Cell-based angiopoietin-1 gene therapy for acute lung injury.

Am J Respir Crit Care Med 2007 May 22;175(10):1014-26. Epub 2007 Feb 22.

St. Michael's Hospital, Toronto, ON, M5B 1W8, Canada.

Rationale: The acute respiratory distress syndrome is a significant cause of morbidity and mortality in critically ill patients. Angiopoietin-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 intraalveolar septal thickening. Moreover, heterozygous Tie2-deficient 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.

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http://dx.doi.org/10.1164/rccm.200609-1370OCDOI Listing
May 2007
33 Reads
40 Citations
13.000 Impact Factor

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