American Journal of Respiratory and Critical Care Medicine

Chronic obstructive pulmonary disease (COPD) is a major worldwide health problem that has an increasing prevalence and mortality (1, 2). Oxidative stress, which can be defined as an increased exposure to oxidants and/or decreased antioxidant capacities, is widely recognized as a central feature of many diseases (3, 4). Considerable evidence now links COPD with increased oxidative stress (5, 6). The purpose of this review is to describe the role and origin of the oxidant–antioxidant disturbances that participate in the development of COPD. Our presentation also addresses ways of assessing the contribution of oxidants and identifies therapeutic approaches that could improve cellular oxidant–antioxidant balance in the lungs of COPD patients.

COPD is an obstructive airway disorder characterized by a slowly progressive and irreversible decrease in FEV1 (1, 2, 7). FEV1 decreases are caused by a narrowing of airway lumen diameters that develops as a result of varying perturbations in both airway and interstitial lung tissue. Airway abnormalities consist of increased wall thickening, intraluminal mucus accumulation, smooth muscle hypertrophy, and small airway lining fluid changes. Additional early lesions include inflammatory cell infiltration and goblet cell metaplasia.

The tissue component of emphysema is defined anatomically as the permanent destructive enlargement of airspaces distal to the terminal bronchioles with a concomitant loss of alveolar attachments (7). Emphysema is recognized in vivo by a decreased diffusing capacity (Dl CO) and reduced lung parenchymal density on chest radiograph and high-resolution computerized tomography.

Chronic bronchitis, a frequent feature of COPD, is a persistent recurrent bronchial hypersecretion that causes expectoration on most days for a minimum of 3 mo per year for at least two successive years (7). The pathology of chronic bronchitis is not unequivocal but primarily includes large airway mucus gland hyperplasia and inflammation; however, hypersecretion may occur without airway obstruction.

Patients with COPD often manifest some reversibility of airway obstruction following treatment with bronchodilators and airway hyperresponsiveness when given constrictor stimuli (8). These similar features often cause difficulties in differentiating COPD from asthma, especially in older patients. However, asthma is usually not related to cigarette smoking, and the reversibility of the obstructive pattern and airway hyperresponsiveness is a more common and more prominent occurrence in asthma than in COPD. In addition, emphysema and chronic hypoxemia are usually absent in asthma (8, 9).

Prevalence and Clinical Course

COPD is rare before the age of 40, but after that age symptoms of hypersecretion occur with increasing frequency. Persistent airflow obstruction becomes more common at around age 60. The prevalence of COPD then increases progressively until 60–70 yr of age when, in large part due to mortality, it becomes more stable. The distribution of COPD in the United States and western Europe shows a similar pattern with respect to age, with an estimated prevalence of more than 10% in individuals who are at least 50 yr of age. The greater prevalence of COPD in men has diminished recently because of increased smoking by women (10).

The clinical manifestations and progression of COPD are influenced by a number of presumed risk factors, which include alpha1-antitrypsin deficiency, recurrent bronchopulmonary infections, air pollution, socioeconomic status, lower birth weight, and a history of severe childhood respiratory infections (11, 12). However, the most striking relationship is between cigarette smoking and COPD. Nearly 90% of all COPD patients are smokers (12, 13). Yet, for unknown reasons, only about 20% of cigarette smokers develop COPD. Smoking may also compound the detrimental effects of inhaled environmental toxins, and vice versa (14).

Because the symptoms and signs of COPD are variable and often attributed mistakenly to increasing age or other conditions, abnormalities in pulmonary function are frequently diagnosed very late or not at all. This is regrettable since earlier diagnosis could be made by measurement of pulmonary function. Assessment of FEV1/FVC is considered the most sensitive indicator for early airway obstruction, and an accelerated decline in pulmonary function can be reliably detected from repeated yearly measurements. Obviously, a great need exists for more effective smoking cessation approaches and/or a safe drug that could reduce the annual decline in FEV1 in COPD patients.

Oxygen Radical–Antioxidant Chemistry

The well-described chemistry of oxygen radicals and antioxidants is depicted in Figure 1 (4, 15). Superoxide anion (O 2) formation from oxygen is the first step. O 2 is generated primarily by mitochondrial metabolism, molybdenum hydroxylase (xanthine, sulfite, and aldehyde oxidases) reactions, arachidonic acid metabolism, and NADPH oxidase-dependent processes in phagocytic cells. Reaction of O 2 and hydrogen peroxide (H2O2) in the presence of transition metal, usually ferrous iron (Fe++), produces the hydroxyl radical (·OH). When catalyzed by neutrophil myeloperoxidase (MPO), H2O2 and a chloride form hypochlorous acid (HOCl). ·OH and HOCl are emphasized because both are extremely potent oxidants. H2O2 gains significance as a central precursor to both ·OH and HOCl (3, 4, 15).

The contribution of iron has become increasingly meaningful in understanding the development of COPD. Iron concentrations were increased in alveolar macrophages (AM) of cigarette smokers, and lung lining fluids obtained from cigarette smokers contained substantially more iron than specimens from nonsmokers (16). Excess iron also appeared to be concentrated in the upper lobes of cigarette smokers (17). The source of the increased iron in lungs of smokers is unknown, but each cigarette contains 0.042 μg of iron (18). Iron also accumulates progressively with age in men and in postmenopausal women—intriguingly, at the time when COPD worsens in both sexes (Figure 2) (19). AM from cigarette smokers also released more iron than AM from nonsmokers in vitro (20). In addition, saturated free fatty acids (mainly stearic and palmitic) concentrated from cigarette smoke bound and transferred ferrous iron into organic phases (21) and enhanced production of HOCl by stimulated polymorphonuclear neutrophils (PMN) in vitro (22). Because of its high reactivity, iron is normally bound to various iron-binding compounds, such as transferrin, ceruloplasmin, and ferritin (23). However, this protective mechanism may be disturbed in the lungs of COPD patients, since cigarette smoke and oxidants can release iron from ferritin (24, 25).

Pulmonary antioxidant defenses are widely distributed and include both enzymatic and nonenzymatic systems (3, 4). The major enzymatic antioxidants are superoxide dismutase (SOD), which degrades O 2 and catalase, and the glutathione (GSH) redox system, which inactivates H2O2 and hydroperoxides (Figure 1). Three forms of SOD may be important: manganese SOD, which is located in mitochondria, Cu-Zn SOD, which resides in the cytoplasm, and extracellular SOD, which lines blood vessels. Another important element is glutathione (GSH), which is a water-soluble, low-molecular-weight tripeptide (L-γ-glutamyl-L-cysteinyl glycine) that is present in high concentrations in each cell. GSH is also present extracellularly and is particularly abundant in lung epithelial lining fluids (ELF). Indeed, GSH concentrations in ELF exceed plasma levels by approximately 100-fold (26, 27). In its antioxidant capacity, GSH forms intermolecular disulphide nonradical end-product-oxidized glutathione (GSSG). GSH is also a cofactor for various enzymes that decrease oxidative stress (3, 4, 15). In contrast, GSSG is either exported from the cell or converted to GSH by a reductase reaction that obtains electrons from NADPH (Figure 1). Vitamin E, β-carotene, vitamin C, uric acid, flavonoids, and bilirubin are some of the nonenzymatic factors that may function as antioxidants (3, 4).

Contribution of Oxidants to COPD

The earliest clue regarding the pathophysiology of COPD was the landmark observation that individuals with congenital α1-antitrypsin deficiency developed emphysema prematurely, especially if they smoked cigarettes (28). This finding pointed convincingly not only to a role for elastase but also for oxidants in COPD because α1-antitrypsin needed to be inactivated by oxidants for elastase to be toxic (29-32). The latter discovery also explained why emphysema developed in individuals who did not have a genetic defect in α1-antitrypsin (30-32). Subsequently, it was shown that cigarette smoke, peroxynitrite, phagocyte, and chemically generated oxidants could inactivate antiproteases in vitro (33-35). In addition, stimulated alveolar type II epithelial cells and AM (but not fibroblasts) from guinea pigs inactivated α1-proteinase inhibitor in the presence of MPO (36). The susceptibility of the α1-antitrypsin methionine site to oxidative injury and the finding that some cigarette smokers had increased levels of α1-antitrypsin with oxidized methionine sites in their lung lavages further implicated oxidant inactivation of α1-antitrypsin as a precursor of elastase-dependent tissue damage in vivo (37, 38). The principle was well demonstrated by studies showing that prior exposure to a small, noninjurious dose of H2O2 remarkably increased the susceptibility of isolated lungs to injury caused by perfusion with neutrophil elastase. In contrast, neutrophil elastase was not appreciably toxic in the absence of oxidant preexposure (39). Additional cardinal aspects in the understanding of COPD were the observations that some cigarette smokers had increased elastase in their lung lavages and that intratracheally instilled human neutrophil elastase or proteinase 3 caused emphysema in animals (37, 40-43).

More needs to be done to validate the protease–antiprotease theory of COPD (32), but many aspects of the pathophysiology of COPD are consistent with the potential consequences of increased lung concentrations of elastase (30). For example, elastase can damage airspaces by degrading elastin and a variety of extracellular membrane proteins, proteoglycans, and glycoproteins. Elastase can also stimulate inflammation by increasing interleukin-8 (IL-8) synthesis, impair healing by inactivating cytokines and growth factors, and produce surfactant abnormalities by cleaving surfactant apoproteins. Additionally, elastase can activate or inactivate various other serpins, inhibitors of neutrophil collagenase, and secretory leukoprotease proteinase inhibitor (SLPI)—an inhibitor of neutrophil elastase (44)—and in that way further modulate inflammation. Cigarette smoke and/or elastase-mediated damage to lung connective tissue structural elements and loss of parenchyma produces overly compliant lungs, early airway closure during expiration, and air trapping, which most likely contribute to the distended, hyperlucent lungs of COPD patients (45).

This historically relevant and pioneering mechanism needs to be viewed in combination with the direct toxicity of oxidants to key lung structures, such as lung connective tissue elements. Oxidants can not only damage DNA, lipids, and proteins (3, 4), but also mediate a variety of processes that could foster the development of COPD. For example, oxidants increase high-molecular-weight glycoconjugate (mucus) production by epithelial cells in culture (Figure 3) (46) and impair cilia function (47). Oxidants also stimulate thromboxane formation, reduce surfactant activity, injure fibroblasts, and produce numerous other effects that might diminish pulmonary lung mechanics and/or lung repair mechanisms in patients with COPD (48-50). Oxidants also promote epithelial permeability (51, 52). Oxidants in cigarette smoke even reduce O 2 generation by PMN in vitro (53). Treatment of endothelial cells with plasma exposed to cigarette smoke activates the pentose phosphate pathway metabolism, increases GSH extrusion, decreases ATP levels, and releases angiotensin-converting enzyme (ACE) (54). These findings were corroborated by findings showing that airway obstruction, reflected by reduced FEV1 levels, correlates with GSH, MPO, and eosinophilic cationic protein (ECP) levels in COPD patients (55), and that treatment with manganese SOD reduces cigarette smoke-induced cytotoxicity (56).

Cigarette Smoke

Cigarette smoke is a rich source of oxidants (Figure 4) (57– 62). The tar component of cigarette smoke (particulate matter that may be decreased by filters) contains an estimated 1018 spins/gram of tar. These cigarette smoke–generated radicals are sufficiently stable to be detected by electron spin resonance. One of these radicals is the semiquinone radical that reduces oxygen to O 2. By comparison, the inhaled gas component of cigarette smoke may contain as many as 1015 organic radicals per puff. The latter radicals are highly reactive, short-lived (< 1 s), carbon- and nitrogen-centered species. Gas phase smoke also contains high concentrations of reactive olefins and dienes. As much as 500 ppm of nitric oxide (NO) exists in cigarette smoke, and cigarette smoke converts tyrosine to 3-nitrotyrosine and dityrosine in a reaction that can be inhibited by GSH, ascorbic acid, or uric acid (63). Exposure to cigarette smoke also rapidly upregulated lung NO synthase activity in rats (64, 65). Peroxynitrates from the reaction of NO and O 2 (4) can also be formed under these circumstances, but their fate and role in COPD are uncertain. Finally, oxidants may increase the toxicity of nitrosamines (66).


The coexistence of airway and parenchymal inflammation in most patients with symptomatic chronic airflow limitation effectively connects inflammation with COPD (67). Airway assessments performed by sputum analysis, bronchoscopy, biopsy, and lung lavage, in some cases separating initial from subsequent samples, have all suggested that inflammation contributes to the development of COPD (68-72). Inflammation may not only be responsible for mild airflow limitation and bronchiolar constriction but also may cause fibrosis, gland hypertrophy, and chronically increased smooth muscle tone. Furthermore, by increasing connective tissue deposition and by decreasing the supporting alveolar structure of the outer wall of the small airways, inflammation may further amplify airway limitation by deforming and narrowing the airway lumen (73-78). Most observations relating to inflammatory cells in COPD have focused on PMN and AM, but eosinophils, lymphocytes, and other cells undoubtedly impact the inflammatory process and may alter oxidant–antioxidant balance (79-82).

