A novel antiapoptotic role for alpha1-antitrypsin in the prevention of pulmonary emphysema.

Abstract:

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.

authors

Petrache I,Fijalkowska I,Zhen L,Medler TR,Brown E,Cruz P,Choe KH,Taraseviciene-Stewart L,Scerbavicius R,Shapiro L,Zhang B,Song S,Hicklin D,Voelkel NF,Flotte T,Tuder RM

doi

10.1164/rccm.200512-1842OC

keywords:

subject

Has Abstract

pub_date

2006-06-01 00:00:00

pages

1222-8

issue

11

eissn

1073-449X

issn

1535-4970

pii

200512-1842OC

journal_volume

173

pub_type

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