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American Journal of Respiratory and Critical Care Medicine Vol 166. pp. S38-S43, (2002)
© 2002 American Thoracic Society

Article

Oxidative Stress in Airways

Is There a Role for Extracellular Superoxide Dismutase?

Russell P. Bowler and James D. Crapo

National Jewish Medical and Research Center; and Department of Cell and Structural Biology, University of Colorado Health Sciences Center, Denver, Colorado

Correspondence and requests for reprints should be addressed to Russell P. Bowler, M.D., Ph.D., National Jewish Medical and Research Center, K707, 1400 Jackson Street, Denver, CO 80206. E-mail: bowlerr{at}njc.org

ABSTRACT

Airways are exposed to high levels of environmental oxidants, yet they also have enriched extracellular antioxidants. Airways disease such as asthma, cystic fibrosis, and chronic obstructive pulmonary disease have evidence of increased oxidative stress, suggesting that reactive oxygen and nitrogen species may overwhelm antioxidant defenses in airway diseases. Extracellular superoxide dismutase is abundant in pulmonary tissues and protects the lung from increased oxidative stress; however, its role in asthma and other airway diseases has not been fully elucidated. Proteolytic processing of extracellular superoxide dismutase decreases its affinity for the extracellular matrix and may be a mechanism to regulate its distribution during conditions of inflammation or oxidative stress.

Key Words: lung • antioxidant • oxidative stress

Airways are unique in both their exposure to high levels of environmental oxidants and their unusually high concentration of extracellular antioxidants. In the resting state, the balance between antioxidants and oxidants is sufficient to prevent the disruption of normal physiologic functions; however, either increases in oxidants or decreases in antioxidants can disrupt this balance. The state of imbalance is collectively referred to as oxidative stress and is associated with diverse airway pathologies (1).

The major oxidants in airways are reactive oxygen and reactive nitrogen species (ROS/RNS). ROS include superoxide, hydrogen peroxide, and hydroxyl radical. RNS include nitric oxide and its derivates such as nitrogen dioxide and peroxynitrite. Other molecules that can contribute to oxidative stress include protein radicals and lipid peroxide radicals. Although these molecules collectively cause nonspecific damage to cells and extracellular matrix when produced in excess, production in highly localized domains is now recognized as essential for normal physiologic function; for instance, superoxide is a crucial component of phagocytosis (2) and nitric oxide mediates smooth muscle relaxation in both blood vessels (3) and airways (4).

ROS are found diffusely throughout the lung and are a by-product of normal metabolism. Mitochondria are the largest producer of ROS because electrons leak from the electron transport chain onto oxygen to form superoxide. It is estimated that 1–3% of O2 reduced in cells may form superoxide in this manner (1). Other sources of superoxide include cytosolic xanthine oxidase (5), mitochondrial respiration, and membrane nicotinamide adenine dinucleotide phosphate oxidases such as the cytochrome P450 system of the endoplasmic reticulum (6). Hydrogen peroxide is formed during the dismutation of superoxide but also by glycolate oxidase in peroxisomes. Hydroxyl radical classically forms in the presence of metals and hydrogen peroxide (Fenton reaction); however, decomposition from other molecules such as peroxynitrite may play a small role (7). Unlike nitric oxide, there are no well-described independent signaling roles for superoxide in the lung.

RNS are primarily derived from nitric oxide. In the resting state, nitric oxide is considered a signaling molecule. The sources of nitric oxide are three nitric oxide synthases (NOSs): (1) constitutive NOS, which is found in respiratory epithelium, blood vessels, and nerve endings; (2) inducible NOS, which is found in respiratory epithelium and activated macrophages (8); and (3) neuronal NOS, which is found in the nerve plexus of the trachea (9). When nitric oxide is produced in high concentrations, such as with inducible NOS, it can react with oxygen or superoxide to form the highly reactive compounds nitrogen dioxide and peroxynitrite. Only inducible NOS is highly upregulated by such cytokines as tumor necrosis factor-{alpha} and interleukin-1ß (10). Location determines the function of nitric oxide in the lung. In pulmonary vessels, nitric oxide is a vasodilator. In airway muscle, nitric oxide functions as a bronchodilator, and in airway epithelium, nitric oxide modulates the immune response.