Neutrophils (PMN). Biopsies from the lungs of COPD patients and specimens from peripheral airway walls of smokers contained increased numbers of neutrophils. Moreover, lungs of smokers with airway obstruction had more PMN than smokers without airway obstruction (56, 83, 84). Since lung lavage and sputum analyses most likely reflect situations in the respiratory bronchioli and alveoli (85), it is not surprising that PMN were increased in lung lavage and sputum specimens from smokers with COPD (86). Furthermore, the degree of airway obstruction and the number of recovered PMN appeared to be related to the amount smoked in most individuals (71, 83).

Many mechanisms could account for the increased numbers of PMN that accumulate in the lungs of cigarette smokers with COPD. For example, PMN transit time was delayed in lungs immediately after smoking (87). In addition, oxidants decreased PMN deformability and, as a result, may enhance PMN sequestration in small blood vessels (88). More PMN may adhere where lung blood vessels are damaged and flow is abnormally low because of lung injury (89). Cigarette smoking also elicited CuZn SOD inhibitable adhesion of PMN to cultured hamster endothelium (90), and CD18 integrins were increased on the surface of sequestered PMN in the pulmonary vessels of rabbits exposed to cigarette smoke (91). Upregulation of E-selectin expression also occurred in patients with chronic bronchitis, and adhering PMN were associated with E-selectin activity in lung vessels (92). Circulating intercellular adhesion molecule-1 (ICAM-1) and circulating E-selectin levels were increased in COPD patients and probably altered PMN retention in the lung (93). In addition, neurokinin (NK1) receptors mediated cigarette smoke-induced adhesion of PMN (and eosinophils) to the endothelium of venules in the rat tracheal mucosa (94).

Recruitment and activation of PMN and other inflammatory cells into the lung may also involve production by AM, epithelial, or other lung cells (95, 96) of interleukin-8 (IL-8). IL-8 levels were increased in sputum recovered from COPD patients compared with nonsmoking control subjects, cigarette smokers, and asthmatic patients (Figure 5) (97). IL-8 is a potent chemotaxin for PMN in vitro. Another AM and lung cell-derived molecule that may contribute to PMN recruitment is LTB4 (98). In addition, nicotine, a chemoattractant for PMN in vitro, may attract PMN into the lung (99), prevent the reduction in PMN deformability induced by cigarette smoke (100), and/or even prolong PMN survival by suppressing apoptosis (101).

The O2 radical-producing activity of PMN that are lodged within the lungs of COPD patients is unknown, but PMN recovered from the blood of smokers who have elevated peripheral blood leukocyte counts elaborated more O 2 than PMN recovered from nonsmokers or PMN recovered from smokers who have normal circulating leukocyte counts (Figure 6) (102). In addition, PMN recovered from some COPD patients had enhanced chemotaxis, proteolytic, and MPO activities in vitro (103, 104). Similarly, individuals subjected to passive smoking also had increased circulating leukocyte counts and cells that released more oxidants (105). Additionally, in one report (106), circulating O 2 release from PMN correlated with bronchial hyperactivity in COPD patients, while in another report (107), O 2 generation from PMN was increased during acute infectious exacerbations. Increased numbers of PMN appear to be making increased amounts of oxidants in the lungs of COPD patients (108).

Alveolar macrophages. Because of their strategic location and robust effector capabilities, AM may be pivotal in the development of COPD. More AM were recovered from the lungs of smokers, and these AM appeared to be activated since they were larger, stickier, and contained more pigmented cytoplasmic inclusions than AM from nonsmokers (109, 110). Increased AM pigmentation has also been associated with poor lung function (111).

Numerous mechanisms, such as those described for PMN, probably contribute to the recruitment of monocytes and their maturation into AM in lungs of patients with COPD (112-115). In addition, elastin fragments were increased substantially in lungs of cigarette smokers and are selective chemotaxins for monocytes in vitro (116). Prostaglandin F2α and thromboxane B2, most likely derived from activated AM, were also increased in lung lavages of smokers and may facilitate inflammatory responses (117).

AM recovered by lung lavage from healthy young cigarette smokers released more O 2 than AM from nonsmoking control subjects in vitro (Figure 7) (118-120). In addition, subpopulations of higher density AM were increased in smokers compared with nonsmokers and were responsible for the increased CD11/CD18 positivity and enhanced O 2 production of AM from smokers (121). Spontaneous release of increased amounts of H2O2 from smoker monocytes has also been observed and related to accelerated maturation and activation (122). Exposure to tobacco smoke in vitro also increased AM oxidative metabolism (123).

Eosinophils. Peripheral blood eosinophilia has been identified as a risk factor for the development of airway obstruction and a negative prognostic sign in newly diagnosed patients with chronic bronchitis (124, 125). Moreover, airway wall biopsies of patients with COPD contained increased numbers of eosinophils (79), and lung lavages from COPD patients had increased levels of eosinophilic cationic proteins (ECP), a marker of eosinophil activation (126). Furthermore, reversibility of airway obstruction correlated with bronchial eosinophilia in patients with very severe airflow limitation and emphysema, suggesting that eosinophils may contribute to pulmonary oxidative stress. This impression is also supported by observations that eosinophils make much more O 2 than PMN or AM in vitro (127-130). For example, in response to phorbol myristate acetate (PMA), normal human eosinophils generated significantly more O 2 (14.1 ± 3.3 nmol of cytochrome C/10 min/ 5 × 105 cells) than matched neutrophil fractions (5.9 ± 0.9 nmol/ 20 min/5 × 105 cells) (127). By comparison, PMA-stimulated human neutrophils (15 ± 0.8 nmol/20 min/5 × 106 cells) made more O 2 than PMA-stimulated human AM (8.6 ± 1.0 nmol/ 20 min/5 × 106 cells). Although the relationship that eosinophils generate more O 2 than PMN, which generate more O 2 than AM, generally holds true, the pattern is dependent on the stimulus (127).

Xanthine oxidase. Xanthine oxidase (XO), which generates O 2 and H2O2, was increased in lungs of rats exposed to cigarette smoke (131). Lung XO increases might reflect conversion of xanthine dehydrogenase (XD) to XO by elastase or oxidants and/or increased synthesis of XD (132). XO was also increased and associated with increased leukocyte adhesion and erythrocyte (RBC) hemolysis in hamsters exposed to cigarette smoke (90). Reaction of XO-derived O2 metabolites with serum forms chemotaxins for PMN and thereby might be another mechanism responsible for recruiting PMN to the lungs of cigarette smokers (133). Moreover, XO activity was increased in cell-free lung lavages from COPD patients compared with nonsmoking normal subjects and associated with increased O 2 generation, clastogenic (DNA damaging) activity, and uric acid production (Figure 8) (134). Increased lung XO activity could contribute to the increased exhaled H2O2 levels of cigarette smokers (135).

Other sources. Increased numbers of lymphocytes, epithelial, mast, and other metabolically active lung cells that consume oxygen probably release O2 radicals that could alter oxidant–antioxidant balance in the lungs of patients with COPD (Figure 9) (3, 4, 36). Mitochondrial and arachidonic acid metabolism also can generate oxidants that might participate in the development of COPD (34).


Infections may contribute to oxidative stress in patients with COPD by facilitating the recruitment and activation of phagocytic cells in the lung (136). Streptococcus pneumoniae and nonencapsulated Haemophilus influenzae emerge during exacerbations and remissions of COPD (137-140), and O 2 production by blood neutrophils was increased in COPD patients during acute exacerbations and then returned to normal during recovery (141). Even clinically stable COPD patients are colonized with bacteria that might stimulate phagocytic cell oxidant production. The bronchi of 50% of COPD patients are colonized with bacteria belonging to the normal oropharyngeal flora (138, 142). Bacterial adherence may favor bacterial persistence and colonization of the respiratory tract (143, 144), and smokers had an enhanced adherence of S. pneumoniae to their buccal cells in vitro (145). In addition, H. influenzae adhered more to the pharyngeal cells of smokers with chronic bronchitis than healthy subjects (146).

Because oxidants play such a pronounced role in cigarette smoke-induced lung damage, the status of pulmonary antioxidant defense mechanisms assumes paramount importance (3, 4, 15). In 1986, Taylor raised the question, “Is antioxidant deficiency related to chronic obstructive pulmonary disease?” and reported a relationship between a deficiency in plasma antioxidant activity and an abnormal FEV1/FVC ratio in patients with COPD (147). Subsequently, a number of antioxidant disturbances have been observed in COPD patients, but a notable inconsistency exists, and the findings are difficult to compare because of the different designs of the various studies. Some examples of both antioxidant decreases and increases include the following observations.

Antioxidant Decreases

One study found that erythrocytes (RBC) from some smokers had decreased G6PD and GPX activity and were more susceptible to lipid peroxidation in vitro than RBCs from nonsmokers (148). Similarly, RBCs from the children of smoking parents were peroxidized more readily in vitro than RBCs from the children of nonsmokers, and this tendency was reversed by vitamin E treatment (149). RBCs from children with smoking parents also had decreased G6PD, GPX, and SOD activities compared with RBCs recovered from the children of nonsmoking parents (149). In addition, cigarette smoking has been associated with decreased plasma ascorbate, plasma β-carotene, and vitamin C levels (150-160). Additionally, vitamin E levels were lower in the lung lavages of young asymptomatic smokers, and this deficiency was linked with enhanced AM cytotoxicity (Figure 10) (161-165). Establishing the relationship between decreased antioxidant capacity and smoking remains difficult because many confounding variables, such as life-style, diet, and social class, may alter both smoking and changes in antioxidant levels.

Antioxidant Increases

A number of studies have revealed increased antioxidants in cigarette smokers. For example, vitamin E and C levels were increased in the plasma and internal mammary arteries of cigarette smokers compared with nonsmokers, and the smokers with higher vitamin C levels had lower levels of lipid peroxidation (166, 167). In certain smokers, oxidatively stressed AM appeared to accumulate vitamin C and perhaps other antioxidants (168). This may be beneficial since treatment with vitamin C prevented cigarette smoke-induced leukocyte aggregation and adhesion to hamster endothelium in skinfolds (169) and altered biochemical responses in rats (170). In another study, vitamin C intake improved the lung function of cigarette smokers, asthmatics, and bronchitics (171). Nonetheless, in a recent trial, β-carotene treatment may have accelerated the development of lung cancer in cigarette smokers (172, 173).

Additional endogenous mechanisms may increase antioxidant levels in certain smokers. Certain cigarette smokers had increased GSH and glutathione peroxidase activities in their ELF compared with nonsmokers (26, 27, 174, 175). These increased GSH levels in ELF from human smokers are consistent with the high GSH levels observed in animals exposed to cigarette smoke and may be functionally important since reducing lung GSH increased lung epithelial permeability (175– 179). For example, cigarette smoke and its condensates caused an oxidant-induced injury to A549 human type II alveolar epithelial cells (reflected by impaired attachment, decreased proliferation, and lysis), which was reversed by adding GSH extracellularly and worsened by depleting GSH intracellularly with buthionine sulfoxamine (177). Moreover, reduced FEV1 levels correlated with decreased lung lavage GSH levels in smokers with chronic bronchitis, underscoring the importance of adequate GSH levels in COPD. GSH levels were also increased in RBCs from certain cigarette smokers compared with nonsmokers. Adding RBCs from cigarette smokers protected cultured endothelial cells against damage by H2O2 better than adding RBCs from nonsmokers (180). Catalase activity in RBCs can decrease oxidative inactivation of α1-antitrypsin by cigarette smoke, further indicating that alterations in RBC antioxidants may be meaningful (181). In related observations, cigarette smoking increased lung SOD, catalase, and glutathione peroxidase activities, but these responses did not protect the rats against cigarette smoke (182, 183). mRNA for gammaglutamylcysteine synthetase—the rate-limiting enzyme in GSH synthesis—was also increased in human alveolar epithelial cells following exposure to cigarette smoke (184).

The increased antioxidant activity in RBCs and lungs of cigarette smokers and the increased activity of SOD and catalase activities in lungs of rats and hamsters exposed to cigarette smoke are both reminiscent of protective antioxidant responses that occur in oxidative “tolerance” models (185). Tolerance is not a well understood phenomenon, but it appears that an antecedent low-grade oxidative stress can confer a subsequent adaptive resistance to oxidative stress, ostensibly by increasing antioxidant defenses (3, 4, 186). Thus, if oxidant stress contributes to COPD, then adaptive increases in antioxidants may be protective and explain why some cigarette smokers do not develop COPD. Indeed, certain cigarette smokers, for genetic or other reasons, may respond by increasing their antioxidant enzymes (Antioxidant Responsive), while other smokers, for unknown reasons, do not increase their lung antioxidants (Antioxidant Unresponsive).

Consistent with the tolerance premise was the finding that individual measurements of GSH levels in RBC and ELF of cigarette smokers showed great individual variability. Therefore, it is possible that individuals with absolutely or relatively lower GSH and other compensating responses are more susceptible to COPD, while individuals with enhanced antioxidant responses are less susceptible to COPD (187-189). A case in point exists in patients with tobacco smoke-induced optic neuropathy who did not develop the increased GSH levels found in cigarette smokers who do not develop the ocular disorder (190). Thus, adaptive increases in antioxidants in certain individuals may be a valuable protective mechanism against COPD induced by cigarette smoke (186, 191).

