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The Proceedings of the American Thoracic Society 3:549 (2006)
© 2006 The American Thoracic Society
doi: 10.1513/pats.200603-079MS
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An Antiapoptotic Role for {alpha}1-Antitrypsin in the Prevention of Emphysema

Irina Petrache, Iwona Fijalkowska, Lijie Zhen, Terry R. Medler, Jarrett Skirball, Terence Flotte and Rubin M. Tuder

Division of Pulmonary and Critical Care Medicine, Department of Medicine, and Division of Cardiopulmonary Pathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland; and Department of Pediatrics, University of Florida, Gainesville Florida

Correspondence and requests for reprints should be addressed to Irina Petrache, M.D., Division of Pulmonary and Critical Care Medicine, Department of Medicine, Indiana University, 1481 West Tenth Street, Indianapolis, IN 46202. E-mail: ipetrach{at}ipvi.edu

We hypothesized that {alpha}1-antitrypsin has broader biological effects in the lung unrelated to its antielastase properties, by means of inhibiting alveolar cell apoptosis and oxidative stress. Accordingly, we tested whether {alpha}1-antitrypsin prevents emphysema through inhibition of alveolar cell apoptosis. Expression of human {alpha}1-antitrypsin by intramuscular or intratracheal administration of adeno-associated virus markedly increased its serum and lung expression in mice and attenuated emphysema caused by inhibition of vascular endothelial growth factor (VEGF) receptors with SU5416, a model of apoptosis-dependent emphysema, which lacks inflammation. The overexpressed serpin suppressed both caspase-3 activation and oxidative stress in lungs treated with the VEGF receptor blocker. The cytoplasmic interaction of {alpha}1-antitrypsin with caspase-3 as detected by co-immunoprecipitation and confocal fluorescence inhibited staurosporine-induced pulmonary endothelial cell apoptosis in vitro. Although {alpha}1-antitrypsin polymerization precludes its elastase inhibitory activity, both naive and polymerized, but not the C-36 (fibrillary) fragment, of {alpha}1-antitrypsin markedly inhibited caspase-3 activity. Our findings suggest a novel, antiapoptotic mechanism by which {alpha}1-antitrypsin protects alveolar destruction in emphysema, involving direct inhibition of caspase-3 activation unrelated to its antielastolytic effect.

FOOTNOTES

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

(Received in original form March 20, 2006; accepted in final form March 28, 2006)




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L. Taraseviciene-Stewart, I. S. Douglas, P. S. Nana-Sinkam, J. D. Lee, R. M. Tuder, M. R. Nicolls, and N. F. Voelkel
Is Alveolar Destruction and Emphysema in Chronic Obstructive Pulmonary Disease an Immune Disease?
Proceedings of the ATS, November 1, 2006; 3(8): 687 - 690.
[Abstract] [Full Text] [PDF]

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