Rubin Tuder

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A novel antiapoptotic role for alpha1-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; et al. (Profiled Authors: Iwona Fijalkowska-Gorzka; Rubin Tuder)

Division of Pulmonary and Critical Care, Department of Medicine, John Hopkins University School of Medicine, Baltimore, Maryland, USA. ipetrach@iupui.edu
American journal of respiratory and critical care medicine 2006;173(11):1222-8.

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 alpha1-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, alpha1-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 alpha1-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 alpha1-antitrypsin intravenously. CONCLUSIONS: Our findings suggest that inhibition of structural alveolar cell apoptosis by alpha1-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 alpha1-antitrypsin.

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