A number of abnormalities and measurement of biomarkers have suggested that increased oxidative stress is occurring and is detrimental in cigarette smokers with COPD. The most convincing way to determine the involvement of oxidative stress in COPD is to directly measure oxygen radicals in lung tissue or exhaled air. However, direct measurement is difficult since oxygen radicals are highly reactive, short-lived species, and electron spin resonance and other direct techniques cannot be easily applied to the lung. The alternative has been to measure damage inflicted by oxygen radicals upon various lung biomolecules, usually lipids, proteins, or DNA. Some of the approaches that have been used which indicate that oxidative stress is occurring in COPD are described below.

H2O2 Exhalation

During acute exacerbations, patients with COPD exhaled more H2O2 by 100% than stable ex-smokers with COPD or normal subjects (Figure 11) (135). The source of the exhaled H2O2 was unknown (192), but AM from smokers released significantly more O 2 than AM from nonsmokers (118), and AM recovered by lung lavage from subjects with a recent lower respiratory tract infection released more H2O2 in vitro (122). Additionally, smokers had increased lung lavage XO levels (134).

Lipid Peroxidation

Free radicals trigger lipid peroxidation chain reactions by abstracting a hydrogen atom from a side-chain methylene carbon (193-198). The resulting carbon-centered lipid radical then reacts with O2 in aerobic cells to give a peroxyl radical that subsequently propagates a chain reaction which transforms polyunsaturated fatty acids (either as free acids or as part of lipids) into lipid hydroperoxides. Lipid peroxidation (LPO) can impair membrane function, inactivate membrane-bound receptors and enzymes, disturb membrane fluidity, and increase permeability (193). Lipid hydroperoxides can also interact with antioxidants (such as α-tocopherol) or decompose after reacting with metal ions (such as iron or copper) or iron proteins (such as hemoglobin), leaving hydrocarbon gases (ethane, pentane) and unsaturated aldehydes (malondialdehyde) as by-products (194). Methods for detecting and quantifying LPO in vitro and in vivo usually examine lipid peroxides or derived radicals directly or else detect lipid peroxide conjugates or decomposition products indirectly (194-198).

Lipid peroxidation products (assessed as thiobarbituric acid-reacting substances) were increased in the plasma and lung lavages of healthy cigarette smokers (24, 166, 199-206), and patients with emphysema, chronic bronchitis, and asthma (203-205). In addition, increased LPO products correlated inversely with the time elapsed from the last exposure to tobacco smoke and the degree of small airway obstruction in COPD patients (205). Cigarette smoke exposure produced lipid peroxidation in plasma in vitro (201). Lipid peroxidation occurred in cigarette smoke-exposed rat tracheal epithelium along with histochemical evidence of continuing production of both H2O2 and O 2 at the apical cell membrane (207). LPO also occurred in lungs of animals exposed to cigarette smoke and sonicates of AM exposed to cigarette smoke in vitro (208). Pentane and ethane exhalation were increased in cigarette smokers (209, 210), and ethane exhalation was decreased by antioxidant treatment (210). Notwithstanding these observations, some concern has persisted because of the difficulty in accurately measuring lipid peroxidation in vivo (211). This worry was mitigated recently by findings that plasma levels of free and esterified F2-isoprostanes (a series of bioactive prostaglandin F2-like compounds that are made by free radical catalyzed peroxidation of arachidonic acid) were increased in smokers compared with nonsmokers (Figure 12) (212). Moreover, free and esterified F2-isoprostane levels decreased following smoking cessation for 2 wk. Additionally, plasma F2-isoprostanes were normal or only slightly increased in some cigarette smokers, consistent with the possibility that certain individuals are more resistant to oxidative stress, perhaps as a consequence of their enhanced antioxidant defenses (212).

DNA Damage

Many different compounds in cigarette smoke can readily react directly to form radicals, while other substances (procarcinogens) must be activated by one or more of the p-450 cytochromes before becoming electrophilic species that enter into damaging interactions which produce single-strand breaks in DNA (213-215). For example, treating human respiratory tract tracheobronchial epithelial cells with gas-phase cigarette smoke produced DNA strand breakage and the formation of double-stranded DNA (216). Moreover, multiple chemical modifications (including guanine and adenine base deamination) occurred in all four DNA bases in a pattern suggestive of reaction with ·OH or deaminating species, such as HNO2, NO2, N2O3, and ONOO in cigarette smoke (216). Hydroquinone and semiquinone radicals in cigarette smoke can also produce oxyradicals that may nick DNA, causing mutations and, ultimately, carcinogenesis (46, 217).

Increased 8-hydroxy-2′-deoxyguanosine activity, a product of the reaction of oxidants and DNA, has been detected in the peripheral blood leukocytes of cigarette smokers and in lung epithelial cells exposed to cigarette smoke in vitro (218, 219). Likewise, oxidant-mediated DNA strand breaks occurred more frequently in mononuclear leukocytes exposed to activated PMN from cigarette smokers (220).

Other “molecular dosimeters” may indicate indirectly the level of biologically relevant exposure to oxidants. Typical examples include polycylic aromatic hydrocarbon (PAH)-DNA adducts, which reflect exposure to tobacco smoke (221, 222). These compounds exist in pulmonary tissue, circulating blood cells, and AM. 4-Hydroxy-1-(3-pyridyl)-1-butanone (HPB)- DNA adducts derived from metabolism of nicotine similarly reflect the amount of oxidative stress induced by cigarette smoke. Alkyl-DNA adducts, which may be formed during oxidation processes in target cells, have been detected in lung tissue and AM of cigarette smokers (223, 224).

Finally, certain gene mutations might be regarded as unique “fingerprints” of oxidative stress to DNA. Mutations of the p53 and K-ras genes are both associated with cigarette smoking, and the higher rate of lung cancer in cigarette smokers suggests the damaging effects of oxidants on DNA (225, 226). Although it has been suggested that benzo(a)pyrenes in tobacco smoke were related to certain mutations (GC → TA transversion), oxidation reactions may be involved, since similar mutations develop following exposure to hyperoxia.

Carbonyl Proteins

Oxygen radicals can modify amino acid side chains, form protein aggregates, cleave peptide bonds, and make proteins more susceptible to proteolytic degradation (227). In the process, some amino acid residues are converted to carbonyl derivatives. Exposure to gas-phase cigarette smoke also modified human plasma proteins, producing carbonyl proteins with lost sulfhydryl groups (228, 229). In one study, the content of oxidized proteins recovered by lung lavage was 0.59 ± 0.14 nmol carbonyl/ml bronchoalveolar lavage fluid in asymptomatic smokers compared with 0.30 ± 0.07 nmol carbonyl/ml bronchoalveolar lavage fluid in nonsmoking control subjects (230). Plasma protein sulfhydryls were also depleted following exposure to cigarette smoke in vitro. Reaction of proteins with nitric oxide or its derivatives may also lead to protein degradation (63). Furthermore, using a Trolox (vitamin E analog)- related assay, plasma antioxidant activity was decreased acutely in cigarette smokers, following acute exacerbations in COPD patients, and associated with protein sulfhydryl oxidation (107).

Improving the quality and duration of life of COPD patients is a distinct challenge. The specific therapeutic goals are to reduce symptoms, preserve lung function, optimize gas exchange, and limit and/or treat acute exacerbations rapidly (231). Because pulmonary function declines with aging, everything must be done to prevent any additional functional loss caused by COPD. Indeed, elderly cigarette smokers who develop COPD may lose as much as 80 ml of FEV1/yr compared with 33 ml/yr for nonsmokers (232).

The treatment for cigarette smoke-induced COPD has been reviewed extensively (233, 234). In general, the accepted strategies encompass approaches that limit initiating and aggravating triggers, such as tobacco smoke (smoking cessation) and inhalation of environmental and work-related irritants. More specific treatment consists of administering bronchodilators, antiinflammatory agents, and/or antibiotics. Additional approaches include nutritional supplementation, immunization, breathing exercises, pulmonary rehabilitation, and ultimately supplemental oxygen, given nocturnally or continuously. Conventional therapies for COPD are discussed below, focusing on their potential effect on oxidant–antioxidant balance.

Smoking Cessation

It is not surprising that the rates of decline in lung function in smokers with mild COPD were reduced by smoking cessation, since smoking cessation potentially decreases most sources of oxidative stress. A prime example of this possibility was the finding that smoking cessation for 6 mo reduced the numbers of AM and PMN recoverable by lung lavage (235-237).


While the primary effect of β2 agonists is to relax airway smooth muscle, some antioxidant benefits may be provided as well (238-240). For example, O 2 production by AM was decreased in chronic bronchitis patients treated with formoterol, and terbutaline reduced O 2 generation by AM in vitro (241, 242). However, the effects of theophylline on oxygen radical generation by PMN remain controversial (243-245). Incubating blood PMN from healthy volunteers with increasing concentrations of theophylline inhibited their oxygen radical production in a dose-dependent fashion. Importantly, inhibition was reached at clinically achievable concentrations of theophylline (244, 245). However, in other studies theophylline treatment enhanced O 2 production by PMN (246, 247). Theophylline treatment also increased O 2 release from eosinophils from patients with peripheral eosinophilia (248).


It is still unclear whether inhaled corticosteroids attenuate COPD, even though several placebo-controlled clinical studies have addressed the question (249-255). However, steroids may have an antioxidant effect by decreasing the numbers as well as the oxidative and chemotactic responses of neutrophils. In one study, prolonged daily oral corticosteroid treatment decreased the O 2 production and the chemotactic responsiveness of unstimulated, but not stimulated, peripheral blood PMN (256). In another study, O 2 generation by PMN was decreased after in vivo prednisolone treatment in patients with emphysema (257). In another study, dexamethasone did not alter unstimulated O 2 production by PMN either in vitro or in vivo (258). Likewise, inhaled corticosteroids did not change PMN numbers or IL-8 levels in the peripheral blood but did decrease the number of PMN in the sputum of COPD patients (259). Steroid therapy did not reduce eosinophil numbers or ECP levels in the sputum of COPD patients (260).


Antibiotics used for treating chronic bronchitis would seem to have a certain role in reducing oxidative stress in COPD by reducing infection and thereby lung inflammation. In addition, tetracycline and other anti-infectives may have independent antioxidant properties.

Miscellaneous Drugs

Nedocromil sodium inhibited O 2 production by PMN in vitro (261). Ambroxol is an expectorant with antioxidant properties that stimulates the formation and release of surfactant by type II pneumocytes (262, 263). Inhaled NO (40 ppm) had no effect on respiratory system resistance in patients with COPD or healthy subjects (264).

N-acetylcysteine (NAC) is the most widely investigated drug with antioxidant properties that has been used in both experimental and clinical settings which are relevant to COPD (265– 267). Although given initially because of its mucolytic properties, NAC is a thiol-containing compound that may act as an antioxidant by providing cysteine intracellularly for the enhanced production of GSH (268). This potentially beneficial antioxidant effect is suggested because NAC decreased H2O2- induced damage to epithelial cells in vitro (269) and NFκB activation in some cells (270). In addition, NAC treatment reduced cigarette smoke-induced abnormalities in PMN (271), AM, fibroblasts, and epithelial cells in vitro (272-275). NAC treatment also attenuated rat secretory cell hyperplasia induced by tobacco smoke (276) and prevented HOCl-mediated inactivation of α1-proteinase inhibitor in vitro (277). NAC treatment may alter lung oxidant–antioxidant imbalance in humans (278). NAC given orally increased lung lavage GSH levels (279), reduced O 2 production by AM recovered by lavage (273), and decreased lung lavage PMN chemiluminescence in vitro (280). However, peripheral blood PMN obtained from healthy nonsmokers treated with NAC produced normal amounts of H2O2 (273).

The clinical efficacy of NAC has been investigated in a number of studies of patients with chronic bronchitis, with and without COPD. Treatment with NAC caused symptomatic improvement in COPD patients, reflected by decreased sputum viscosity and purulence and improved sputum expectoration (281). In addition, NAC treatment reduced the number of exacerbations and sick-leave days in some (282, 283), but not other (284-286), investigations of COPD patients. Parenthetically, NAC treatment also decreased the number of viral infections (287, 288) and airway bacterial colonization (289) in patients with COPD. In a recent investigation in Sweden, the decline in FEV1 in COPD patients who took NAC for 2 yr was less than in a reference group (Figure 13) (290). This favorable effect of NAC was particularly apparent in COPD patients over 50 yr of age (yearly decline of 30 ml in FEV1) compared with the reference group (yearly decline of 54 ml in FEV1).

COPD is a costly health problem (291). As reviewed herein, a myriad of evidence suggests that oxidative stress contributes to COPD (Figure 14) (292). Nonetheless, obtaining definitive proof that oxidants contribute to COPD and/or that antioxidant therapy is beneficial in COPD remains problematic. Indeed, because COPD is a chronic, progressive disease, long-term study of many patients would be required. Furthermore, evaluation is complicated because of coincident decreases in pulmonary function related to aging and other maladies. Clinical investigations must also account for variations in the duration of smoking, daily smoking consumption, and smoking cessation, as well as for other confounding factors, such as cardiovascular disease and cancer. Suitable endpoints are also difficult because objective decreases in FEV1 and mortality do not change sufficiently in the short term. Other changes, such as exacerbations and sick days, which occur more rapidly, are not as convincing because of their subjectivity. Not surprisingly, for the aforementioned reasons, none of the presently used short-term therapies, such as antibiotics or steroids, has been shown to unequivocally improve FEV1 or survival in COPD. So far, appreciable improvement in declines in FEV1 has been found in COPD patients only after smoking cessation (293, 294).

