The Role of Oxidative Stress in Chronic Obstructive Pulmonary Disease

Figures & data

Figure 1. Oxidative stress is an imbalance between reactive oxygen species (ROS) and antioxidants. (A) Under normal conditions there are sufficient antioxidants in the lung to overcome endogenous ROS. (B) During pathologic states there is an increase in ROS that may be balanced by increase in antioxidants. (C) When either ROS production is excessive or antioxidants are inadequate, the balance is tipped toward oxidative stress and injury from ROS may occur. (Full color version available online.)

Figure 2. Derivation of reactive oxygen species. Sequential electron (e⁻) addition to oxygen results in the formation of reactive oxygen species (red): superoxide (O₂‐), hydrogen peroxide (H₂0₂) and hydroxyl radical (OH). Superoxide can combine with nitric oxide (NO) to form peroxynitrite (ONOO‐). Both O₂⁻ and OH⁻ can initiate lipid peroxidation to form lipid peroxides (ROO) that can propagate free radical chain reactions. (Full color version available online.)

Figure 3. Oxidants in cigarette smoke. Nitric oxide (NO), nitrogen dioxides (NO₂), carbon monoxide (CO), ammonia (NH₃), cyanide (HCN), hydrogen peroxide (H₂O₂), superoxide (O₂⁻), and peroxynitrite (ONOO‐). (Full color version available online.)

Table 1.  Low Molecular Weight Antioxidants in Normal Subjects

Antioxidant	Plasma	Epithelial lining fluid
Glutathione	1.0 ± 0.7 µM	109 ± 64 µM
Urate	387 ± 132 µM	207 ± 167 µM
Ascorbate (Vitamin C)	67 ± 25 µM	40 ± 18 µM
α‐tocopherol (Vitamin E)	16 ± 5 µM	0.7 ± 0.3 µM

*Adapted from Ref. [[31]].

Figure 4. Pulmonary distribution of extracellular superoxide dismutase. Histochemical localization of the superoxide dismutases in human lung using rabbit anti‐human extracellular superoxide dismutase extracellular superoxide dismutase (ECSOD) antibodies. ECSOD labeling of a small airway (A) and small pulmonary vessel (B). Strong labeling is seen in the airway and vessel walls (arrows). (A) Reprinted by permission from Ref. [[206]] and (B) reprinted by permission from Ref. [[207]]. (Full color version available online.)

Table 2.  Free Radicals and Their Footprints in COPD

Marker	Change
Carbon monoxide	↑ [[197]]
8‐isoprostanes	↑ [[84]][[86]]
Ethane	↑ [[85]]
Nitrotyrosine	↑ [[198]]
α1‐PI activity	↓ [[134]]
Hydrogen peroxide	↑ [[90]][[97]]
Nitric oxide	↑ [[99]]

*See text for details.

Figure 5. Treatment with an SOD mimetic (M40419) attenuates anti‐VEGF‐(SU5416) mediated emphysema. (a) SU5416‐treated lungs show increased size of alveolar structures. (b) SU5416 + M40419‐treatment protects against alveolar loss and these animals show normal alveolar size and architecture (bar = 100 µm). Adapted with permission from Ref. [[150]]. (Full color version available online.)

Figure 6. Stimulation of normal alveolar macrophages activates nuclear factor‐κB (NF‐κB) and other transcription factors to switch on histone acetyltransferase leading to histone acetylation and transcription of genes encoding inflammatory proteins, such as tumor necrosis factor‐α (TNF‐α), interleukin‐8 (IL‐8) and matrix metalloproteinase‐9 (MMP‐9). Corticosteroids reverse this by binding to glucocorticoid receptors (GR) and recruiting histone deacetylase‐2 (HDAC2). This reverses the histone acetylation induced by NF‐κB and switches off the activated inflammatory genes. In COPD patients cigarette smoke activates macrophages, as in normal subjects, but oxidative stress (perhaps acting through the formation of peroxynitrite) impairs the activity of HDAC2. This both amplifies the inflammatory response to NF‐κB activation, and reduces the anti‐inflammatory effect of corticosteroids as HDAC2 is now unable to reverse histone acetylation. (Full color version available online.)

Figure 7. Low levels of plasma ascorbate increase the risk of COPD independently of smoking history. The relative risks of having COPD in light (white bar), medium (black bar) and heavy (cross hatched bar) smokers compared to never smokers are shown for each quintile of plasma ascorbate concentration. The risk of COPD was highest in the patients with the very low quintile of plasma concentration (3–37 µM), compared to low (28–49 µM), median (50–58 µM), high (59–68 µM), or very high quintiles (69–174 µM). Adapted from Ref. (176).