Antioxidants are the primary defense against ROS/RNS (Figure 1) . The antioxidant effect can be either enzymatic or nonenzymatic. Antioxidant enzymes include the families of superoxide dismutase (SOD), catalase, glutathione peroxidase, glutathione S-transferase, and thioredoxin. Each family has isoenzymes that are distinguished primarily by their distribution. For instance, the three mammalian SODs are cytosolic (SOD1) (11), mitochondrial (SOD2) (12), and extracellular (SOD3) (13), and the two thioredoxins are cytosolic (Trx1) and mitochondrial (Trx2) (14). The nonenzymatic antioxidants include low molecular weight compounds such as glutathione, ascorbate, urate, {alpha}-tocopherol, bilirubin, and lipoic acid. Concentrations of these antioxidants vary depending on both the subcellular and anatomic location. For instance, glutathione is 100-fold more concentrated in the airway epithelial lining fluid compared with plasma (15). Other high molecular weight molecules that might be considered antioxidants include proteins that have oxidizable thiol groups such as albumin or proteins that bind free metals such as transferrin. Albumin and transferrin are found in high concentration in serum but are in a much lower concentration in airway lining fluid (16). Thus, both the lung parenchyma and airways have several antioxidant systems.



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  		Figure 1. Extracellular airway oxidants and antioxidants in asthma. (A) Normal airways are replete with antioxidants such as glutathione (GSH), urate, ascorbate, and EC-SOD. In normal airways, ROS/RNS concentrations are suppressed by antioxidants or are highly localized for signaling functions. For instance, neuronal NOS (nNOS) makes nitric oxide (NO·) at nerve terminals to dilate airway smooth muscle, and constitutive NOS (ecNOS) dilates blood vessels. (B) In asthma, there are increased eosinophils (EOS) and neutrophils (PMN). The airways inflammation is associated with increases in inducible NOS (iNOS) and membrane oxidases that make superoxide (O2-). Superoxide and nitric oxide rapidly combine to form peroxynitrite (ONOO-), leading to tissue injury and proinflammatory responses. Increased ROS/RNS also deplete antioxidants; for instance, GSH is oxidized to GSSG. The role of EC-SOD in asthma is not known, but insufficient EC-SOD is likely to perpetuate the inflammatory response.

 
OXIDATIVE STRESS IN AIRWAYS DISEASES

In many airways diseases, the delicate balance between ROS/RNS and antioxidants is in disequilibrium because of excess production of ROS/RNS or depletion of antioxidants. Because direct measurement of ROS/RNS is technically difficult in vivo, there are few reports of direct measurements of ROS/RNS in airways diseases (Table 1) . Instead, many investigators report the footprints of oxidative stress (Table 2) . These footprints are thought to be the result of nonenzymatic reactions between ROS/RNS and proteins, lipids, or DNA. For instance, in the airways of patients with asthma, ROS/RNS react with proteins to form amino acid adducts such as nitrotyrosine or chlorotyrosine, with lipids to generate ethane and isoprostanes and with DNA to form base pair adducts such as 8-oxo-2-deoxyguanosine. In diseases such as asthma and cystic fibrosis, inflammation may be the most significant contributor to oxidative stress. Several studies have shown that the footprints of oxidative stress correlate with disease activity (17, 18).


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  		TABLE 1. Exhaled ros/rns in airway diseases*

 

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  		TABLE 2. Footprints of airways oxidative stress in airway diseases*

 
Several observations make asthma a good paradigm of oxidative stress in airways. First, individuals with asthma demonstrate depressed lavage ascorbate and {alpha}-tocopherol and elevated oxidized-reduced glutathione ratio, suggesting both increased ROS/RNS and decreased antioxidant capacity (19). Second, SOD activity is diminished in cells from lavage and brushings of patients with asthma (20). Third, airway macrophages from individuals with asthma produce more superoxide than control subjects when stimulated (21). Oxidative stress may also play a role in the pathogenesis of cystic fibrosis; for instance, the diminished capacity of the cystic fibrosis transmembrane receptor to secrete glutathione into airways is thought to contribute to lung injury in cystic fibrosis (22). The role of oxidative stress in noninflammatory airways disease such as chronic obstructive pulmonary disease is unclear, although it is postulated that oxidative stress from cigarette smoke contributes to the pathogenesis of emphysema (see review in 23).

EXTRACELLULAR-SOD IN LUNGS

The SOD family catalyzes the dismutation of superoxide radicals into hydrogen peroxide and oxygen. The reaction is pseudo first-order and almost diffusion limited (Michaelis-Menten constant of more than 109 M-1 s-1) (24). Three SOD isoenzymes have been identified in mammals. The major intracellular SOD is a 32-kD copper and zinc containing homodimer (Cu/Zn SOD or SOD1) present throughout the cytoplasm and nucleus (25). Cu/Zn mutants have recently been shown to be important in the pathogenesis of amyotrophic lateral sclerosis (26). The mitochondrial SOD (MnSOD or SOD2) is a manganese-containing 93-kD homotetramer that is synthesized in the cytoplasm and translocated to the inner matrix of mitochondria (12, 27). A lack of mitochondrial SOD may cause cardiomyopathies and neurodegenerative diseases (28). The last mammalian SOD to be discovered is primarily extracellular (EC-SOD or SOD3) (13).