It should be possible to gain meaningful information from studies using surrogate markers that reflect oxidative status (295). If an acceptable marker of oxidative stress increased in COPD patients and correlated with either an increased rate of pulmonary dysfunction and/or the severity of COPD, then the association between oxidants and COPD would be strengthened. Likewise, if antioxidant therapy decreased both the marker and meaningful endpoints, then the role of oxidants and the value of antioxidant therapy in COPD would be further supported, even if there was no significant effect on mortality or FEV1 during the short-term analyses. Finally, if these approaches could be applied to subpopulations of individuals who have rapid declines in FEV1, then a definitive answer to this important premise might be secured even more rapidly.

It is obvious from this review that lung oxidant–antioxidant balance is abnormal in cigarette smokers (Figure 14). However, it remains unclear why only certain cigarette smokers (actually a minority) develop COPD and, for that matter, lung cancer and atherosclerosis. Exposure to inhaled oxidants from cigarette smoke would seem to be fairly consistent among individuals with comparable smoking histories. The answer to this intriguing question lies in an improved understanding of the nature of the oxidant–antioxidant balance and the genetic factors and other intrinsic factors, including dietary factors, that control this balance (296). Unfortunately, because of the great variability that exists in the individuals who smoke and difficulties in measuring oxidative status, many challenges remain in understanding, treating, and preventing COPD.

William de Backer, M.D., Ph.D.

Professor of Pulmonary Medicine

University Hospital of Antwerp, Belgium

Richard Dekhuijzen, M.D., Ph.D.

Department of Pulmonary Medicine

University Hospital of Nijmegen, The Netherlands

Maurice Demedts, M.D., Ph.D.

Professor of Pulmonary Medicine

University Hospital of Leuven, Belgium

Cees van Herwaarden, M.D., Ph.D.

Professor of Pulmonary Medicine

University Hospital of Nijmegen, The Netherlands

Robert van Klaveren, M.D., Ph.D.

Department of Pulmonary Medicine

University Hospital of Antwerp, Belgium

Jan-Willem Lammers, M.D., Ph.D.

Professor of Pulmonary Medicine

University Hospital of Utrecht, The Netherlands

Sven Larsson, M.D., Ph.D.

Professor of Pulmonary Medicine

Sahlgrenska University Hospital

Gothenburg, Sweden

Bo Lundback, M.D., Ph.D.

National Institute of Occupational Health

Umea, Sweden

Stefano Petruzzelli, M.D., Ph.D.

Department of Respiratory Physiology

University of Pisa, Italy

Dirkje Postma. M.D., Ph.D.

Professor of Pulmonary Medicine

University Hospital of Groningen, The Netherlands

Gerdt Riise, M.D., Ph.D.

Department of Pulmonary Medicine

Sahlgrenska University Hospital

Gothenburg, Sweden

Paul Vermeire, M.D., Ph.D.

Professor of Pulmonary Medicine

University Hospital of Antwerp, Belgium

Emiel Wouters, M.D., Ph.D.

Professor of Pulmonary Medicine

University Hospital Maastricht, The Netherlands

Jean Claude Yernault, M.D., Ph.D.

Professor of Pulmonary Medicine

Erasmus University Brussels, Belgium

Nico van Zandwijk, M.D., Ph.D.