Table 3.  Randomized Controlled Trials Using N‐Acetylcysteine to Treat COPD Patients

Study	N	Odds ratio [95% CI] of at least 1 exacerbation
Boman, et al. [[199]]	203	0.36 [0.19–0.67]
British Thoracic Society [[200]]	148	0.65 [0.25–1.73]
Grassi, et al. [[201]]	69	0.45 [0.17–1.20]
Hansen, et al. [[202]]	129	0.60 [0.30–1.22]
Multicenter Study Group [[203]]	495	0.28 [0.19–0.42]
Pela, et al. [[204]]	163	0.39 [0.20–0.76]
Rasmussen, et al. [[205]]	91	0.59 [0.20–1.73]

Figure 8. Three classes of superoxide dismutase mimetics. Side chains (R‐) can be substituted.

Figure 9. Effects of tobacco smoke on airways. Catalytic antioxidants attenuate squamous metaplasia from tobacco smoke. (A) Epithelial cell changes in airways from tobacco smoke‐exposed and filtered air (control) rats (epithelium is indicated between arrows). Lung sections were stained with hematoxylin and eosin for general morphology. Airway epithelium from filtered air control rats do not show the striking squamous cell metaplasia with prominent filamentous‐like cytoplasmic extensions (*) observed in the airways from rats exposed to tobacco smoke for 8 weeks. (B) Squamous metaplasia in rat lungs with or without a superoxide dismutase mimetic. The percent of airway surface expressing the type of squamous metaplasia illustrated in Fig. 9A is shown. Data are presented as mean ± SE (n = 5−6). *p < 0.05 for comparison to the tobacco smoke alone group. Adapted from Ref. [[57]]. (Full color version available online.)

van der Vliet A, O'Neill C A, Cross C E, Koostra J M, Volz W G, Halliwell B, Louie S. Determination of low‐molecular‐mass antioxidant concentrations in human respiratory tract lining fluids. Am J Physiol 1999; 276(2 Pt 1)L289–L296, [PUBMED], [INFOTRIEVE]

 PubMed Web of Science ®Google Scholar

Crapo J D, Day B J. Modulation of nitric oxide responses in asthma by extracellular antioxidants. J Allergy Clin Immunol 1999; 104(4 Pt 1)743–746, [PUBMED], [INFOTRIEVE], [CSA]

 PubMed Web of Science ®Google Scholar

Bowler R P. Regulation of Extracellular Superoxide Dismutase, in Department of Cellular and Structural Biology. University of Colorado Health Sciences Center, Denver 2001; 111

 Google Scholar

Symonds G, Renzetti A.D., Jr., Mitchell M M. The diffusing capacity in pulmonary emphysema. Am Rev Respir Dis 1974; 109(3)391–394, [PUBMED], [INFOTRIEVE]

 PubMed Web of Science ®Google Scholar

Pratico D, Basili S, Vieri M, Cordova C, Violi F, Fitzgerald G A. Chronic obstructive pulmonary disease is associated with an increase in urinary levels of isoprostane F2alpha‐III, an index of oxidant stress. Am J Respir Crit Care Med 1998; 158(6)1709–1714, [PUBMED], [INFOTRIEVE], [CSA]

 PubMed Web of Science ®Google Scholar

Montuschi P, Collins J V, Ciabattoni G, Lazzeri N, Corradi M, Kharitonov S A, Barnes P J. Exhaled 8‐isoprostane as an in vivo biomarker of lung oxidative stress in patients with COPD and healthy smokers. Am J Respir Crit Care Med 2000; 162(3 Pt 1)1175–1177, [PUBMED], [INFOTRIEVE], [CSA]

 PubMed Web of Science ®Google Scholar

Paredi P, Kharitonov S A, Leak D, Ward S, Cramer D, Barnes P J. Exhaled ethane, a marker of lipid peroxidation, is elevated in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000; 162(2 Pt 1)369–373, [PUBMED], [INFOTRIEVE], [CSA]

 PubMed Web of Science ®Google Scholar

Paredi P, Kharitonov S A, Leak D, Shah P L, Cramer D, Hodson M E, Barnes P J. Exhaled ethane is elevated in cystic fibrosis and correlates with carbon monoxide levels and airway obstruction. Am J Respir Crit Care Med 2000; 161(4 Pt 1)1247–1251, [PUBMED], [INFOTRIEVE], [CSA]

