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

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.

authors

McCarter SD,Mei SH,Lai PF,Zhang QW,Parker CH,Suen RS,Hood RD,Zhao YD,Deng Y,Han RN,Dumont DJ,Stewart DJ

doi

10.1164/rccm.200609-1370OC

subject

Has Abstract

pub_date

2007-05-15 00:00:00

pages

1014-26

issue

10

eissn

1073-449X

issn

1535-4970

pii

200609-1370OC

journal_volume

175

pub_type

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