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The Proceedings of the American Thoracic Society 3:543 (2006)
© 2006 The American Thoracic Society
doi: 10.1513/pats.200603-044MS
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Modifier Role of Nrf2 in Cigarette Smoke–induced Emphysema

Shyam Biswal, Tirumalai Rangasamy and Rubin M. Tuder

Department of Environmental Health Sciences, Bloomberg School of Public Health; and Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland

Correspondence and requests for reprints should be addressed to Shyam Biswal, Ph.D., Assistant Professor of Toxicology, Oncology, Department of Environmental Health Sciences, Johns Hopkins University School of Public Health, Ross Building, Room 519, 720 Rutland Avenue, Baltimore, MD 21205-2109. E-mail: sbiswal{at}jhsph.edu

Even though inflammation and protease/antiprotease imbalance have been postulated to be critical in cigarette smoke (CS)–induced emphysema, oxidative stress has been suspected to play an important role in chronic obstructive pulmonary diseases. Other than congenital deficiencies of {alpha}1-antitrypsin, which contribute to less than 5% of cases, the genes that determine susceptibility to emphysema are unknown. Susceptibility of the lung to oxidative injury, such as that originating from inhalation of CS, depends largely on its up-regulation of antioxidant systems. Nrf2 is a redox-sensitive basic leucine zipper (bZIP) transcription factor that is involved in the regulation of many detoxification and antioxidant genes. Disruption of the nrf2 gene in (emphysema-resistant) CD-1 (ICR) mice led to earlier onset and more extensive CS-induced emphysema than is seen in wild-type littermates. The nrf2-deficient mice exposed to CS for 6 mo had more pronounced bronchoalveolar inflammation, with enhanced alveolar expression of markers of oxidative stress, and with an increased number of apoptotic alveolar septal cells, predominantly endothelial and type II epithelial cells, as compared with wild-type mice. Microarray analysis identified the expression of nearly 50 Nrf2-dependent antioxidant and cytoprotective genes in the lung, which may work in concert to counteract CS-induced oxidative stress and inflammation. There was lesser response of Nrf2 in the lungs of emphysema-sensitive C57BL/6J mice than in the resistant ICR mice. The study shows that the Nrf2 pathway is an important risk modifier of emphysema.

FOOTNOTES

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received in original form March 16, 2006; accepted in final form April 12, 2006)





This Article
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Right arrow Articles by Tuder, R. M.

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