The Netherlands Cancer Institute

Antoni van Leeuwenhoek Huis Amsterdam, The Netherlands

1. ATS StatementStandards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med152(Suppl.)1995S77S121
2. Siafakas N. M., Vermeire P., Pride N. B., Paoletti P., Gibson J., Howard P., Yernault J. C., DeCramer M., Higgenbottom T., Postma D. S., Rees J.Optimal assessment and management of chronic obstructive pulmonary disease (COPD): a consensus statement of the European Respiratory Society (ERS). Eur. Respir. J8199513981420
3. Heffner J. A., Repine J. E.State of the art: pulmonary strategies of antioxidant defense. Am. Rev. Respir. Dis1401989531554
4. Halliwell B.Antioxidants in human health and disease. Ann. Rev. Nutr1619963350
5. Cantin A. M., Crystal R. G.Oxidants, antioxidants and the pathogenesis of emphysema. Eur. J. Respir. Dis661985717
6. Church, D. F., and W. A. Pryor. 1991. The oxidative stress placed on the lung by cigarette smoke. In R. G. Crystal and J. B. West, editors. The Lung: Scientific Foundations. Raven Press, New York. 1971– 1979.
7. Fletcher C., Pride N. B.Definitions of emphysema, chronic bronchitis, asthma, and airflow obstruction: 25 years on from the Ciba symposium. Thorax3919848185
8. Vermeire, P. 1993. Differential diagnosis in asthma and chronic obstructive pulmonary disease. In N. J. Gross, editor. Anticholinergic Therapy in Obstructive Airways Disease. Franklin Scientific Publ. 48–60.
9. Vermeire P. A., Pride N. B.A splitting look at chronic nonspecific lung disease (CNSLD): common features but diverse pathogenesis. Eur. Respir. J41991490496
10. Feinleib M., Rosenberg H. M., Collins J. G., Delozier J. E., Pokras R., Chevarley F. M.Trends in COPD morbidity and mortality in the United States. Am. Rev. Respir. Dis1401989918
11. Edelman N. H., Kaplan R. M., Buist A. S., Cohen A. B., Hoffman L. A., Kleinhenz M. E., Snider G. L., Speizer F. E.Chronic obstructive pulmonary disease: task force on research and education for the prevention of control of respiratory diseases. Chest1021992243256
12. Snider G. L.Chronic obstructive pulmonary disease: risk factors, pathophysiology, and pathogenesis. Ann. Rev. Med401989411429
13. Peto R., Lopez A. D., Boreham J., Thun M., Heatch C.Mortality from tobacco in developed countries: indirect estimation from national vital statistics. Lancet339199212681278
14. Oxman A. D., Muir D. C. F., Shannon H. S., Stock S. R., Hnizdo E., Lange H. J.Occupational dust exposure and chronic obstructive pulmonary disease. Am. Rev. Respir. Dis14819933848
15. Bast A., Haenen G. R. M. M., Doelman C. J. A.Oxidants and antioxidants: state of the art. Am. J. Med911991213
16. Thompson A. B., Bohling T., Heires A., Linder J., Rennard S. I.Lower respiratory tract iron burden is increased in association with cigarette smoking. J. Lab. Clin. Med1171991494499
17. Nelson M. E., O'Brien-Ladner A. R., Wesselius L. J.Regional variation in iron and iron-binding proteins within the lungs of smokers. Am. J. Respir. Crit. Care Med152199613531358
18. U.S. Public Health Service. 1979. Smoking and Health: A Report of the Surgeon General. U.S. Government Printing Office, Washington, DC. DHEW Publication No. 79-50066.
19. Cook J. D., Finch C. A., Smith N. J.Evaluation of the iron status of a population. Blood481976449455
20. Wesselius L. J., Nelson M. E., Skikne B. S.Increased release of ferritin and iron by iron loaded alveolar macrophages in cigarette smokers. Am. J. Respir. Crit. Care Med.1501994690695
21. Qian M. W., Eaton J. W.Iron translocation by free fatty acids. Am. J. Pathol139199114251434
22. Qian M. W., Eaton J. W.Free fatty acids enhance hypochlorous acid production by activated neutrophils. J. Lab. Clin. Med12419948695
23. Gladston M., Feldman J. G., Levytska V., Magnussen B.Antioxidant activity of serum ceruloplasmin and transferrin available iron-binding capacity in smokers and nonsmokers. Am. Rev. Respir. Dis1351987783787
24. Lapenna D., De Gioia S., Mezzetii A., Ciofani G., Consoli A., Marzio L., Cuccurullo F.Cigarette smoke, ferritin, and lipid peroxidation. Am. J. Respir. Crit. Care Med1511995431435
25. Moreno J. J., Foroozesh M., Church D. F., Pryor W. A.Release of iron from ferritin by aqueous extracts of cigarette smoke. Chem. Res. Toxicol51992116123
26. Cantin A. M., North S. L., Fells G. A., Hubbard R. C., Crystal R. G.Oxidant-mediated epithelial cell injury in idiopathic pulmonary fibrosis. J. Clin. Invest79198716651673
27. Cantin A. M., North S. L., Hubbard R. C., Crystal R. G.Normal alveolar epithelial lining fluid contains high levels of glutathione. J. Appl. Physiol631989152157
28. Laurell C. B., Ericksson S.The electrophoretic alpha-globulin pattern of serum in alpha-1-antitrypsin deficiency. Scand. J. Clin. Invest151963132140
29. Fujita J., Nelson N. L., Daughton D. M., Dobry C. A., Spurzem J. R., Irino S., Rennard S. J.Evaluation of elastase and antielastase balance in patients with chronic bronchitis and pulmonary emphysema. Am. Rev. Respir. Dis14219905762
30. Janoff A.Biochemical links between cigarette smoking and pulmonary emphysema. J. Appl. Physiol551983285293
31. Janoff A.Elastases and emphysema: current assessment of the protease-antiprotease hypothesis. Am. Rev. Respir. Dis1321985417433
32. Shapiro S. D.The pathogenesis of emphysema: the elastase: antielastase hypothesis 30 years later. Proceedings of the Assoc. Amer. Phys.1071995346352
33. Pryor W. A., Dooley M. D., Church D. F.The mechanisms of inactivation of human alpha-1-proteinase inhibitor by gas phase cigarette smoke. Free Radic. Biol. Med.21986161168
34. Hubbard R. C., Ogushi F., Fells G. A., Cantin A. M., Jallat S., Courtnery M., Crystal R. G.Oxidants spontaneously released by alveolar macrophages of cigarette smokers can inactivate the active site of alpha 1-antitrypsin, rendering it ineffective as an inhibitor of neutrophil elastase. J. Clin. Invest80198712891295
35. Wallaert B., Gressier B., Marquette C. H., Gosset P., Remy-Jardin M., Mizon J., Tonnel A. B.Inactivation of α1-proteinase inhibitor by alveolar inflammatory cells from smoking patients with or without emphysema. Am. Rev. Respir. Dis147199315371543
36. Wallaert B., Certs A., Gressier B., Gosset P., Voisen C.Oxidative inactivation of α-1-proteinase inhibitor by alveolar epithelial type II cells. J. Appl. Physiol75199323762382
37. Carp H., Miller F., Hoidal J. R., Janoff A.Potential mechanism of emphysema: alpha-1-proteinase inhibitor recovered from lungs of cigarette smokers contains oxidized methionine and has decreased elastase inhibitor capacity. Proc. Natl. Acad. Sci. U.S.A.79198220412045
38. Maier K. L., Leuschel L., Constabel U.Increased oxidized methionine residues in BAL fluid proteins in acute or chronic bronchitis. Eur. Respir. J51992651658
39. Baird B. R., Cheronis J. C., Sandhaus R. A., Berger E. M., White C. W., Repine J. E.Oxygen metabolites and neutrophil elastase synergistically cause edematous injury in isolated rat lungs. J. Appl. Physiol61198622242229
40. Janoff A., Sloan B., Weinbaum G.Experimental emphysema induced with purified human neutrophil elastase: tissue localization of the instilled protease. Am. Rev. Respir. Dis1151977461
41. Senior R. M., Tegner H., Kuhn C., Ohlsson K., Starcher B. C., Pierce J. A.The induction of pulmonary emphysema induced with human leukocyte elastase. Am. Rev. Respir. Dis1161977469475
42. Snider G., Lucey L. E. C., Christensen T. G., Stone P. J., Calore J. D., Catanese A., Franzblau C.Emphysema and bronchial secretory cell metaplasia induced in hamsters by human neutrophil products. Am. Rev. Respir. Dis1291984155160
43. Kao R. C., Wehner N. G., Skubitz K. M., Gray B. H., Hoidal J. R.Proteinase 3: a distinct human polymorphonuclear leukocyte proteinase that produces emphysema in hamsters. J. Clin. Invest82198819631973
44. Kramps J. A., van Twisk C., Digkman D. H.Oxidative inactivation of antileukoprotease is triggered by polymorphonuclear leukocytes. Clin. Sci7519885362
45. Laurent P., Janoff A., Kagan H. M.Cigarette smoke blocks cross-linking of elastin in vitro. Am. Rev. Respir. Dis1271983189192
46. Adler K. B., Holden-Stauffer W. J., Repine J. E.Oxygen metabolites stimulate release of high molecular weight glycoconjugates by cell and organ cultures of rodent respiratory epithelium via an arachidonic acid-dependent mechanism. J. Clin. Invest8519907585
47. Feldman C., Anderson R., Kanthakumar K., Vargas A., Cole P. J., Wilson R.Oxidant-mediated ciliary dysfunction. Free Radic. Biol. Med171994110
48. Tate R. M., Morris H. G., Schroeder W. R., Repine J. E.Oxygen metabolites stimulate thromboxane production and vasoconstriction in isolated saline-perfused rabbit lungs. J. Clin. Invest741984608613
49. Baker R. R., Panus P. C., Holm B. A., Engstrom P. C., Freeman B. A., Matalon S.Endogenous xanthine oxidase-derived O2 metabolites inhibit surfactant metabolism. Am. J. Physiol2591990328334
50. Barrows S., Ward P., Sleightholm M., Ritter J., Dollery C.Cigarette smoking: profiles of thromboxane- and prostacyclin-derived products in human urine. Biochim. Biophys. Acta9931979121127
51. Jones J. G., Lawler P., Crawler J. C. W., Mintz B. D., Hulands G., Veall N.Increased alveolar epithelial permeability in cigarette smokers. Lancet119806668
52. Li X. Y., Donaldson K., Rahman I., MacNee W.An investigation of the role of glutathione in the increased epithelial permeability induced by cigarette smoke in vivo and in vitro. Am. J. Respir. Crit. Care Med149199415181525
53. Tsuchiya M., Thompson D. F., Suzuki Y. J., Cross C. E., Parker L.Superoxide formed from cigarette smoke impairs polymorphonuclear leukocyte active oxygen generation activity. Arch. Biochem. Biophys29919923037
54. Noronha-Dutra A. A., Epperlein M. M., Woolf N.Effect of cigarette smoking on cultured human endothelial cells. Cardiovasc. Res271993774778
55. Linden M., Rasmussen J. B., Piitulainen E., Tunek A., Larson M., Tegner H., Venge P., Laitinen L. A., Brattsand R.Airway inflammation in smokers with nonobstructive and obstructive chronic bronchitis. Am. Rev. Respir. Dis148199312261232
56. Jordan J., Wan S., Gairola C., St. Clair D.Protective role of manganese superoxide dismutase in cigarette smoke-induced cytotoxicity (abstract). Proceedings of the Annual Meeting of the American Association of Cancer Researchers341993A97
57. Pryor W. A., Stone K.Oxidants in cigarette smoke: radicals, hydrogen peroxides, peroxynitrate, and peroxynitrite. Ann. N.Y. Acad. Sci68619931228
58. Church D. F., Pryor W. A.Free-radical chemistry of cigarette smoke and its toxicological implications. Environ. Health Perspect641985111126
59. Pryor W. A., Prier D. G., Church D. F.Electron-spin resonance study of mainstream and sidestream cigarette smoke: nature of free radicals in gas-phase smoke and cigarette tar. Environ. Health Perspect471983345355
60. Church D. F., Burkey T. J., Pryor W. A.Preparation of human lung tissue from cigarette smokers for analysis by electron spin resonance spectroscopy. Methods Enzymol1681990665669
61. Bluhm A. L., Weinstein J., Sousa J. A.Free radicals in tobacco smoke. Nature2291971500
62. Zang L. Y., Stone K., Pryor W. A.Detection of free radicals in aqueous extracts of cigarette tar by electronspin resonance. Free Radic. Biol. Med191995161167
63. Eiserich J. P., Vossen V., O'Neill C. A., Halliwell B., Cross C. E., van der Vliet A.Molecular mechanisms of damage by excess nitrogen oxides: nitration of tyrosine by gas-phase cigarette smoke (abstract). FEBS Lett35319945356
64. Wurzel H., Yeh C. C., Gairola C., Chow C. K.Oxidative damage and antioxidant status in the lungs and bronchoalveolar lavage fluid of rats exposed chronically to cigarette smoke. Journal of Biochemical Toxicology1019951117
65. Zhou C., Gilks B., Churg A., Wright J. L.Exposure to cigarette smoke causes rapid upregulation of pulmonary nitric oxide synthetase (abstract). Am. J. Respir. Crit. Care Med1531996A734
66. Weitberg A. B., Converse D.Oxygen radicals potentiate the genetic toxicity of tobacco-specific nitrosamines. Clin. Genet4319938891
67. Jeffery P. K.Morphology of the airway wall in asthma and in chronic obstructive pulmonary disease. Am. Rev. Respir. Dis143199111521158
68. Adesina A. M., Vallyathan V., McQuillen E. N., Weaver S. O., Craighead J. E.Bronchiolar inflammation and fibrosis associated with smoking. Am. Rev. Respir. Dis1431991144149
69. Ollerenshaw S. L., Woolcock A. J.Characteristics of inflammation in biopsies from large airways of subjects with asthma and subjects with chronic airflow limitation. Am. Rev. Respir. Dis1451992922927
70. Martin T. R., Raghu G., Maunder R. J., Springmeyer S. C.The effects of chronic bronchitis and chronic air-flow obstruction on lung cell populations recovered by bronchoalveolar lavage. Am. Rev. Respir. Dis1321985254260
71. Eidelman D., Saetta M. P., Nai-San H. G., Wang, Hoidal J. R., King M., Cosio M. G.Cellularity of the alveolar walls in smokers and its relation to alveolar destruction. Am. Rev. Respir. Dis141199015471552
72. Merchant R. K., Schwartz D. A., Helmers R. A., Dayton C. S., Hunninghake G. W.Bronchoalveolar lavage cellularity. Am. Rev. Respir. Dis1461992488453
73. Dunnill M. S., Massarella G. R., Anderson J. A.A comparison of the quantitative anatomy of the bronchi in normal subjects, in status asthmaticus, in chronic bronchitis, and in emphysema. Thorax6919693942
74. Wright J. L., Hobson J. E., Wiggs B., Pare P. D., Hogg J. C.Airway inflammation and peribronchiolar attachments in the lungs of nonsmokers, current and ex-smokers. Lung1661988277286
75. Wiggs B. R., Bosken C., Paré P. D., James A., Hogg J. C.A model of airway narrowing in asthma and in chronic obstructive pulmonary disease. Am. Rev. Respir. Dis145199212511258
76. Hobson J. E., Wright J. L., Wiggs B. R., Hogg J. C.Comparison of the cell content of lung lavage fluid with the presence of emphysema and peripheral airways inflammation in resected lungs. Respiration50198618
77. Matsuba K., Wright J. L., Wiggs B. R., Paré P. D., Hogg J. C.The changes in airways structure associated with reduced forced expiratory volume in one second. Eur. Respir. J21989834839
