or extracellular ROS in vitro.
Supplementation of GSH in cell culture to physiological levels
potentiates the induction of eGPx mRNA in response to ROS (28). This effect is not reproduced by
N-acetylcysteine, suggesting that other effects of thiol
groups are necessary to achieve the synergistic effect on induction of
the eGPx gene (28). Although GSH is usually considered an
antioxidant, it can also act as an oxidant when present at
physiological levels (6). GSH may participate in oxidizing
processes and/or accelerate the generation of ROS, specifically
O
· (6, 84, 121, 133). Previous
reports have shown that GPx can function as an ONOO
reductase and thereby prevent nitration reactions caused by RNS (45). On the other hand, NO donors
(S-nitroso-N-acetyl-D,L, penicillamine/GSNO) induce eGPx gene expression in a time- and dose-dependent matter.
Transcriptional regulation.
The regulation of genes in response to oxidative stress occurs via
transcription and/or stabilization of mRNA. Studies support that the
ROS regulation of the eGPx gene expression occurs at a transcriptional
level (28). In general, ROS and RNS regulate the
expression of numerous genes via signaling mechanisms. Redox-sensitive transcription factors such as signal transducers and activators of
transcription (STAT), nuclear factor-
B, and transcription factor
activator protein-1 (AP-1) are activated in epithelial cells and
inflammatory cells during oxidative stress (98,
100). Although the STAT family of transcription
factors is activated by many cytokines and growth factors, it can also
be activated by oxidative stress such as H2O2
(108, 112, 116). The activation of STATs by oxidative
stress is inhibited by antioxidants. Several ROS-induced target genes
have known STAT binding sites in their promoters. These include genes
involved in antioxidant defense (111) such as SOD1
(10) and genes involved in cell growth regulation such as
c-fos (128).
Studies from several laboratories have demonstrated that oxidant stress
such as cigarette smoke, treatment with H2O2,
depletion of intracellular GSH, or an increase in the GSH:GSSG ratio
stimulates AP-1 activation and binding (83, 99). AP-1
regulates many of the inflammatory and immune genes in oxidant-mediated
diseases (69, 110, 118). AP-1 is a protein dimer composed
of the Jun and Fos gene products (100). These gene
products can form homodimeric (Jun-Jun) or heterodimeric (Jun-Fos)
complexes (100). The 5'-flanking region of the eGPx gene
contains the DNA-binding element for AP-1 (137) (Fig.
3). Cigarette smoke increases AP-1 DNA
binding in human epithelial cells in vivo (99).
Based on our results and those of others, we propose that increased
formation of ROS and RNS in inflammatory cells and epithelium leads to
alterations in the redox system, sensed by the epithelial cells, and
leads to the activation of transcription factors such as STATs and AP-1 and downstream target gene expression.

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Fig. 3.
Proposed scheme for eGPx gene induction by oxidative
stress. Reactive oxygen species (ROS) and RNS cross the cell membrane,
which together with inflammatory mediators activate different
transcription factors, such as nuclear factor (NF)- B and activator
protein-1 (AP-1). The 5'-flanking region of the eGPx gene necessary for
transcriptional activation shows that the inducible promoter element
contains the DNA binding element for AP-1. The activation and binding
of AP-1 to the eGPx promoter is a possible mechanism for eGPx mRNA and
protein induction. I B, inhibitor of NF- B.
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Function.
On the basis of our studies and the studies of others, we have
generated a model for the function of eGPx in lung diseases associated
with oxidative stress (Fig. 3). NO is produced in mammalian airways,
and increased levels are found in many inflammatory lung diseases such
as asthma and hyperoxia (28, 30, 61). Inflammation leads
to increased levels of ROS (Fig. 4,
pathway a). NO reacts slowly with O2 to form the
cytotoxic compound NO
or very rapidly with
O
· to form ONOO
(Fig. 4,
pathway b) (51). This results in tyrosine
nitration in lung tissue (Fig. 5 and Fig.
4, pathway c). Thus when O
· is produced
at high rates during lung inflammation, NO may accelerate the formation
of ONOO
, leading to tyrosine nitration and aggravate lung
damage (61). The NO/O
· pathway in
vitro appears to be significantly shifted toward the formation of GSNO
in the presence of physiological levels of GSH (Fig. 4, pathway
d) (30, 45, 77). Recent studies have shown that GPx
(Fig. 4, pathway e) can protect against NO-mediated protein
oxidation (48) and can reduce GSNO. Thus the increased
eGPx in lung inflammation may have two functions: reduction of ROS
(e.g., H2O2 and O
·) and
possibly protection against NO-mediated protein oxidation by regulation
of RSNO levels.

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Fig. 4.
Detoxification of ROS and RNS by eGPx in asthmatic
individuals. a: Superoxide is detoxified through eGPx to
H2O; b: in the presence of low levels of
superoxide dismutase, NO and superoxide (O ·)
combine to form ONOOH; c: peroxynitrite is able to nitrate
tyrosine residues; d: nitrosation of reduced glutathione
(GSH) by peroxynitrite leads to
S-nitroso-L-glutathione (GSNO); e:
detoxification and liberation of NO through eGPx. GSSG, glutathione
disulfide.
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Fig. 5.
Nitrotyrosine staining of asthmatic bronchial mucosa.
Cytoplasm of bronchial epithelial cells shows positive immunoreactivity
to nitrotyrosine (red; arrow); g, goblet cell; bm, basement membrane.
Magnification, ×40; hematoxylin counterstaining.
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In conclusion, lung diseases occur in response to oxidative and
nitrosative stress. The lung's ability to respond to oxidative stress
depends largely on its capacity to upregulate protective antioxidants.
The antioxidant responses to lung disease vary widely, but the
upregulation of eGPx in oxidant-mediated lung diseases is likely
important to defend airway surfaces from ROS and RNS injury.
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ACKNOWLEDGEMENTS |
We thank J. H. J. M. van Krieken, F. B. J. M. Thunnissen, P. N. R. Dekhuijzen, D. Roos, A. Bast,
and P. Scheepers for helpful discussion and comments.
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FOOTNOTES |
This work was supported in part by National Heart, Lung, and Blood
Institute Grant HL-60917.
Address for reprint requests and other correspondence:
S. A. A. Comhair, Dept. of Pulmonary and Critical Care
Medicine, Cleveland Clinic Foundation, 9500 Euclid Ave./NB4-107,
Cleveland, OH 44195 (E-mail:
comhais{at}ccf.org).
10.1152/ajplung.00491.2001
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