Oxidant/antioxidant imbalance in smokers and chronic obstructive pulmonary disease.

An imbalance between oxidants and antioxidants has been proposed in the pathogenesis of chronic obstructive pulmonary disease (COPD). ' Although much research has focused on the protease/antiprotease theory of the pathogenesis of COPD, particularly emphysema, less attention has been paid to the role of the oxidant/antioxidant imbalance in this condition. This is surprising since cigarette smoke, which is the major risk factor for the development of COPD, contains 10'7 oxidant molecules per puff of which 1014 are oxygen free radicals.2 There is a delicate balance between the toxicity of oxidants and the protective function of the intracellular and extracellular antioxidant defence systems which is critically important for the maintenance of normal pulmonary cellular functions.3 In this editorial we will examine the oxidant/antioxidant imbalance in smokers and patients with COPD to determine if there is enough evidence to warrant therapeutic trials with antioxidant therapy in patients with COPD. Cigarette smoke is a complex mixture of over 4700 chemical compounds including high concentrations of oxidants and free radicals present in both the gas phase and the tar phase of cigarette smoke.24 Those in the gas phase are both organic and inorganic including reactive oxygen species and free radicals, aldehydes, peroxides and oxides of nitrogen. In the tar phase radicals are stable and predominantly organic, such as semiquinone which can react to produce superoxide anion (02). Short lived radicals in the gas phase of cigarette smoke may be quenched immediately in the epithelial lining fluid (ELF); however, redox reactions in cigarette smoke condensate may produce reactive oxygen intermediates for a considerable time. ' In normal lungs there are 50-70 inflammatory cells per alveolus; more than 80% are alveolar macrophages and less than 1% neutrophils.6 In cigarette smokers the numbers of alveolar macrophages increase by at least 2-4 times and neutrophils by 10 times.7 In vitro studies have shown that alveolar leucocytes and macrophages from cigarette smokers spontaneously release increased amounts of oxidants such as 02and hydrogen peroxide (H202) compared with non-smokers.89 It has also been suggested that neutrophils sequestered in the pulmonary circulation are primed to release oxidants in cigarette smokers. '01 Passive cigarette smoking has also been associated with increased peripheral blood leucocyte counts which show enhanced release of oxidants. '2 Oxidants, whether inhaled or generated from leucocytes, can inactivate the major antiprotease in the airways alpha,-proteinase inhibitor (o,PI) by oxidation of its active site. '3 14 This diminishes the binding of c,1PI to elastase, hence reducing its inactivation and allowing it to bind to and destroy elastin, leading to emphysema. 15 Although this hypothesis is supported by in vitro studies,'3 it has been more difficult to demonstrate convincingly oxidative inactivation of ocaPI in vivo.14 Other antiproteases which may have a protective role against proteolytic attack and hence may prevent the development of emphysema, such as antileucoprotease, can also be inactivated by oxidants. "6 Components of the lung matrix for example, elastin and collagen can be directly damaged or fragmented by oxidants in cigarette smoke. '5 Cigarette smoke-derived oxidants also decrease the deformability of circulating neutrophils'7 leading to increased neutrophil sequestration in the pulmonary microvasculature. '0 Inhalation of cigarette smoke in hamsters activates neutrophils, increasing their adhesion to the endothelium of both arterioles and venules. '8 This increased neutrophil adhesion is mediated by superoxide anion in cigarette smoke, since it is inhibited by pretreatment with copper/zinc superoxide dismutase. '8 Neutrophils sequestered in the pulmonary circulation following cigarette smoke inhalation in the rabbit show increased expression ofCD 18 integrins,19 although this effect has not been demonstrated following in vitro exposure.20 Thus, by several mechanisms involving oxidants, cigarette smoke causes neutrophil sequestration in the pulmonary microcirculation'o and hence their migration into the airspaces in smokers. These migrated cells remain primed to release more reactive oxygen intermediates. ' 12 All tissues are vulnerable to oxidant damage but, by virtue of its location, the airspace epithelium is particularly vulnerable.2' Reactive oxygen species may influence airway cells in a number of ways. Oxygen radicals generated close to a cell membrane oxidise membrane phospholipids (lipid peroxidation), a process which may continue in a chain reaction. Lannan and colleagues22 showed an oxidantmediated cytotoxicity of human alveolar epithelial cells with decreased epithelial cell adherence and increased detachment and lysis following exposure to cigarette smoke condensate. Li et al23 demonstrated that the deleterious effects of cigarette smoke condensate on epithelial permeability in vitro in epithelial cell monolayers and in vivo in rat lungs were associated with changes in the homeostasis of the antioxidant glutathione. These in vitro and animal studies are supported by human studies of increased epithelial permeability in smokers, shown by increased technetium-99m labelled diethylenetriamine pentaacetate (99mTc-DTPA) lung clearance.24 Preliminary data by Morrison and coworkers showed a further increase in DTPA clearance following acute smoking.25 There are technical difficulties in measuring specific markers of oxidative injury. The only definitive way to demonstrate excessive free radical activity is by electron spin resonance which cannot be applied to the study of tissues at present. Instead, investigators rely on indirect measurements of free radical activity in biological fluids such as measurements which assess oxidative damage to lipids, proteins, or DNA. These markers indicate that oxidative damage has occurred, but not that this event is involved in the pathogenesis of the condition. A major site of free radical attack is on polyunsatured fatty acids in cell membranes, producing lipid peroxidation which generates hydroperoxides and long lived aldehydes. The end products of these reactions are malondialdehyde, ethane, and pentane. Levels of lipid peroxides in plasma and bronchoalveolar lavage fluid, measured as thiobarbituric acid reactive substances (TBARS), are significantly increased in healthy smokers and patients with acute exacerbations of COPD compared with healthy nonsmokers.2"28 There is, however, a problem with the specificity of the assays used to measure the metabolites of lipid peroxide reactions. Evidence for increased oxidative stress in COPD is emerging. Patients with COPD have increased numbers of activated intravascular and airspace neutrophils and macrophages which release more 02 than those from 348