78. Niewoehner D. E., Kleinerman J., Rice D. B.Pathologic changes in the peripheral airways of young cigarette smokers. N. Engl. J. Med2911974755758
79. Saetta M., Stefano A., Maestrelli P., Ferraresso A., Drigo R., Potena A., Ciaccia A., Fabbri L. M.Activated T-lymphocytes and macrophages in bronchial mucosa of subjects with chronic bronchitis. Am. Rev. Respir. Dis1471993301306
80. Glynn A. A., Michaels L.Bronchial biopsy in chronic bronchitis and asthma. Thorax151960142153
81. Fournier M., Lebargy F., Le Roy F., Ladurie, Lenormand E., Pariente R.Intraepithelial T-lymphocyte subsets in the airways of normal subjects and of patients with chronic bronchitis. Am. Rev. Respir. Dis1401989737742
82. Salvato G.Some histological changes in chronic bronchitis and asthma. Thorax231968168172
83. Bosken C. H., Hards J., Gatter K., Hogg J. C.Characterization of the inflammatory reaction in the peripheral airways of cigarette smokers using immunocytochemistry. Am. Rev. Respir. Dis1451992911917
84. Kilburn K. H., McKenzie W.Leucocyte recruitment to airways by cigarette smoke and particle phase in contrast to cytotoxicity of vapor. Science1891975634637
85. Wright J. L., Hobson J., Wiggs B. R., Hogg J. C.Comparison of inflammatory cells in bronchoalveolar fluid with those in the lumen and tissue peripheral airways and alveolar airspace. Lung16619887583
86. Hunninghake G. W., Crystal R. G.Cigarette smoking and lung destruction: accumulation of neutrophils in lungs of cigarette smokers. Am. Rev. Respir. Dis.1281983833838
87. MacNee W., Wiggs B., Belzberg A. S., Hogg J. C.The effect of cigarette smoking on neutrophil kinetics in human lungs. N. Engl. J. Med3211989924928
88. Drost E. M., Selby C., Lannan S., Lowe G. D., MacNee W.Changes in neutrophil deformity following in vitro smoke exposure: mechanisms and protection. Am. J. Respir. Cell Mol. Biol61992287295
89. Selby C., Drost E., Lannan S., Wraith P. K., MacNee W.Neutrophil retention in the lungs of patients with chronic obstructive pulmonary disease. Am. Rev. Respir. Dis143199113591364
90. Lehr H. A., Kress E., Menger M. D., Friedl H. P., Hubner C., Arfors K. E., Messner K.Cigarette smoke elicits leukocyte adhesion to endothelium in hamsters: inhibition by CuZn-SOD. Free Radic. Biol. Med141993573581
91. Klut M. E., Doerschuk C. M., Hogg J. C., Vaneedow S. F., Burns A. R.Activation of neutrophils within pulmonary microvessels of rabbits exposed to cigarette smoke. Am. J. Respir. Cell Mol. Biol919938290
92. Di Stefano A., Maestrelli P., Roggeri A., Turato G., Calabro S., Potena A., Mapp C. E., Ciaccia A., Covacev L., Fabbri L. M., Saetta M.Upregulation of adhesion molecules in the bronchial mucosa of subjects with chronic obstructive bronchitis. Am. J. Respir. Crit. Care Med1491994803810
93. Riise G. C., Larsson S., Lofdahl C. G., Andersson B. A.Circulating cell adhesion molecules in bronchial lavage and serum in COPD patients with chronic bronchitis. Eur. Respir. J7199416731677
94. Baluk P., Bertrand C., Geppetti P., McDonald D. M., Nadel J. A.NKK1 receptor antagonist CP-99,994 inhibits cigarette smoke-induced neutrophil and eosinophil adhesion in rat tracheal venules. Exp. Lung Res221996409418
95. Yamamoto C., Yoneda T., Yoshikawa M., Fu A., Takenaka H., Tokuyama T., Okamoto Y., Tomoda K., Nakaya M., Kobayashi A., Tsukaguchi K., Narita N.Airway inflammation in chronic obstructive pulmonary disease is mediated by interleukin-8 (abstract). Am. J. Respir. Crit. Care Med1531996A821
96. Shoji S., Ertl R. F., Koyama S., Robbins R., Leikauf G., Essen S. V., Renard S. I.Cigarette smoke stimulates release of neutrophil chemotactic activity from cultured bovine bronchial epithelial cells. Clin. Sci881995337344
97. Keatings V. M., Collins P. D., Scott D. M., Barnes P. J.Differences in interleukin-8 and tumor necrosis factor-α in induced sputum from patients with chronic obstructive pulmonary disease or asthma. Am. J. Respir. Crit. Care Med1531996530534
98. Segger J. S., Thornton W. H., Edes T. E.Serum leukotriene B4 levels in patients with obstructive pulmonary disease. Chest991991289291
99. Totti N., McCusker K. T., Campbell E. J., Griffin G. L., Senior R. M.Nicotine is chemotactic for neutrophils and enhances neutrophil responsiveness to chemotactic peptides. Science131984169171
100. Aoshiba K., Nagai A., Konno K.Nicotine prevents a reduction in neutrophil filterability induced by cigarette smoke exposure. Am. J. Respir. Crit. Care Med150199411011107
101. Aoshiba K., Nagai A., Yasui S., Konno K.Nicotine prolongs neutrophil survival by suppressing apoptosis. J. Lab. Clin. Med1271996186194
102. Ludwig P. W., Hoidal J. R.Alterations in leukocyte oxidative metabolism in cigarette smokers. Am. Rev. Respir. Dis1261982977980
103. Burnett D., Chamba A., Hill S. L., Stockley R. A.Neutrophils from subjects with chronic obstructive lung disease show enhanced chemotaxis and extracellular proteolysis. Lancet2198710431046
104. Bridges R. B., Fu M. C., Rehm S. R.Increased neutrophil myeloperoxidase activity associated with cigarette smoking. Eur. J. Respir. Dis6719858493
105. Anderson R., Theron A. J., Richards G. A., Myers M. S., Rensbury A. J. V.Passive smoking by humans sensitizes circulating neutrophils. Am. Rev. Respir. Dis1441991570574
106. Postma D. S., Renkema T. E. J., Noordhoek J. A., Faber H., Sluiter H. J., Kauffman H.Association between non-specific bronchial hyperreactivity and superoxide anion production by polymorphonuclear leukocytes in chronic airflow obstruction. Am. Rev. Respir. Dis13719885761
107. Rahman I., MacNee W.Oxidant/antioxidant imbalance in smokers and chronic obstructive pulmonary disease. Thorax511996348350
108. Brown D., Brown G., Williams J. H., MacNee W.Priming of neutrophils sequestered in the pulmonary vasculature in acute alveolitis. Am. Rev. Respir. Dis1441993668
109. Rasp F. L., Clawson C. C., Hoidal J. R., Repine J. E.Reversible impairment of the adherence of alveolar macrophages from cigarette smokers. Am. Rev. Respir. Dis1181978979986
110. Costabel U., Guyman J.Effect of smoking on bronchoalveolar lavage constituents. Eur. Respir. J51992776779
111. Swan G. E., Roby T. J., Hodgkin J. E., Mittman C., Peters J. A., Jacobo N.Relationship of cytomorphology to spirometric findings in cigarette smokers. Acta Cytologica381994547553
112. Koyama S., Rennard S. I., Daughton D., Shoji S., Robbins R. A.Bronchoalveolar lavage fluid obtained from smokers exhibits increased monocyte chemokinetic activity. J. Appl. Physiol70199112081214
113. Hotter G., Closa D., Prats N., Pi F., Gelpi E., Rosello-Catafau J.Free radical enhancement promotes leucocyte recruitment through a PAF and LTB4 dependent mechanism. Free Radic. Biol. Med221997947954
114. Hoogsteden H. C., Van Hal P. T. W., Wijkhuijs J. M., Hop W., Verkaik A. P. K., Hilvering C.Expression of the CD11/CD18 cell surface adhesion glycoprotein family on alveolar macrophages in smokers and nonsmokers. Chest100199115671571
115. Kosmas E. N., Roussou T., Ikonomou K., Vassailareas V., Michaellides S., Polychronopoulos V., Baxevania C. N.Different patterns of intercellular adhesion molecule-1 (ICAM-1) and L-selectin expression on peripheral blood mononuclear cells in patients with chronic bronchitis and emphysema (abstract). Am. J. Respir. Crit. Care Med1531996624A
116. Senior R. M., Griffin G. L., Mecham R. P.Chemotactic activity of elastin-derived peptides. J. Clin. Invest661980859862
117. Zijlstra F. J., Vincent J. E., Mol W. M., Hoogsteden H. C., Van Hal P. W., Jongejan R. C.Eicosanoid levels in bronchoalveolar lavage fluid of young female smokers and non-smokers. Eur. J. Clin. Invest221992301306
118. Hoidal J. R., Fox R. B., LeMarbe P. A., Perri R., Repine J. E.Altered oxidative metabolic responses in vitro of alveolar macrophages from asymptomatic cigarette smokers. Am. Rev. Respir. Dis12319818589
119. Nakashima H., Ando M., Sugimoto M., Suga M., Soda K., Araki S.Receptor-mediated O2 release by alveolar macrophages and peripheral blood monocytes from smokers and nonsmokers. Am. Rev. Respir. Dis1361987310315
120. Schaberg T., Haller H., Rau M., Kaiser D., Fassbender M., Lode H.Superoxide anion release induced by platelet-activating factor is increased in human alveolar macrophages from smokers. Eur. Respir. J5199238773393
121. Schaberg T., Klein U., Rau M., Eller J., Lode H.Subpopulation of alveolar macrophages in smokers and nonsmokers: relation to the expression of CD11/CD18 molecules and superoxide anion production. Am. J. Respir. Crit. Care Med151199515511558
122. Greening A. P., Lowrie D. B.Extracellular release of hydrogen peroxide by human alveolar macrophages: the relationship to cigarette smoking and lower respiratory tract infections. Clin. Sci651983661664
123. Drath D. B., Karnovsky M. L., Huber G. L.The effects of experimental exposure to tobacco smoke on the oxidative metabolism of alveolar macrophages. Journal of the Reticuloendothelial Society251970597604
124. Lacoste J. Y., Bousquet J., Chanez P., Van Vyve T., Simony-Lafontaine J., Laqueu N., Vic P., Enander I., Godard P., Michel F. B.Eosinophilic and neutrophilic inflammation in asthma, chronic bronchitis and chronic obstructive pulmonary disease. J. Allergy Clin. Immunol921993537548
125. Lebowitz M. D., Postma D. S.Adverse effects of eosinophilic and smoking on the natural history of newly diagnosed chronic bronchitis. Chest10819955561
126. Riise G. T., Ahlstedt S., Larsson S., Enander I., Jones I., Larsson P., Andersson B.Bronchial inflammation in chronic bronchitis assessed by measurement of cell products in bronchial lavage fluid. Thorax501995360365
127. Sedgwick J. B., Vrtis R. F., Gourley M. F., Busse W. W.Stimulus-dependent differences in superoxide anion generation by normal human eosinophils and neutrophils. J. Allergy Clin. Immunol811988876883
128. Mabuchi K., Sugiura T., Ojima-Uchiyama A., Masuzawa Y., Wako K.Differential effects of platelet-activating factor on superoxide anion production in human eosinophils and neutrophils. Biochemistry International26199211051113
129. Hoidal J. R., Beall G. D., Repine J. E.Production of hydroxyl radical by human alveolar macrophages. Infect. Immunol26197910881092
130. Zoratti E. M., Sedgwick J. B., Vrtis R. F., Busse W. W.The effect of platelet-activating factor on the generation of superoxide anion in human eosinophils and neutrophils. J. Allergy Clin. Immunol881991749758
131. Toth K. M., Burton L. L., Berger E. M., Beehler C. J., Rodell T. C., Cheronis J. C., Halek M. M., White C. W., Repine J. E.Cigarette smoke exposure increases erythrocyte (RBC) and lung antioxidant levels and lung xanthine oxidase (XO) activities (abstract). Clin. Res351987172A
132. Phan S. H., Gannon D. E., Ward P. A., Karmiol S.Mechanisms of neutrophil-induced xanthine dehydrogenase to xanthine oxidase conversion in endothelial cells: evidence of a role for elastase. Am. J. Respir. Cell Mol. Biol61992270278
133. Petrone W. F., English D. K., Wong K., McCord J. M.Free radicals and inflammation: superoxide dependent activation of a neutrophil chemotactic factor in plasma. Proc. Natl. Acad. Sci. U.S.A.77198011591163
134. Pinamonti S., Muzzuli M., Chicca M. C., Papi A., Ravenna F., Fabri L. M., Ciaccia A.Xanthine oxidase activity in bronchoalveolar lavage fluid from patients with chronic obstructive lung disease. Free Radic. Biol. Med211996147155
135. DeKhuijzen P. N. R., Aben K. K. H., Dekker I., Aarts L. P. H. J., Weidlers P. L. M. L., van Herwaarden C. L. A., Bast A.Increased exhalation of hydrogen peroxide in patients with stable and unstable chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med1541996813816
136. Rahman I., MacNee W.Role oxidants/antioxidants in smoking induced lung diseases. Free Radic. Biol. Med211996669681
137. Tager T., Speizer F. E.Role of infection of chronic bronchitis. N. Engl. J. Med2921975563
138. Gump D. W., Phillips C. A., Forsyth B. R., McIntosh K., Lamborn K. R., Stouch W. H.Role of infection in chronic bronchitis. Am. Rev. Respir. Dis1131976465474
139. Haas H., Morris J. F., Samson S., Kilbourn J. P., Kim P. J.Bacterial flora of the respiratory tract in chronic bronchitis: comparison of transtracheal, fiberbronchoscopic, and oropharyngeal sampling methods. Am. Rev. Respir. Dis11619774147
140. Chodosh S.Acute bacterial exacerbations in bronchitis and asthma. Am. J. Med821987154163
141. Riise G. C., Larsson S., Andersson B. A.Bacterial adhesion to oropharyngeal and bronchial epithelial cells in smokers with chronic bronchitis, smaller with COPD and healthy nonsmokers. Eur. Respir. J7199417591764
142. Irwin R. S., Erickson A. D., Pratter M. R., Currso W. M., Garrity F. L., Myers J. R., Kaemmerlen J. T.Prediction of tracheobronchial colonization in current cigarette smokers with chronic obstructive bronchitis. J. Invest. Dis1451982234241
143. Beachey E. H., Giampapa G. S., Abraham S. N.Bacterial adherence: adhesion receptor-mediated attachment of pathogenic bacteria to mucosal surfaces. Am. Rev. Respir. Dis1381988S45S48
144. Plotkowski M. C., Bajolet-Laudinat O., Puchelle E.Cellular and molecular mechanisms of bacterial adhesion to respiratory mucosa. Eur. Respir. J.61993903916
145. Raman A. S., Swimhume A. J., Fedullo A. J.Pneumococcal adherence to the buccal epithelial cells of cigarette smokers. Chest8319832327
146. Feinstein V., Musher D.Bacterial adherence to pharyngeal cells in smokers, nonsmokers, and chronic bronchitis. Infect. Immunol261979178182
147. Taylor J. C., Madison R., Kosinska D.Is antioxidant deficiency related to chronic obstructive pulmonary disease? Am. Rev. Respir. Dis1341986285289
148. Duthie G. G., Arthur J. R., James W. P.Effects of smoking and vitamin E on blood antioxidant status. Am. J. Clin. Nutr53199110611063
149. Jendrychko A., Szoyrka G., Gruszczynski J., Kozowicz M.Cigarette smoke exposure of school children: effect of passive smoking and vitamin E supplementation on blood antioxidant status. Neoplasia401993199203
