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Superoxide Dismutase Expression Attenuates Cigarette Smoke– or Elastase-generated Emphysema in Mice

Department of Medicine, Columbia University, New York, New York; Department of Biochemistry, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey; and Department of Pathology, Keio University, Tokyo, Japan

Correspondence and requests for reprints should be addressed to Jeanine D'Armiento, M.D., Ph.D., Department of Medicine, 630 West 168th Street, P&S 8–401, New York, NY 10032. E-mail: jmd12{at}columbia.edu

Rationale: Oxidants are believed to play a major role in the development 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 immunofluorescence for 3-nitrotyrosine and 8-hydroxydeoxyguanosine and lipid peroxidation levels. The development of emphysema was determined by measuring the mean linear intercept (L_m).

Main Results: Smoke exposure caused a fourfold increase in neutrophilic inflammation and doubled lung myeloperoxidase activity. This inflammatory response did not occur in the smoke-exposed CuZnSOD mice. 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 (L_m, 68 exposed control vs. 58 exposed transgenic; p < 0.04) and elastase-generated model (L_m, 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 proteolytic cascade that leads to emphysema formation in two separate animal models of the disease.

Conclusions: These findings indicate that strategies aimed at enhancing or supplementing lung antioxidants could be effective for the prevention and treatment of this disease.

Key Words: emphysema • inflammation • oxidants

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