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Published ahead of print on December 30, 2005, doi:10.1164/rccm.200506-850OC

Am. J. Respir. Crit. Care Med., Volume 173, Number 6, March 2006, 623-631

A more recent version of this article appeared on March 15, 2006
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Submitted on June 2, 2005
Accepted on December 29, 2005

Superoxide Dismutase Expression Attenuates Cigarette Smoke or Elastase Generated Emphysema in Mice

Robert F Foronjy1, Oleg Mirochnitchenko2, Olga Propokenko2, Vincent Lemaitre1, Yuxia Jia1, Masayori Inouye2, Yasunori Okada3, and Jeanine M D'Armiento1*

1 Department of Medicine, Columbia University, New York, NY, USA, 2 UMDNJ, Piscataway, NJ, USA, 3 Department of Pathology, Keio University, Tokyo, Japan

* To whom correspondence should be addressed. 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 CuZn superoxide dismutase (SOD) within the lungs of mice protects against the development of emphysema. Methods: Transgenic CuZn SOD and littermate mice were exposed to cigarette smoke (6 hours/day; 5 days/week for one year) and compared to non-exposed mice. A second group was treated with intratracheal elastase in order 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. Main Results: Smoke exposure caused a four fold increase in neutrophilic inflammation and doubled lung myeloperoxidase activity. This inflammatory response did not occur in the smoke exposed SOD mice. Similarly, SOD expression prevented the 58% increase in lung lipid peroxidation products that occurred following smoke exposure. Most importantly, SOD prevented the onset of emphysema in both the smoke-induced (Lm 68 exposed control vs. 58 exposed transgenic; p<0.04) and elastase-generated (Lm 80 exposed control vs. 63 exposed transgenic; p<0.03) models. 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 and proteases




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