EC-SOD is the primary extracellular SOD enzyme and is highly expressed in many organs. The uterus, pancreas, and lung have the highest EC-SOD activity levels among solid organs; EC-SOD activity in the human lung is approximately eight times that of the liver, six times that of the brain, two to three times that of the heart, and one to two times that of the kidney (29). Within the lung, EC-SOD protein is particularly abundant in blood vessels but is also increased in airways (Figure 2) . EC-SOD mRNA is abundant in airway epithelium and vascular endothelium and is expressed at levels four times of that in heart and 15 times that in liver (30). Immunohistochemistry reveals that the protein is mainly associated with the connective tissue matrix around vessels and airways in the lung but is also found in close proximity to airway and vascular smooth muscle cells (Figure 3) (31, 32). Electron microscopic immunocytochemistry reveals that EC-SOD is seen in areas rich in type I collagen, on the surface of smooth muscle cells, and in extracellular matrix associated with airway and vascular smooth muscle cells (31, 32). The prominent expression of EC-SOD around airways and airway smooth muscle raises the possibility that it may play a role in airway diseases.



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  		Figure 2. The distribution of EC-SOD within human lung. Pulmonary airways and blood vessels have higher levels of EC-SOD than the lung as a whole (black bars). EC-SOD protein levels in systemic blood vessels are shown for comparison and are also high (cross-hatched). Means are represented by bars and with SEs (adapted from Oury and colleagues [31]).

 


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  		Figure 3. Immunostaining for EC-SOD in human airways. Brown areas show EC-SOD antibody staining. In large airways, there is intense staining of the luminal surface of the bronchial epithelium, beneath the epithelium around smooth muscle cells, and in alveolar septae. Reprinted by permission from Reference 82.

 
EC-SOD IN PULMONARY DISEASES

Mice that are deficient in EC-SOD have a normal phenotype. Although the role of EC-SOD in airway diseases such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis is not clear, two studies suggest that SOD activity might play a role in asthma. First, SOD activity is diminished in the cells of broncoalveolar lavage and brushings of patients with asthma (20). Second, intravenous administration of polyethylene glycol–conjugated SOD leads to reduced airway hyper-responsiveness in rabbits, suggesting that increased SOD activity attenuates asthma (33). Although these studies raise the possibility that EC-SOD activity might play an important role in airway diseases, a recently published report using an ovalbumin model of asthma found that mice lacking EC-SOD had only a mild increase of infiltration of monocytes and airway interleukin-5 compared with wild-type mice, but this occurred only in female mice and not in male mice (34). In addition, these investigators found no differences in lavage total protein and lactate dehydrogenase nor were there any differences in inflammation between wild-type and EC-SOD–deficient mice 1 day after exposure to lipopolysaccharide plus opsonized zymosan. Thus, any putative role for EC-SOD in airways must be speculative.

Despite the dearth of studies of EC-SOD in airways diseases, there is substantial evidence that EC-SOD may protect the lung from oxidative stress. Mice that overexpress EC-SOD in the lung are partially protected from hyperoxia-induced injury (35, 36), hemorrhagic shock (37), influenza (38), bleomycin (39), and oil fly ash (40). These studies suggest that EC-SOD may be sufficient to attenuate the effects of superoxide in extracellular spaces under normal conditions, but not during pathologic states.

Another mechanism by which EC-SOD might influence airway physiology is through modulation of nitric oxide. Nitric oxide is a potent signaling molecule that may cause nonadrenergic mediated bronchodilation (41, 42). Superoxide inactivates nitric oxide by rapidly reacting with it to form peroxynitrite. A recent report implicates EC-SOD as a modulator of nitric oxide–mediated signaling in blood pressure control (43). The relative abundance of EC-SOD in the bronchi and blood vessels raises the possibility the EC-SOD might also modulate pulmonary blood flow or neurally mediated bronchodilation; however, the significance of EC-SOD in modulating nitric oxide signaling pathways in airways remains to be shown.

PROTEOLYTIC PROCESSING OF EC-SOD

A distinguishing feature of EC-SOD is its high affinity for glycosaminoglycans. Six basic amino acid residues (Arg-Lys-Lys-Arg-Arg-Arg) within the last 14 amino acid residues are essential for this high affinity (44–46). Mutations within this region lead to elevations of EC-SOD in plasma, presumably from decreased affinity toward the extracellular matrix (47–49). Removal of the polybasic region decreases the tissue half-life of EC-SOD by approximately 15-fold, from 85 hours to 7 hours, but does not affect the enzymatic activity of EC-SOD (50). Further characterization of the glycosaminoglycan-binding region revealed that the more sulfated glycosaminoglycans, such as heparin, had higher affinity compared with less sulfated glycosaminoglycans such as heparan sulfate (51). A recent study found the heparin interaction may be limited to 8–10 sugar residues and may require {alpha}-helix formation in the carboxyterminus (52). The lack of glycosaminoglycan specificity and the ability of high sodium chloride concentrations to elute EC-SOD from glycosaminoglycans suggest that EC-SOD's interaction with glycosaminoglycans is electrostatic and not saccharide specific. It has been assumed that this electrostatic interaction with extracellular matrix is the predominant determinant of EC-SOD localization and immobilization within tissues.

