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Published ahead of print on December 30, 2005, doi:10.1164/rccm.200506-850OC
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American Journal of Respiratory and Critical Care Medicine Vol 173. pp. 623-631, (2006)
© 2006 American Thoracic Society
doi: 10.1164/rccm.200506-850OC

Original Article

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

Robert F. Foronjy, Oleg Mirochnitchenko, Olga Propokenko, Vincent Lemaitre, Yuxia Jia, Masayori Inouye, Yasunori Okada and Jeanine M. D'Armiento

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 (Lm).

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 (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 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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