150. Murata A., Shiraski L., Fukazaki K., Kittara T., Arada Y.Lower levels of vitamin C in plasma and urine of Japanese male smokers. Int. J. Vitam. Nutr. Res591989184189
151. Duthie G. G., Arthur J. R., Beattie J. A., Brown K. M., Morrice P. C., Robertson J. D., Shortt C. T., Walker K. A., James W. P.Cigarette smoking, antioxidants, lipid peroxidation, and coronary heart disease. Ann. N.Y. Acad. Sci6861993120129
152. Anderson R.Assessment of the roles of vitamin C, vitamin E, and β-carotene in the modulation of oxidant stress mediated by cigarette smoke-activated phagocytes. Am. J. Clin. Nutr531991358361
153. Anderson R., Theron A. J., Ras G. J.Ascorbic acid neutralizes reactive oxidants released by hyperactive phagocytes from cigarette smokers. Lung1661988149159
154. Chow C. K., Thacker R. R., Changchit C., Bridges R. B., Rehm S. R., Humble J., Turbek J.Lower levels of vitamin C and carotenes in plasma of cigarette smokers. J. Am. Coll. Nutr51986305312
155. Van Poppel G., Spanhaak S., Ockhuzen T.Effect of beta-carotene on immunological indexes in healthy male smokers. Am. J. Clin. Nutr.571993402407
156. Basu J., Mikhail M. S., Paysaudean P. H., Palan P. R., Romney S. L.Smoking and the antioxidant ascorbic acid: plasma, leukocyte, and cervicovaginal cell concentrations in normal healthy women. Am. J. Obstet. Gynecol163199019481952
157. Schectman G., Byrd J. C., Gruehow H. W.The influence of smoking on vitamin C status in adults. Am. J. Public Health791989158162
158. Schectman G.Estimating ascorbic acid requirements for cigarette smokers. Ann. N.Y. Acad. Sci.6861993335345
159. VanRensburg C. E. J., Theron A., Richards G. A., van der Merwe C. A., Anderson R.Investigation of the relationships between plasma levels of ascorbate, vitamin E and β-carotene and the frequency of sister-chromatid exchanges and release of reactive oxidants by blood leukocytes from cigarette smokers. Mutat. Res2151989167172
160. Pelletier O.Vitamin C status of cigarette smokers and non-smokers. J. Am. Coll. Nutr51986305312
161. Antwerpen L. V., Theron A. J., Myer M. S., Richards G. A., Wolmarans L., Booysen U.Cigarette smoke-mediated oxidant stress, phagocytes, vitamin C, vitamin E and tissue injury. Ann. N.Y. Acad. Sci68619935365
162. Theron A. J., Richard G. A., Rensburg A. J., Vander C. A., Merwe, Anderson R.Investigation of the role of phagocytes and antioxidant nutrients in oxidant stress mediated by cigarette smoke. Int. J. Vitam. Nutr. Res601990261266
163. Kondo T., Tsgami S., Yohioka A., Nishumura M., Kawakami Y.Current smoking of elderly men reduces antioxidants in alveolar macrophages. Am. J. Respir. Crit. Care Med1491994178182
164. Pacht E. R., Kaseki H., Mohammed J. R., Cornwell D. G., Davis W. B.Deficiency of vitamin E in the alveolar fluid of cigarette smokers: influence on alveolar macrophage cytotoxicity. J. Clin. Invest771986789796
165. Comstock G. W., Menkes M. S., Schober S. E., Vuilleumier J. P., Helsing K. F.Serum levels of retinal β-carotene and alpha tocopherol in older adults. Am. J. Epidemiol1271988114123
166. Mezzetti A., Lapenna D., Pierdomenico S. D., Calafiore A. M., Costantini F., Riario-Sforza G., Imbastaro T., Neri M., Cuccurullo F.Vitamins E, C and lipid peroxidation in plasma and arterial tissue of smokers and non-smokers. Atherosclerosis11219959199
167. Bui M. H., Saury A., Collet F., Leuenberger P.Dietary vitamin C intake and concentrations in the body fluids and cells of male smokers and non-smokers. J. Nutr1221992312316
168. McGowan S. E., Parenti C. M., Hoidal J. R., Niewoehner D. E.Differences in ascorbic acid content and accumulation by alveolar macrophages from cigarette smokers and non-smokers. J. Lab. Clin. Med1041984127134
169. Lehr H. A., Frei B., Arfors K. E.Vitamin C prevents cigarette smoke-induced leukocyte aggregation and adhesion to endothelium in vivo. Proc. Natl. Acad. Sci. U.S.A.91199476887692
170. Chow C. K., Chen L. H., Thacker R. R., Griffith R. B.Dietary vitamin E and pulmonary biochemical responses of rats to cigarette smoke. Exp. Mol. Pathol381984368379
171. Schwartz J., Weiss S. T.Relationship between dietary vitamin C intake and pulmonary function in the First National Health and Nutrition Examination Survey (NHANES 1). Am. J. Clin. Nutr59199411101114
172. α-Tocopherol, β-Carotene Prevention Study GroupThe effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N. Engl. J. Med330199410291035
173. Rowe P. M.Beta-carotene takes a collective beating. Lancet3471996249
174. Kathawalla S. A., Comhair S., Erzurum S. C.Correlation of secretory glutathione peroxidase and glutathione in airways of smoking individuals (abstract). Am. J. Respir. Crit. Care Med1531996A812
175. Linden M., Hakansson L., Ohlsson K., Sjodin K., Tegner A., Tunek A., Venge P.Glutathione in bronchoalveolar lavage fluid from smokers is related to humoral markers of inflammatory cell activity. Inflammation131989651658
176. Li X. Y., Donaldson K., Rahman I., MacNee W.An investigation of the role of glutathione in increased epithelial permeability induced by cigarette smoke in vivo and in vitro. Am. J. Respir. Crit. Care Med149199415181525
177. Lannen S., Donaldson K., Brown D., MacNee W.Effect of cigarette smoke and its condensates on alveolar epithelial cell injury in vitro. Am. J. Physiol266199491100
178. Jones J. G., Lawler P., Crawley J. C. W., Minry B. D., Hulands G., Veall N.Increased alveolar epithelial permeability in cigarette smokers. Lancet119906668
179. Morrison D., Lannan S., Langridge A., Rahman I., MacNee W.Effect of acute cigarette smoking on epithelial permeability, inflammation and oxidant status in the airspaces of chronic smokers. Thorax4919961077
180. Toth K. M., Berger E. M., Beehler C. J., Repine J. E.Erythrocytes from cigarette smokers contain more glutathione and catalase and protect endothelial cells from hydrogen peroxide better than erythrocytes from nonsmokers. Am. Rev. Respir. Dis1341986281284
181. Mangione S., Kueppers F., Puglia C., Greenspon L. W.Erythrocytes prevent inactivation of alpha-1-antitrypsin by cigarette smoke. Eur. Respir. J419912630
182. Mukherjee S., Woods L., Weston Z., Williams A. B., Das S. K.The effect of mainstream and sidestream cigarette smoke exposure on oxygen defense mechanisms of guinea pig erythrocytes. J. Biochem. Toxicol81993119125
183. Sohn H. O., Lim H. B., Lee Y. G., Lee D. W., Kim Y. T.Effect of subchronic administration of antioxidants against cigarette smoke exposure in rats. Arch. Toxicol671993667673
184. Rahman I., Lawson M., Harrison D. J., MacNee W.γ-Glutamyl cysteine synthetase induction by cigarette smoke exposure in alveolar epithelial cells. Respir. Med881994809
185. McCusker K., Hoidal J.Selective increase of antioxidant enzyme activity in the alveolar macrophage from cigarette smokers and smoke-exposed hamsters. Am. Rev. Respir. Dis1411990678682
186. Repine J. E.Interleukin-1-mediated acute lung injury and tolerance to oxidative injury. Environ. Health Perspect10219947578
187. York G. K., Pierce T. H., Schwartz L. W., Cross C. E.Stimulation by cigarette smoke of glutathione peroxidase system enzyme activities in rat lung. Arch. Environ. Health311976286289
188. Rushmore T. H., Morton M. R., Pickett C. B.The antioxidant response element: activation by oxidative stress and identification of the DNA consensus sequence required for functional activity. J. Biol. Chem26619911163211639
189. Repine J. E.Oxidant-antioxidant balance: some observations from studies in isolated rat hearts subjected to ischemia-reperfusion. Am. J. Med9119914553
190. Costagliola C., Rinaldi M., Giacola A., Ropsaka S., Cotticelli L., Rinaldi E.Red cell glutathione as a marker of tobacco smoke induced optic neuropathy. Exp. Eye Res481989583586
191. Chow C. K.Cigarette smoking oxidative damage in the lung. Ann. N.Y. Acad. Sci6861993289298
192. Sznajder J. I., Fraiman A., Hall J. B., Sanders W., Schmidt G., Crawford G., Nahurn A., Factor P., Wood L. D.Increased hydrogen peroxide in the expired breath of patients with acute hypoxemic respiratory failure. Chest961989606612
193. Halliwell B., Chirico S.Lipid peroxidation: its mechanism, measurement and significance. Am. J. Clin. Nutr571993715725
194. Hageman J. J., Bast A., Vermeulen N. P. E.Monitoring of oxidative free radical damage in vivo: analytical aspects. Chem. Biol. Interact821992243293
195. Thomas D. W., van Kuijk F. J. G. M., Dratz E. A., Stephens R. J.Quantitative determination of 6-hydroxy fatty acids as an indicator of in vivo lipid peroxidation: gas chromatography-mass spectrometry methods. Anal. Biochem1981991104111
196. Miyazawa T.Determination of phospholipid hydroperoxides in human blood plasma by chemiluminescence HPLC assay. Free Radic. Biol. Med71989208217
197. Van Gossum A., Decuyper J.Breath alkane as an index of lipid peroxidation. Eur. Respir. J21989787791
198. Frei B., Forte T. M., Ames B. N., Cross C. E.Gas-phase oxidants of cigarette smoke induce lipid peroxidation and changes in lipoprotein properties in human blood. Biochem. J2771991133138
199. Nadiger H. A., Mathew C. A., Sadasivudu B.Serum malondialdehyde (TBA reactive substance) levels in cigarette smokers. Atherosclerosis6419877173
200. Kalra J., Chaudhary A. K., Prasad K.Increased production of oxygen free radicals in cigarette smokers. Int. J. Exp. Pathol72199117
201. Cross C. E., O'Neill C. A., Reznick A. Z., Hu M. L., Marcocci L., Packer L., Frei B.Cigarette smoke oxidation of human plasma constituents. Ann. N.Y. Acad. Sci68619937289
202. Pre J., LeFloch A., Vassg R., Lenoble C.Increased plasma levels of fluorescent lipid peroxidation products in cigarette smokers. Med. Sci. Res17198910291030
203. Bridges A. B., Scott N. A., Parry G. J., Belch J. J. F.Age, sex, cigarette smoking and indices of free radical activity in healthy humans. Eur. J. Med21993205208
204. Barnes P. J.Reactive oxygen species and airway inflammation. Free Radic. Biol. Med91990235243
205. Petruzzelli S., Hietanen E., Bartsch H., Camus A. M., Mussi A., Angeletti C. A., Saracci R., Giuntini C.Pulmonary lipid peroxidation in cigarette smokers and lung cancer patients. Chest981990930935
206. Lapenna D., Mezzetti A., Giola S. D., Pierdomenico S., Danielee F., Cuccurullo F.Plasma copper and lipid peroxidation in cigarette smokers. Free Radic. Biol. Med191995849852
207. Hobson J., Wright J., Churg A.Histochemical evidence for generation of active oxygen species on the apical surface of cigarette smoke-exposed tracheal explants. Am. J. Pathol1391991573580
208. Lentz P. E., DiLuzio N. R.Peroxidation of lipids in alveolar macrophages: production by aqueous extracts of cigarette smoke. Arch. Environ. Health281974279282
209. Hoshino E., Shariff R., Van Gossum A., Allard J. P., Pichard C., Kurian R., Jeejeebhoy K. N.Vitamin E supresses increased lipid peroxidation in cigarette smokers. Journal of Parenteral and Enteral Nutrition141990300305
210. Habib M. P., Do B. K. Q., Clements N. C., Garewal H. S.Fall in exhaled ethane (EE) in smokers after antioxidants associated with preserved lung function (abstract). Am. J. Respir. Crit. Care Med1531996A740
211. Gutteridge J. M. C., Halliwell B.The measurement and mechanisms of lipid peroxidation in biological systems. Trends Biochem. Sci151990129135
212. Morrow J. D., Frei B., Longmire A. W., Gaziano J. M., Lynch S. M., Yu S., Strauss W., Oates J. A., Roberts L. J.Increased in circulating products of lipid peroxidation (F2-isoprostanes) in smokers: smoking as a cause of oxidative damage. N. Engl. J. Med332199511981203
213. Miller E.Some current perspectives on chemical carcinogenesis in humans and experimental animals: presidential address. Cancer Res38197814791496
214. Cuzick J., Routledge M. N., Jenkins D., Gamer X. C.DNA adducts in different tissues of smokers and non-smokers. Int. J. Cancer451990673678
215. Nakayama T., Kaneko M., Kodama M., Nagate C.Cigarette smoke induces DNA single-strand breaks in human cells. Nature3141985462464
216. Spencer J. P. E., Jenner A., Chimel K., Aruoma O. I., Cross C. E., Wu R., Halliwell B.DNA damage in human respiratory tract epithelial cells: damage by gas phase cigarette smoke apparently involves attack by reactive nitrogen species in addition to oxygen radicals. FEBS Lett3751995179182
217. Jackson J. H., Schraufstatter I. U., Hyslop P. A., Vosbeck K., Sauerheber R., Weitzman S. A., Cochrane C. G.Role of oxidants in DNA damage: hydroxyl radical mediates the synergistic DNA damaging effects of asbestos and cigarette smoke. J. Clin. Invest80198710901095
218. Kiyosawa H., Suko M., Okudaira H., Murata K., Miyamoto T., Chung M.-H., Kasai H., Nishimura S.Cigarette smoking induces formation of 8-hydroxydeoxyguanosine, one of the oxidative DNA damages in human peripheral leukocytes. Free Radic. Res. Commun1119902327
219. Leanderson P., Tagesson C.Cigarette smoke-induced DNA damage in cultured human lung cells: role of hydroxyl radicals and endonuclease activation. Chem. Biol. Interact811992197208
220. Schwalb G., Anderson R.Increased frequency of oxidant-mediated DNA strand breaks in mononuclear leukocytes exposed to activated neutrophils from cigarette smokers. Mutation Res22819899599
221. Hecht S. S., Carmella S. C., Foiles P. G., Murphy S. E.Biomarkers of human uptake and metabolic activation of tobacco-specific nitrosamines. Cancer Res54199419121917
222. Van Schooten F. J., Hillebrand M. J. X., Van Leeuwen F. E., Lutgerink J. T., Van Zandwijk N., Jansen H. M., Kriek E.Polycyclic aromatic hydrocarbon-DNA adducts in lung tissue from lung cancer patients. Carcinogenesis11199016771681
223. Kato S., Petruzzelli S., Bowman E. D., Turteltaub K. W., Blomeke B., Weston A., Shields P. G.7-Alkyl-deoxyguanosine adduct detection by two-step HPLC and the 22P-postlabeling assay. Carcinogenesis141993545550
224. Petruzzelli S., Tavanti L. M., Celi A., Giuntini C.Detection of N7-methyldeoxygunosine in human pulmonary alveolar cells. Am. J. Respir. Cell Mol. Biol151996216223