The potential for regulating the heparin-binding region has only recently been appreciated. We have reported that cells secrete two forms of EC-SOD that have a different carboxyterminus (53). Pulse chase and sequencing experiments suggest that the two forms of EC-SOD are due to post-translational, proteolytic processing of the carboxyterminus containing the polybasic residues (Figure 4) . Removal of these residues has been previously shown to decrease the tissue half-life (50) and affinity for binding the extracellular matrix (45, 46). Recently, we have shown that furin and an unknown carboxypeptidase are capable of proteolytically processing EC-SOD (54). Proteolytic processing of EC-SOD is under both cell type and organ control, suggesting that both half-life and affinity for extracellular matrix are regulated. The biologic significance of this is unknown; however, a recent study showed that proteolytic processing is associated with increased EC-SOD in airways after bleomycin treatment (Figure 5) (55). Thus, secretion of intact EC-SOD may be used primarily by cells that need highly localized EC-SOD activity, whereas secretion of cleaved EC-SOD could be a mechanism to increase EC-SOD activity in areas that are incapable of locally increasing EC-SOD secretion.



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  		Figure 4. Intracellular proteolytic processing of EC-SOD occurs in a multistep process. Furin cleaves EC-SOD within the heparin-binding, polybasic region of the carboxyterminus (cross-hatched). Unknown carboxypeptidases then trim the remaining amino acids back to glutamic acid -209. A loss of the heparin-binding region decreases EC-SOD's affinity for the extracellular matrix and tissue half-life.

 


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  		Figure 5. Bleomycin treatment increases expression of EC-SOD in airways and also increases the ratio of proteolytic processing. Mice were given bleomycin 0.075 units intratracheally and then killed after 7 days. There was a twofold increase in intact EC-SOD (gray bars) but a three-fold increase in cleaved EC-SOD (black bars) in airways of mice 7 days after bleomycin (adapted from Fattman and colleagues [55]). p < 0.01; *p < 0.01.

 
CONCLUSION
Oxidative stress is a feature of most airways diseases, particularly when inflammation is prominent. Both an increase in ROS/RNS and depletion of antioxidants are thought to contribute the pathogenesis of oxidative stress; however, it is still unclear which species are the most active in airways. Excess extracellular superoxide is a prominent feature of airway inflammation and may play an important role in both decreasing the bioavailability of nitric oxide and leading to excessive ROS injury. The prominence of EC-SOD in airways and blood vessels suggests that extracellular superoxide concentrations are finely tuned under normal conditions. Animal studies using mice that are deficient in or overexpress EC-SOD suggest that pathologic states of oxidative stress may overwhelm the activity of EC-SOD, but additional work will be required to prove that this is important in airway diseases such as asthma.

FOOTNOTES

Supported by National Institutes of Health grants HL-04407, HL-31992, HL-42444

Received in original form June 14, 2002; accepted in final form September 10, 2002

