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

Am J Respir Crit Care Med. 2006 Jun 1;173(11):1222-8. doi: 10.1164/rccm.200512-1842OC. Epub 2006 Mar 2.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae
  • Animals
  • Apoptosis / drug effects*
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Oxidative Stress / drug effects
  • Pulmonary Alveoli / cytology
  • Pulmonary Emphysema / etiology
  • Pulmonary Emphysema / prevention & control*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors
  • Receptors, Vascular Endothelial Growth Factor / immunology
  • Trypsin Inhibitors / pharmacology*
  • Trypsin Inhibitors / therapeutic use
  • alpha 1-Antitrypsin / pharmacology*
  • alpha 1-Antitrypsin / therapeutic use


  • Trypsin Inhibitors
  • alpha 1-Antitrypsin
  • Receptors, Vascular Endothelial Growth Factor