Cell-based Anqiopoietin-1 Gene Therapy for Acute Lung Injury

• Published in: American journal of respiratory and critical care medicine 2007-05, Vol.175 (10), p.1014-1026
• Main Authors: McCarter, S D, Mei, SHJ, Lai, PFH, Zhang, Q W, Parker, CH, Suen, R S, Hood, R D, Zhao, Y D, Deng, Y, Han, RNN, Dumont, D J, Stewart, D J
• Format: Article
• Language: English
• ISSN: 1073-449X
• DOI: 10.1164/rccm.200609-1370OC

Rationale: The acute respiratory distress syndrome is a significant cause of morbidity and mortality in critically ill patients. Angio-poietin-1 (Ang-1), a ligand for the endothelial Tie2 receptor, is an endothelial survival and vascular stabilization factor that reduces endothelial permeability and inhibits leukocyte-endothelium interactions. Objectives: We hypothesized that Ang-1 counteracts vascular inflammation and pulmonary vascular leak in experimental acute lung injury. Methods: We used cell-based gene therapy in a rat model of ALI. Transgenic mice overexpressing Ang-1 or deficient in the Tie2 receptor were also studied to better elucidate the mechanisms of protection. Measurements and Main Results: The present report provides data that support a strong protective role for the Ang-1/Tie2 system in two experimental models of LPS-induced acute lung injury. In a rat model, cell-based Ang-1 gene transfer improved morphological, biochemical, and molecular indices of lung injury and inflammation. These findings were confirmed in a gain-of-function conditional, targeted transgenic mouse model, in which Ang-1 reduced endothelial cell activation and the expression of adhesion molecules, associated with a marked improvement in airspace inflammation and intraal-veolar septal thickening. Moreover, heterozygous Tie2-defident mice demonstrated enhanced evidence of lung injury and increased early mortality. Conclusions: These results support a critical role for the Ang-1/Tie2 axis in modulating the pulmonary vascular response to lung injury and suggest that Ang-1 therapy may represent a potential new strategy for the treatment and/or prevention of acute respiratory distress syndrome in critically ill patients.