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Published ahead of print on March 2, 2006, doi:10.1164/rccm.200512-1842OC
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American Journal of Respiratory and Critical Care Medicine Vol 173. pp. 1222-1228, (2006)
© 2006 American Thoracic Society
doi: 10.1164/rccm.200512-1842OC

Original Article

A Novel Antiapoptotic Role for {alpha}1-Antitrypsin in the Prevention of Pulmonary Emphysema

Irina Petrache, Iwona Fijalkowska, Lijie Zhen, Terry R. Medler, Emile Brown, Pedro Cruz, Kang-Hyeon Choe, Laimute Taraseviciene-Stewart, Robertas Scerbavicius, Lee Shapiro, Bing Zhang, Sihong Song, Dan Hicklin, Norbert F. Voelkel, 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; Department of Pediatrics, School of Medicine, and Department of Pharmaceutics, College of Pharmacy, University of Florida at Gainesville, Gainesville, Florida; Division of Pulmonary Sciences and Critical Care Medicine, Pulmonary Hypertension Center, and Division of Infectious Disease, Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado; and Imclone Systems, Inc., New York, New York

Correspondence and requests for reprints should be addressed to Irina Petrache, M.D., Pulmonary, Allergy, Critical Care, and Occupational Medicine, Indiana University, 1481 West 10th Street, 111P-IU, Indianapolis, IN 46202. E-mail: ipetrach{at}iupui.edu

Rationale: There is growing evidence that alveolar cell apoptosis plays an important role in emphysema pathogenesis, a chronic inflammatory lung disease characterized by alveolar destruction. The association of {alpha}1-antitrypsin deficiency with the development of emphysema has supported the concept that protease/antiprotease imbalance mediates cigarette smoke–induced emphysema.

Objectives: We propose that, in addition to its antielastolytic effects, {alpha}1-antitrypsin may have broader biological effects in the lung, preventing emphysema through inhibition of alveolar cells apoptosis.

Methods, Measurements, and Main Results: Transduction of human {alpha}1-antitrypsin via replication-deficient adeno-associated virus attenuated airspace enlargement and emphysema caused by inhibition of vascular endothelial growth factor (VEGF) receptors with SU5416 in mice, a model of apoptosis-dependent emphysema lacking neutrophilic inflammation. The overexpressed human serine protease inhibitor accumulated in lung cells and suppressed caspase-3 activation and oxidative stress in lungs treated with the VEGF blocker or with VEGF receptor-1 and -2 antibodies. Similar results were obtained in SU5416-treated rats given human {alpha}1-antitrypsin intravenously.

Conclusions: Our findings suggest that inhibition of structural alveolar cell apoptosis by {alpha}1-antitrypsin represents a novel protective mechanism of the serpin against emphysema. Further elucidation of this mechanism may extend the therapeutic options for emphysema caused by reduced level or loss of function of {alpha}1-antitrypsin.

Key Words: antiprotease • caspase • chronic obstructive pulmonary disease • oxidative stress • serpin




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