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Am J Respir Crit Care Med. 2007 May 15;175(10):1014-26. Epub 2007 Feb 22.

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

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

Abstract

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.

PMID:
17322110
[PubMed - indexed for MEDLINE]
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