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Published ahead of print on February 22, 2007, doi:10.1164/rccm.200609-1370OC

Am. J. Respir. Crit. Care Med., Volume 175, Number 10, May 2007, 1014-1026

A more recent version of this article appeared on May 15, 2007
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Submitted on September 26, 2006
Accepted on February 16, 2007

Cell-Based Angiopoietin-1 Gene Therapy for Acute Lung Injury

Sarah D McCarter1, Shirley H Mei2, Patrick F Lai2, QiuWang Zhang1, Colleen H Parker1, Renee S Suen2, Roberta D Hood1, Yidan D Zhao1, Yupu Deng1, Robin N Han1, Dan J Dumont3, and Duncan J Stewart4*

1 Division of Cardiology, Terrence Donnelly Research Laboratories, St. Michael's Hospital, Toronto, Ontario, Canada, 2 Division of Cardiology, Terrence Donnelly Research Laboratories, St. Michael's Hospital, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada, 3 Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Molecular and Cellular Biology Research, Sunnybrook Research Institute, Toronto, Ontario, Canada, 4 Division of Cardiology, Terrence Donnelly Research Laboratories, St. Michael's Hospital, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Department of Medicine and McLaughlin Centre for Molecular Medicine, University of Toronto, Toronto, Ontario, Canada

* To whom correspondence should be addressed. E-mail: stewartd{at}smh.toronto.on.ca.

Rationale: The Acute Respiratory Distress Syndrome (ARDS) 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 (ALI). Methods, Measurements and Main Results: The present report provides data that supports a strong protective role for the Ang-1/Tie2 system in two experimental models of LPS-induced ALI. 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 intra-alveolar 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 ARDS in critically ill patients.
Key words: Acute Respiratory Distress Syndrome, Tie2, inflammation, ICAM-1, VCAM-1, E-Selectin, P-Selectin, TNF-{alpha}, IL-1{beta}, IL-6, LPS




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