期刊
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
卷 173, 期 11, 页码 1222-1228出版社
AMER THORACIC SOC
DOI: 10.1164/rccm.200512-1842OC
关键词
antiprotease; caspase; chronic obstructive pulmonary disease; oxidative stress; serpin
资金
- NHLBI NIH HHS [R01- HL69877, K08 HL04396-04, R01HL66554, R01 HL60913-01] Funding Source: Medline
- NIDDK NIH HHS [P01-DK58327] Funding Source: Medline
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/antiprotease imbalance mediates cigarette smoke-induced emphysema. Objectives: We propose that, in addition to its antielastolytic 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 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 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.
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