REFERENCES

  1. Halliwell B, Gutteridge JMC. Free radicals in biology and medicine, 3rd ed. Oxford: Oxford University Press; 1999.
  2. Ottonello L, Dapino P, Pastorino G, Dallegri F, Sacchetti C. Neutrophil dysfunction and increased susceptibility to infection. Eur J Clin Invest 1995;25:687–692.[Medline]
  3. Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 1987;327:524–526.[CrossRef][Medline]
  4. Dupuy PM, Shore SA, Drazen JM, Frostell C, Hill WA, Zapol WM. Bronchodilator action of inhaled nitric oxide in guinea pigs. J Clin Invest 1992;90:421–428.
  5. Quinlan GJ, Lamb NJ, Tilley R, Evans TW, Gutteridge JM. Plasma hypoxanthine levels in ARDS: implications for oxidative stress, morbidity, and mortality. Am J Respir Crit Care Med 1997;155:479–484.[Abstract]
  6. Goeptar AR, Scheerens H, Vermeulen NP. Oxygen and xenobiotic reductase activities of cytochrome P450. Crit Rev Toxicol 1995;25:25–65.[Medline]
  7. Merenyi G, Lind J, Goldstein S, Czapski G. Peroxynitrous acid homolyzes into *OH and *NO2 radicals. Chem Res Toxicol 1998;11:712–713.[CrossRef][Medline]
  8. Kobzik L, Bredt DS, Lowenstein CJ, Drazen J, Gaston B, Sugarbaker D, Stamler JS. Nitric oxide synthase in human and rat lung: immunocytochemical and histochemical localization. Am J Respir Cell Mol Biol 1993;9:371–377.
  9. Guembe L, Villaro AC. Histochemical demonstration of neuronal nitric oxide synthase during development of mouse respiratory tract. Am J Respir Cell Mol Biol 1999;20:342–351.[Abstract/Free Full Text]
  10. Radomski MW, Vallance P, Whitley G, Foxwell N, Moncada S. Platelet adhesion to human vascular endothelium is modulated by constitutive and cytokine induced nitric oxide. Cardiovasc Res 1993;27:1380–1382.[Abstract/Free Full Text]
  11. McCord JM, Fridovich I. Superoxide dismutase: an enzymic function for erythrocuprein (hemocuprein). J Biol Chem 1969;244:6049–6055.[Abstract/Free Full Text]
  12. Weisiger RA, Fridovich I. Mitochondrial superoxide simutase: site of synthesis and intramitochondrial localization. J Biol Chem 1973;248:4793–4796.[Abstract/Free Full Text]
  13. Marklund SL. Human copper-containing superoxide dismutase of high molecular weight. Proc Natl Acad Sci USA 1982;79:7634–7638.[Abstract/Free Full Text]
  14. Arner ES, Holmgren A. Physiological functions of thioredoxin and thioredoxin reductase. Eur J Biochem 2000;267:6102–6109.[Medline]
  15. van der Vliet A, O'Neill CA, Cross CE, Koostra JM, Volz WG, Halliwell B, Louie S. Determination of low-molecular-mass antioxidant concentrations in human respiratory tract lining fluids. Am J Physiol 1999;276:L289–L296.[Abstract/Free Full Text]
  16. Reynolds HY, Newball HH. Analysis of proteins and respiratory cells obtained from human lungs by bronchial lavage. J Lab Clin Med 1974;84:559–573.[Medline]
  17. Horvath I, Donnelly LE, Kiss A, Kharitonov SA, Lim S, Fan Chung K, Barnes PJ. Combined use of exhaled hydrogen peroxide and nitric oxide in monitoring asthma. Am J Respir Crit Care Med 1998;158:1042–1046.[Abstract/Free Full Text]
  18. Montuschi P, Kharitonov SA, Ciabattoni G, Corradi M, van Rensen L, Geddes DM, Hodson ME, Barnes PJ. Exhaled 8-isoprostane as a new non-invasive biomarker of oxidative stress in cystic fibrosis. Thorax 2000;55:205–209.[Abstract/Free Full Text]
  19. Kelly FJ, Mudway I, Blomberg A, Frew A, Sandstrom T. Altered lung antioxidant status in patients with mild asthma [letter]. Lancet 1999;354:482–483.[CrossRef][Medline]
  20. Smith LJ, Shamsuddin M, Sporn PH, Denenberg M, Anderson J. Reduced superoxide dismutase in lung cells of patients with asthma. Free Radic Biol Med 1997;22:1301–1307.[CrossRef][Medline]
  21. Calhoun WJ, Reed HE, Moest DR, Stevens CA. Enhanced superoxide production by alveolar macrophages and air-space cells, airway inflammation, and alveolar macrophage density changes after segmental antigen bronchoprovocation in allergic subjects. Am Rev Respir Dis 1992;145:317–325.[Medline]
  22. Velsor LW, van Heeckeren A, Day BJ. Antioxidant imbalance in the lungs of cystic fibrosis transmembrane conductance regulator protein mutant mice. Am J Physiol Lung Cell Mol Physiol 2001;281:L31–L38.[Abstract/Free Full Text]
