A novel antiapoptotic role for α1-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, Rubin M. Tuder

Research output: Contribution to journalArticlepeer-review

154 Scopus citations

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 α1- 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, α1-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 α1-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 α1-antitrypsin intravenously. Conclusions: Our findings suggest that inhibition of structural alveolar cell apoptosis by α1-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 α1-antitrypsin.

Original languageEnglish (US)
Pages (from-to)1222-1228
Number of pages7
JournalAmerican journal of respiratory and critical care medicine
Volume173
Issue number11
DOIs
StatePublished - Jun 1 2006

Keywords

  • Antiprotease
  • Caspase
  • Chronic obstructive pulmonary disease
  • Oxidative stress
  • Serpin

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

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