Superoxide dismutase expression attenuates cigarette smoke- or elastase-generated emphysema in mice

Rationale:Oxidants are believed to play a major role in the develop-ment of emphysema. Objectives: This study aimed to determine if the expression of human copper–zinc superoxide dismutase (CuZnSOD) within the lungs of mice protects against the development of emphysema. Methods: Transgenic CuZnSOD and littermate mice were exposed to cigarette smoke (6 h/d, 5 d/wk, for 1 yr) and compared with nonexposed mice. A second group was treated with intratracheal elastase to induce emphysema. Measurements: Lung inflammation was measured by cell counts and myeloperoxidase levels. Oxidative damage was assessed by immu-nofluorescence for 3-nitrotyrosine and 8-hydroxydeoxyguanosine and lipid peroxidation levels. The development of emphysema was determined by measuring the mean linear intercept (Lm). Main Results: Smoke exposure caused a fourfold increase in neutro-philic inflammation and doubled lung myeloperoxidase activity. This inflammatory response did not occur in the smoke-exposed CuZnSODmice. Similarly, CuZnSOD expression prevented the 58% increase in lung lipid peroxidation products that occurred after smoke exposure. Most important, CuZnSOD prevented the onset of emphysema in both the smoke-induced model (Lm, 68 exposed control vs. 58 exposed transgenic; p 0.04) and elastase-generated model (Lm, 80 exposed control vs. 63 exposed transgenic; p 0.03). These results demonstrate for the first time that antioxidants can prevent smoke-induced inflammation and can counteract the pro-teolytic cascade that leads to emphysema formation in two separate animal models of the disease. Conclusions:These findings indicate that strategies aimed at enhanc-ing or supplementing lung antioxidants could be effective for the prevention and treatment of this disease