  23. MacNee W. Oxidants/antioxidants and COPD. Chest 2000;117(5 Suppl 1):303S–317S.[Free Full Text]
  24. Forman HJ, Fridovich I. Superoxide dismutase: a comparison of rate constants. Arch Biochem Biophys 1973;158:396–400.[CrossRef][Medline]
  25. Crapo JD, Oury T, Rabouille C, Slot JW, Chang LY. Copper, zinc superoxide dismutase is primarily a cytosolic protein in human cells. Proc Natl Acad Sci USA 1992;89:10405–10409.[Abstract/Free Full Text]
  26. Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, Donaldson D, Goto J, O'Regan JP, Deng HX, et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 1993;362:59–62.[CrossRef][Medline]
  27. Weisiger RA, Fridovich I. Superoxide dismutase: organelle specificity. J Biol Chem 1973;248:3582–3592.[Abstract/Free Full Text]
  28. Robinson BH. The role of manganese superoxide dismutase in health and disease. J Inherit Metab Dis 1998;21:598–603.[CrossRef][Medline]
  29. Marklund SL. Extracellular superoxide dismutase in human tissues and human cell lines. J Clin Invest 1984;74:1398–1403.
  30. Su WY, Folz R, Chen JS, Crapo JD, Chang LY. Extracellular superoxide dismutase mRNA expressions in the human lung by in situ hybridization. Am J Respir Cell Mol Biol 1997;16:162–170.[Abstract]
  31. Oury TD, Day BJ, Crapo JD. Extracellular superoxide dismutase in vessels and airways of humans and baboons. Free Radic Biol Med 1996;20:957–965.[CrossRef][Medline]
  32. Oury TD, Chang LY, Marklund SL, Day BJ, Crapo JD. Immunocytochemical localization of extracellular superoxide dismutase in human lung. Lab Invest 1994;70:889–898.[Medline]
  33. Assa'ad AH, Ballard ET, Sebastian KD, Loven DP, Boivin GP, Lierl MB. Effect of superoxide dismutase on a rabbit model of chronic allergic asthma. Ann Allergy Asthma Immunol 1998;80:215–224.[Medline]
  34. Sentman ML, Brannstrom T, Marklund SL. EC-SOD and the response to inflammatory reactions and aging in mouse lung. Free Radic Biol Med 2002;32:975–981.[CrossRef][Medline]
  35. Carlsson LM, Jonsson J, Edlund T, Marklund SL. Mice lacking extracellular superoxide dismutase are more sensitive to hyperoxia. Proc Natl Acad Sci USA 1995;92:6264–6268.[Abstract/Free Full Text]
  36. Folz RJ, Abushamaa AM, Suliman HB. Extracellular superoxide dismutase in the airways of transgenic mice reduces inflammation and attenuates lung toxicity following hyperoxia. J Clin Invest 1999;103:1055–1066.[Medline]
  37. Bowler RP, Arcaroli J, Crapo JD, Ross A, Slot JW, Abraham E. Extracellular superoxide dismutase attenuates lung injury after hemorrhage. Am J Respir Crit Care Med 2001;164:290–294.[Abstract/Free Full Text]
  38. Suliman HB, Ryan LK, Bishop L, Folz RJ. Prevention of influenza-induced lung injury in mice overexpressing extracellular superoxide dismutase. Am J Physiol Lung Cell Mol Physiol 2001;280:L69–L78.[Abstract/Free Full Text]
  39. Bowler RP, Nicks M, Warnick K, Crapo JD. Role of extracellular superoxide dismutase in bleomycin-induced pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 2002;282:L719–L726.[Abstract/Free Full Text]
  40. Ghio AJ, Suliman HB, Carter JD, Abushamaa AM, Folz RJ. Overexpression of extracellular superoxide dismutase decreases lung injury after exposure to oil fly ash. Am J Physiol Lung Cell Mol Physiol 2002;283:L211–L218.[Abstract/Free Full Text]
  41. Di Maria GU, Spicuzza L, Mistretta A, Mazzarella G. Role of endogenous nitric oxide in asthma. Allergy 2000;55:31–35.
  42. Hogman M, Frostell CG, Hedenstrom H, Hedenstierna G. Inhalation of nitric oxide modulates adult human bronchial tone. Am Rev Respir Dis 1993;148:1474–1478.[Medline]
  43. Jonsson LM, Rees DD, Edlund T, Marklund SL. Nitric oxide and blood pressure in mice lacking extracellular-superoxide dismutase. Free Radic Res 2002;36:755–758.[CrossRef][Medline]
  44. Hjalmarsson K, Marklund SL, Engstrom A, Edlund T. Isolation and sequence of complementary DNA encoding human extracellular superoxide dismutase. Proc Natl Acad Sci USA 1987;84:6340–6344.[Abstract/Free Full Text]
  45. Adachi T, Kodera T, Ohta H, Hayashi K, Hirano K. The heparin binding site of human extracellular-superoxide dismutase. Arch Biochem Biophys 1992;297:155–161.[CrossRef][Medline]