 PubMed Web of Science ®Google Scholar

Janoff A, Carp H, Laurent P, Raju L. The role of oxidative processes in emphysema. Am Rev Respir Dis 1983; 127(2)S31–S38, [PUBMED], [INFOTRIEVE]

 PubMed Web of Science ®Google Scholar

Kasielski M, Nowak D. Long‐term administration of N‐acetylcysteine decreases hydrogen peroxide exhalation in subjects with chronic obstructive pulmonary disease. Respir Med 2001; 95(6)448–456, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]

 PubMed Web of Science ®Google Scholar

Dekhuijzen P N, Aben K K, Dekker I, Aarts L P, Wielders P L, van Herwaarden C L, Bast A. Increased exhalation of hydrogen peroxide in patients with stable and unstable chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1996; 154(3 Pt 1)813–816, [PUBMED], [INFOTRIEVE], [CSA]

 PubMed Web of Science ®Google Scholar

Ansarin K, Chatkin J M, Ferreira I M, Gutierrez C A, Zamel N, Chapman K R. Exhaled nitric oxide in chronic obstructive pulmonary disease: relationship to pulmonary function. Eur Respir J 2001; 17(5)934–938, [PUBMED], [INFOTRIEVE], [CROSSREF]

 PubMed Web of Science ®Google Scholar

Tuder R M, Zhen L, Cho C Y, Taraseviciene‐Stewart L, Kasahara Y, Salvemini D, Voelkel N F, Flores S C. Oxidative stress and apoptosis interact and cause emphysema due to vascular endothelial growth factor receptor blockade. Am J Respir Cell Mol Biol 2003; 29(1)88–97, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]

 PubMed Web of Science ®Google Scholar

Boman G, Backer U, Larsson S, Melander B, Wahlander L. Oral acetylcysteine reduces exacerbation rate in chronic bronchitis: report of a trial organized by the Swedish Society for Pulmonary Diseases. Eur J Respir Dis 1983; 64(6)405–415, [PUBMED], [INFOTRIEVE]

 PubMedGoogle Scholar

Oral N‐acetylcysteine and exacerbation rates in patients with chronic bronchitis and severe airways obstruction. British Thoracic Society Research Committee. Thorax 1985; 40(11)832–835

 PubMed Web of Science ®Google Scholar

Grassi C, Morandini G C. A controlled trial of intermittent oral acetylcysteine in the long‐term treatment of chronic bronchitis. Eur J Clin Pharmacol 1976; 09(5–6)393–396, [PUBMED], [INFOTRIEVE], [CROSSREF], [CROSSREF]

 PubMedGoogle Scholar

Hansen N C, Skriver A, Brorsen‐Riis L, Balslov S, Evald T, Maltbaek N, Gunnersen G, Garsdal P, Sander P, Pedersen J Z, Ibsen T B, Rasmussen F V. Orally administered N‐acetylcysteine may improve general well‐being in patients with mild chronic bronchitis. Respir Med 1994; 88(7)531–535, [PUBMED], [INFOTRIEVE], [CSA]

 PubMed Web of Science ®Google Scholar

Long‐term oral acetylcysteine in chronic bronchitis. A double‐blind controlled study. Eur J Respir Dis Suppl 1980; 111: 93–108

 PubMedGoogle Scholar

Pela R, Calcagni A M, Subiaco S, Isidori P, Tubaldi A, Sanguinetti C M. N‐acetylcysteine reduces the exacerbation rate in patients with moderate to severe COPD. Respiration 1999; 66(6)495–500, [PUBMED], [INFOTRIEVE], [CROSSREF], [CROSSREF], [CSA]

 PubMed Web of Science ®Google Scholar

Rasmussen J B, Glennow C. Reduction in days of illness after long‐term treatment with N‐acetylcysteine controlled‐release tablets in patients with chronic bronchitis. Eur Respir J 1988; 1(4)351–355, [PUBMED], [INFOTRIEVE]

 PubMed Web of Science ®Google Scholar

Smith K R, Uyeminami D L, Kodavanti U P, Crapo J D, Chang L Y, Pinkerton K E. Inhibition of tobacco smoke‐induced lung inflammation by a catalytic antioxidant. Free Radic Biol Med 2002; 33(8)1106–1114, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]

 PubMed Web of Science ®Google Scholar