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Published ahead of print on March 2, 2006, doi:10.1164/rccm.200512-1842OC

Am. J. Respir. Crit. Care Med., Volume 173, Number 11, June 2006, 1222-1228

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Submitted on December 2, 2005
Accepted on February 28, 2006

A Novel Anti-apoptotic Role for Alpha-1 Antitrypsin in the Prevention of Pulmonary Emphysema

Irina Petrache1*, Iwona Fijalkowska2, Lijie Zhen2, Terry R Medler3, Emil Brown2, Pedro Cruz4, Kang-Hyeon Choe5, Laimute Taraseviciene-Stewart5, Robertas Scerbavicius5, Lee Shapiro6, Bing Zhang7, Sihong Song7, Dan Hicklin8, Norbert F Voelkel5, Terence Flotte4, and Rubin M Tuder1

1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Division of Cardiopulmonary Pathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA, 2 Division of Cardiopulmonary Pathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA, 3 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA, 4 Department of Pediatrics, University of Florida, School of Medicine, Gainesville, FL, USA, 5 Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, CO, USA, 6 Pulmonary Hypertension Center and Division of Infectious Disease, Department of Medicine, University of Colorado Health Sciences Center, Denver, CO, USA, 7 Department of Pharmaceutics, University of Florida, College of Pharmacy, Gainesville, FL, USA, 8 Imclone Systems, Inc., New York, NY, USA

* To whom correspondence should be addressed. E-mail: ipetra{at}jhmi.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/anti-protease imbalance mediates cigarette smoke-induced emphysema. Objectives: We propose that in addition to its anti-elastolytic 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, 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: serpin, COPD, caspase, oxidative stress, anti-protease




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