  46. Sandstrom J, Carlsson L, Marklund SL, Edlund T. The heparin-binding domain of extracellular superoxide dismutase C and formation of variants with reduced heparin affinity. J Biol Chem 1992;267:18205–18209.[Abstract/Free Full Text]
  47. Adachi T, Morihara N, Yamazaki N, Yamada H, Futenma A, Kato K, Hirano K. An arginine-213 to glycine mutation in human extracellular-superoxide dismutase reduces susceptibility to trypsin-like proteinases. J Biochem (Tokyo) 1996;120:184–188.[Abstract/Free Full Text]
  48. Adachi T, Yamada H, Yamada Y, Morihara N, Yamazaki N, Murakami T, Futenma A, Kato K, Hirano K. Substitution of glycine for arginine-213 in extracellular-superoxide dismutase impairs affinity for heparin and endothelial cell surface. Biochem J 1996;313:235–239.
  49. Marklund SL, Nilsson P, Israelsson K, Schampi I, Peltonen M, Asplund K. Two variants of extracellular-superoxide dismutase: relationship to cardiovascular risk factors in an unselected middle-aged population. J Intern Med 1997;242:5–14.[CrossRef][Medline]
  50. Karlsson K, Sandstrom J, Edlund A, Marklund SL. Turnover of extracellular-superoxide dismutase in tissues. Lab Invest 1994;70:705–710.[Medline]
  51. Karlsson K, Lindahl U, Marklund SL. Binding of human extracellular superoxide dismutase C to sulphated glycosaminoglycans. Biochem J 1988;256:29–33.[Medline]
  52. Lookene A, Stenlund P, Tibell LA. Characterization of heparin binding of human extracellular superoxide dismutase. Biochemistry 2000;39:230–236.[CrossRef][Medline]
  53. Enghild JJ, Thogersen IB, Oury TD, Valnickova Z, Hojrup P, Crapo JD. The heparin-binding domain of extracellular superoxide dismutase is proteolytically processed intracellularly during biosynthesis. J Biol Chem 1999;274:14818–14822.[Abstract/Free Full Text]
  54. Bowler RP, Nicks M, Olsen DA, Thogersen IB, Valnickova Z, Hojrup P, Franzusoff A, Enghild JJ, Crapo JD. Furin proteolytically processes the heparin-binding region of extracellular superoxide dismutase. J Biol Chem 2002;277:16505–16511.[Abstract/Free Full Text]
  55. Fattman CL, Chu CT, Kulich SM, Enghild JJ, Oury TD. Altered expression of extracellular superoxide dismutase in mouse lung after bleomycin treatment. Free Radic Biol Med 2001;31:1198–1207.[CrossRef][Medline]
  56. Emelyanov A, Fedoseev G, Abulimity A, Rudinski K, Fedoulov A, Karabanov A, Barnes PJ. Elevated concentrations of exhaled hydrogen peroxide in asthmatic patients. Chest 2001;120:1136–1139.[Abstract/Free Full Text]
  57. Loukides S, Bouros D, Papatheodorou G, Panagou P, Siafakas NM. The relationships among hydrogen peroxide in expired breath condensate, airway inflammation, and asthma severity. Chest 2002;121:338–346.[Abstract/Free Full Text]
  58. Dekhuijzen PN, Aben KK, Dekker I, Aarts LP, Wielders PL, van Herwaarden CL, Bast A. Increased exhalation of hydrogen peroxide in patients with stable and unstable chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1996;154:813–816.[Abstract]
  59. Kasielski M, Nowak D. Long-term administration of N-acetylcysteine decreases hydrogen peroxide exhalation in subjects with chronic obstructive pulmonary disease. Respir Med 2001;95:448–456.[CrossRef][Medline]
  60. Ho LP, Faccenda J, Innes JA, Greening AP. Expired hydrogen peroxide in breath condensate of cystic fibrosis patients. Eur Respir J 1999;13:103–106.[Abstract]
  61. Deykin A, Massaro AF, Drazen JM, Israel E. Exhaled nitric oxide as a diagnostic test for asthma: online versus offline techniques and effect of flow rate. Am J Respir Crit Care Med 2002;165:1597–1601.[Abstract/Free Full Text]
  62. Zanconato S, Scollo M, Zaramella C, Landi L, Zacchello F, Baraldi E. Exhaled carbon monoxide levels after a course of oral prednisone in children with asthma exacerbation. J Allergy Clin Immunol 2002;109:440–445.[CrossRef][Medline]
  63. Ansarin K, Chatkin JM, Ferreira IM, Gutierrez CA, Zamel N, Chapman KR. Exhaled nitric oxide in chronic obstructive pulmonary disease: relationship to pulmonary function. Eur Respir J 2001;17:934–938.[Abstract/Free Full Text]