225. Brennan J. A., Boyle J. O., Koch W. M., Goodman S. N., Hruban R. H., Eby Y. J., Couch M. J., Forastiere A. A., Sidransky D.Association between cigarette smoking and mutation of the P53 gene in squamous-cell carcinoma of the head and neck. N. Engl. J. Med3321995712717
226. Slebos R. J. C., Hruban R. H., Dalesio O., Mooi W. J., Offerhaus G. J. A., Rodenhuis S.Relationship between K-ras oncogene activation and smoking in adenocarcinoma of the human lung. J. Natl. Cancer Inst83199110241027
227. Stadtman E. R.Metal ion-catalyzed oxidation of proteins: biochemical mechanism and biological consequences. Free Radic. Biol. Med91990315325
228. Reznick A. Z., Cross C. E., Hu M. L., Suzuki Y. J., Khwaja S., Safadi A., Motchnik P. A., Packer L., Halliwell B.Modification of plasma proteins by cigarette smoke as measured by protein carbonyl formation. Biochem. J2861992607611
229. O'Neill C. A., Halliwell B., van der Vliet A., Davis P. A., Packer L., Tritschler H., Strohman W. J., Rieland T., Cross C. E., Reznick A. Z.Aldehyde-induced protein modifications in human plasma: protection by glutathione and dihydrolipoic acid. J. Lab. Clin. Med1241994359370
230. Lenz A. G., Costabel U., Maier K. L.Oxidized BAL fluid proteins in patients with interstitial lung diseases. Eur. Respir. J91996307312
231. Piquette, C. A., and S. I. Rennard. 1996. Chronic bronchitis: focus on maintaining pulmonary function. Intern. Med. 82–91.
232. Rubin B. K., King M.The physiologic effects of smoking in COPD. J. Respir. Dis14199319
233. Ferguson G. T., Cherniack R. M.Management of chronic obstructive pulmonary disease. N. Engl. J. Med328199310171022
234. Schilero, G. J., P. L. Almenoff, and M. Lesser. 1995. Changing therapies for COPD. Intern. Med. 17–32.
235. Anthonisen N. R., Connett J. E., Kiley J. P., Altose M. D., Bailey W. C., Buist A. S., Conway W. A. J., Enright P. L., Kanner R. E., O'Hara alEffects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1: The Lung Health Study. J.A.M.A272199414971505
236. Rennard S. I., Daughton D., Fujita J., Oehlerking M., Dobson J. R., Stahl M. G., Robbins R. A., Thompson A. B.Short-term smoking reduction is associated with reduction in measures of lower respiratory tract inflammation in heavy smokers. Eur. Respir. J31990752759
237. Skold C. M., Hed J., Eklund A.Smoking cessation rapidly reduces cell recovery in bronchoalveolar lavage fluid, while alveolar macrophage fluorescence remains high. Chest1011992989995
238. COMBIVENT Inhalation Aerosol Study GroupIn Chronic obstructive pulmonary disease, a combination of ipratropium and albuterol is more effective than either agent alone. Chest105199414111419
239. Easton P. A., Jadue C., Dhingra S., Anthonisen N. R.A comparison of the bronchodilating effects of a beta-2 adrenergic agent (albuterol) and an anticholinergic agent (ipratropium bromide), given by aerosol alone or in sequence. N. Engl. J. Med3151986735739
240. Karpel J. P., Pesin J., Greenberg E., Gentry E.A comparison of the effects of ipratropium bromide and metaproterenol sulfate in acute exacerbations of COPD. Chest981990835839
241. Llewellyn-Jones C. G., Stockley R. A.The effects of B2-agonists and methylxanthines on neutrophil function in vitro. Eur. Respir. J73199414601466
242. Llewellyn-Jones C. G., Hill S. L., Stockley R. A.Effect of fluticasone propionate on neutrophil chemotaxis, superoxide generation, and extracellular proteolytic activity in vitro. Thorax491994207212
243. Nielson C. P., Crowley J. J., Cusack B. J., Vestal R. E.Therapeutic concentrations of theophylline and enprofylline potentiate catecholamine effects and inhibit leukocyte activation. J. Allergy Clin. Immunol781986660667
244. Nielson C. P., Crowley J. J., Morgan M. E., Vestal R. E.Polymorphonuclear leukocyte inhibition by therapeutic concentrations of theophylline is mediated by cyclic-3′,5′-adenosine monophosphate. Am. Rev. Respir. Dis13719882530
245. Nielson C. P., Vestal R. E., Sturm R. J., Heaslip R.Effects of selective phosphodiesterase inhibitors on the polymorphonuclear leukocyte respiratory burst. J. Allergy Clin. Immunol861990801808
246. Schrier D. J., Imre K. M.The effects of adenosine agonists on human neutrophil function. J. Immunol137198632843289
247. Kaneko M., Suzuki K., Furui H., Takagi K., Satake T.Comparison of theophylline and enprofylline effects on human neutrophil superoxide production. Clin. Exp. Pharmacol. Physiol171990849859
248. Yukawa T., Kroegel C., Chanez P., Dent G., Ukena D., Chung K. F., Barnes P. J.Effect of theophylline and adenosine on eosinophil function. Am. Rev. Respir. Dis1401989327333
249. Hudson L. D., Monti C. M.Rationale and use of corticosteroids in chronic obstructive pulmonary disease. Med. Clin. North Am741990661690
250. Postma, D. S., and T. E. J. Renkema. 1995. Corticosteroid treatment. In P. Calverley and N. Pride, editors. Chronic Obstructive Pulmonary Disease. Chapman & Hall, London. 447–459.
251. Callahan C. M., Dittus R. S., Katz B. P.Oral corticosteroid therapy for patients with stable chronic obstructive pulmonary disease: a metaanalysis. Ann. Intern. Med1141991216223
252. Engel T., Heinig J. H., Madsen O., Hansen M., Weeke E. R.A trial of inhaled budesonide on airway responsiveness in smokers with chronic bronchitis. Eur. Respir. J21989935939
253. Auffarth B., Postma D. S., de Monchy J. G. R., van der Mark T. W., Boorsma M., Koëter G. H.Effects of inhaled budesonide on spirometric values, reversibility, airway responsiveness, and cough threshold in smokers with chronic obstructive lung disease. Thorax461991372377
254. Watson A., Lim T. K., Joyce H., Pride N. B.Failure of inhaled corticosteroids to modify bronchoconstrictor or bronchodilator responsiveness in middle-aged smokers with mild airflow obstruction. Chest1011992350355
255. Dompeling E., van Schayck C. P., van Grunsven P. M., van Herwaarden C. L. A., Akkermans R., Molema J., Folgering H. T. M., van Weel C.Slowing the deterioration of asthma and chronic obstructive pulmonary disease observed during bronchodilator therapy by adding inhaled corticosteroids: a four-year prospective study. Ann. Intern. Med1181993770778
256. Fukushima K., Ando M., Ito K., Suga M., Araki S.Stimulus- and cumulative dose-dependent inhibition of O2-production by polymorphonuclear leukocytes of patients receiving corticosteroids. J. Clin. Lab. Immunol331990117123
257. Renkema T. E. J., Postma D. S., Noordhoek J. A., Sluster H. J., Kauffman H. F.Influence of in vivo prednisolone on increased in vitro O2 generation by neutrophils in emphysema. Eur. Respir. J619939095
258. Lomas D. A., Ip M., Chamba A., Stockley R. A.The effect of in vitro and in vivo dexamethasone on human neutrophil function. Agents Actions331991279285
259. DeBacker W. A., Pecivora J., van Overweld E. J., Vermeire P. A.The effects of treatment with inhaled corticosteroids on inflammation in stable chronic obstructive pulmonary disease (abstract). Am. J. Respir. Crit. Care Med1531996A822
260. Keatings V. M., Jatakanon A., Barnes P. F.Oral corticosteroids do not reduce eosinophil numbers or concentrations of eosinophilic cationic protein in chronic obstructive pulmonary disease (abstract). Am. J. Respir. Crit. Care Med1531996A823
261. Rubin R. P., Thompson R. H., Naps M. S.Differential inhibition by nedocromil sodium of superoxide generation elicited by platelet activating factor in human neutrophils. Agents Actions311990237242
262. Nowak D., Antczak A., Krol M., Bialasiewicz P., Pietras T.Antioxidant properties of ambroxol. Free Radic. Biol. Med161994517522
263. Olivieri D., Zavattini G., Tomasini G., Daniotti S., Bonsignore G., Ferrara G., Carnimeo N., Chianese R., Catena E., Marcatili alAmbroxol for the prevention of chronic bronchitis exacerbations: long-term multicenter trial. Protective effect of ambroxol against winter semester exacerbations: a double-blind study versus placebo. Respiration5119874251
264. Roger N., Barbera J. A., Farre R., Cobos A., Roca J., Rodriquez R.Effect of nitric oxide inhalation on respiratory system resistance in chronic obstructive pulmonary disease. Eur. Respir. J91996190195
265. Menzel D. B.Antioxidant vitamins and prevention of lung disease. Ann. N.Y. Acad. Sci6691992141145
266. Sarnstrand B.Is n-acetylcysteine a free radical scavenger in vivo? The effect of n-acetylcysteine in oxygen induced lung injury. Eur. Respir. Rev219921115
267. Aruoma O. I., Halliwell B., Hoey B. M., Butler J.The antioxidant action of N-acetylcysteine: its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid. Free Radic. Biol. Med61989593597
268. Moldeus P., Cotgreave I. A., Berggren M.Lung protection by a thiol-containing antioxidant: N-acetylcysteine. Respiration5019863142
269. Cotgreave I. A., Moldeus P.Lung protection by thiol-containing antioxidants. Bull. Eur. Physiopathol. Respir231987275277
270. Schreck R., Albermann K. A. J., Baeuerle P. A.Nuclear factor kB: an oxidative stress-responsive transcription factor of eukaryotic cells (a review). Free Radic. Res. Commun171992221237
271. Bridges A. B.Protective action of thiols on neutrophil function. Eur. J. Respir. Dis6619854048
272. Voisin C., Aerts C., Wallaert B.Prevention of in vitro oxidant-mediated alveolar macrophage injury by cellular glutathione and precursors. Bull. Eur. Physiopathol. Respir231987309313
273. Linden M., Wieslander E., Eklund A., Larsson K., Brattsand R.Effects of oral N-acetylcysteine on cell content and macrophage function in bronchoalveolar lavage from healthy smokers. Eur. Respir. J11988645650
274. Moldeus, P., M. Berggren, and R. Graffström. 1985. N-acetylcysteine protection against the toxicity of cigarette smoke and cigarette smoke condensates in various tissues and cells in vitro. Eur. J. Respir. Dis. 66(Suppl. 139):123–129.
275. Drost E., Lannan S., Bridgeman M. M. E., Brown D., Selby C., Donaldson K., MacNee W.Lack of effect of N-acetylcysteine on the release of oxygen radicals from neutrophils and alveolar macrophages. Eur. Respir. J41991723729
276. Jeffery P. K., Rogers D. F., Ayers M. M.Effect of oral acetylcysteine on tobacco smoke-induced secretory cell hyperplasia. Eur. J. Respir. Dis661985117122
277. Borregaard N., Jensen H. S., Bjerrum O. W.Prevention of tissue damage: inhibition of myeloperoxidase mediated inactivation of alpha-1-proteinase inhibitor by N-acetylcysteine, glutathione, and methionine. Agents Actions221987255260
278. Anderson L. W., Thirs J., Kharazami A., Rygg I.The role of N-acetylcysteine administration on the oxidative response of neutrophils during cardiopulmonary bypass. Perfusion1019952126
279. Bridgeman M. M. E., Marsden M., MacNee W., Flenley D. C., Ryle A. P.Cysteine and glutathione concentrations in plasma and bronchoalveolar lavage fluid after treatment with N-acetylcysteine. Thorax4619913942
280. Jankowska R., Passowiez-Muszynska E., Medrala W., Banas T., Marcinkowska A.The influence of N-acetylcysteine on granulocyte chemiluminescence in patients with chronic bronchitis. Pneumonol. Alergol. Pol611993586591
281. Multicenter Study GroupLong-term oral acetylcysteine in chronic bronchitis: a double-blind controlled study. Eur. J. Respir. Dis61198093108
282. Aylward M., Maddock J., Dewland P.Clinical evaluation of acetylcysteine in the treatment of patients with chronic obstructive bronchitis: a balanced double-blind trial with placebo control. Eur. J. Respir. Dis6119808189
283. Boman G., Bäcker U., Larsson S., Melander B., Wählander L.Oral acetylcysteine reduces exacerbation rate in chronic bronchitis: report of a trial organized by the Swedish Society for Pulmonary Diseases. Eur. J. Respir. Dis641983405415
284. Rasmussen J. B., Glennon C.Reduction in days of illness after long-term treatment with N-acetylcysteine controlled-release tablets in patients with chronic bronchitis. Eur. Respir. J11988351355
285. McFarlane J. T.Oral N-acetylcysteine and exacerbation rates in patients with chronic bronchitis and severe airways obstruction. Thorax401985832835
286. British Thoracic Society Research CommitteeOral N-acetylcysteine and exacerbation rates in patients with chronic bronchitis and severe airways obstruction. Thorax401985832835
287. Todisco T., Palmieri G. C., Pezza A., Carati L.Protective effect of N-acetylcysteine on immune system of elderly patients in acute respiratory viral infections. Eur. Respir. J61993559
288. Matsuse T., Hayashi S., Kuwano K., Keunecke H., Jefferies W. A., Hogg J. C.Latent adenoviral infection in the pathogenesis of chronic airways obstruction. Am. Rev. Respir. Dis1461992177184
289. Riise G. C., Larsson S., Larsson P., Jeansson S., Andersson B. A.The intrabronchial microbial flora in chronic bronchitis patients: a target for N-acetylcysteine therapy? Eur. Respir. J7199494101
290. Lundbäck, B., M. Linström, S. Andersson, L. Nyström, L. Rosenhall, and N. Stjernberg. 1995. Possible effect of acetylcysteine on lung function. Eur. Respir. J. 5(Suppl. 15):895.
291. MacKenzie T. D., Bartecchi C. E., Schrier R. W.The human costs of tobacco abuse. N. Engl. J. Med3301994975980
292. McCusker K.Mechanisms of respiratory tissue injury from cigarette smoking. Am. J. Med9319921821
293. Burchfiel C. M., Marcus E. B., Curb J. D., MacLean C. J., Vollmer W. M., Johnson L. M., Fong K.-O., Rodriguez B. L., Masaki K. H., Buist A. S.Effects of smoking and smoking cessation on longitudinal decline in pulmonary function. Am. J. Respir. Crit. Care Med151199517781785
294. Nocturnal Oxygen Therapy Trial GroupContinuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease: a clinical trial. Ann. Intern. Med931980391398
295. Connelly K. G., Repine J. E.Markers for predicting the development of acute respiratory distress syndrome. Ann. Rev. Med481997429445
296. Burney P.The origins of obstructive airways disease: a role for diet? Am. J. Respir. Crit. Care Med151199512921293
Correspondence and requests for reprints should be addressed to John E. Repine, M.D., Webb-Waring Institute for Biomedical Research, 4200 East Ninth Avenue, Box C321, Denver, CO 80262.


No related items
American Journal of Respiratory and Critical Care Medicine

Click to see any corrections or updates and to confirm this is the authentic version of record