  64. Paredi P, Shah PL, Montuschi P, Sullivan P, Hodson ME, Kharitonov SA, Barnes PJ. Increased carbon monoxide in exhaled air of patients with cystic fibrosis. Thorax 1999;54:917–920.[Abstract/Free Full Text]
  65. Narang I, Ersu R, Wilson NM, Bush A. Nitric oxide in chronic airway inflammation in children: diagnostic use and pathophysiological significance. Thorax 2002;57:586–589.[Abstract/Free Full Text]
  66. Symonds G, Renzetti AD Jr, Mitchell MM. The diffusing capacity in pulmonary emphysema. Am Rev Respir Dis 1974;109:391–394.[Medline]
  67. Balint B, Kharitonov SA, Hanazawa T, Donnelly LE, Shah PL, Hodson ME, Barnes PJ. Increased nitrotyrosine in exhaled breath condensate in cystic fibrosis. Eur Respir J 2001;17:1201–1207.[Abstract/Free Full Text]
  68. Montuschi P, Collins JV, Ciabattoni G, Lazzeri N, Corradi M, Kharitonov SA, Barnes PJ. Exhaled 8-isoprostane as an in vivo biomarker of lung oxidative stress in patients with COPD and healthy smokers. Am J Respir Crit Care Med 2000;162:1175–1177.[Abstract/Free Full Text]
  69. Pratico D, Basili S, Vieri M, Cordova C, Violi F, Fitzgerald GA. Chronic obstructive pulmonary disease is associated with an increase in urinary levels of isoprostane F2alpha-III, an index of oxidant stress. Am J Respir Crit Care Med 1998;158:1709–1714.[Abstract/Free Full Text]
  70. Paredi P, Kharitonov SA, Barnes PJ. Elevation of exhaled ethane concentration in asthma. Am J Respir Crit Care Med 2000;162:1450–1454.[Abstract/Free Full Text]
  71. Paredi P, Kharitonov SA, Leak D, Ward S, Cramer D, Barnes PJ. Exhaled ethane, a marker of lipid peroxidation, is elevated in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;162:369–373.[Abstract/Free Full Text]
  72. Paredi P, Kharitonov SA, Leak D, Shah PL, Cramer D, Hodson ME, Barnes PJ. Exhaled ethane is elevated in cystic fibrosis and correlates with carbon monoxide levels and airway obstruction. Am J Respir Crit Care Med 2000;161:1247–1251.[Abstract/Free Full Text]
  73. Hanazawa T, Kharitonov SA, Barnes PJ. Increased nitrotyrosine in exhaled breath condensate of patients with asthma. Am J Respir Crit Care Med 2000;162:1273–1276.[Abstract/Free Full Text]
  74. Gaillard MC, Kilroe-Smith TA, Nogueira C, Dunn D, Jenkins T, Fine B, Kallenbach J. Alpha-1-protease inhibitor in bronchial asthma: phenotypes and biochemical characteristics. Am Rev Respir Dis 1992;145:1311–1315.[Medline]
  75. Plusa T, Tchorzewski H. Analysis of proteolytic enzymes and their natural inhibitors in serum and bronchial lavage fluid in atopic bronchial asthma, chronic bronchitis and pneumonia. Allerg Immunol (Leipz) 1985;31:169–178.
  76. Janoff A, Carp H, Laurent P, Raju L. The role of oxidative processes in emphysema. Am Rev Respir Dis 1983;127:S31–S38.[Medline]
  77. Birrer P, McElvaney NG, Rudeberg A, Sommer CW, Liechti-Gallati S, Kraemer R, Hubbard R, Crystal RG. Protease-antiprotease imbalance in the lungs of children with cystic fibrosis. Am J Respir Crit Care Med 1994;150:207–213.[Abstract]
  78. Wu W, Samoszuk MK, Comhair SA, Thomassen MJ, Farver CF, Dweik RA, Kavuru MS, Erzurum SC, Hazen SL. Eosinophils generate brominating oxidants in allergen-induced asthma. J Clin Invest 2000;105:1455–1463.[Medline]
  79. MacPherson JC, Comhair SA, Erzurum SC, Klein DF, Lipscomb MF, Kavuru MS, Samoszuk MK, Hazen SL. Eosinophils are a major source of nitric oxide-derived oxidants in severe asthma: characterization of pathways available to eosinophils for generating reactive nitrogen species. J Immunol 2001;166:5763–5772.[Abstract/Free Full Text]
  80. Van Der Vliet A, Nguyen MN, Shigenaga MK, Eiserich JP, Marelich GP, Cross CE. Myeloperoxidase and protein oxidation in cystic fibrosis. Am J Physiol Lung Cell Mol Physiol 2000;279:L537–L546.[Abstract/Free Full Text]
  81. Roum JH, Buhl R, McElvaney NG, Borok Z, Crystal RG. Systemic deficiency of glutathione in cystic fibrosis. J Appl Physiol 1993;75:2419–2424.[Abstract/Free Full Text]
  82. Crapo JD, Day BJ. Modulation of nitric oxide responses in asthma by extracellular antioxidants. J Allergy Clin Immunol 1999;104:743–746.[CrossRef][Medline]



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