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

¹ Terrence Donnelly Research Laboratories, Division of Cardiology, St. Michael's Hospital, Toronto, Ontario, Canada; ² Institute of Medical Science, Departments of ³ Medical Biophysics and ⁴ Medicine and the McLaughlin Centre for Molecular Medicine, University of Toronto, Toronto, Ontario, Canada; and ⁵ Molecular and Cellular Biology Research, Sunnybrook Research Institute, Toronto, Ontario, Canada

Correspondence and requests for reprints should be addressed to Duncan J. Stewart, M.D., F.R.C.P.C., University of Toronto, Room 6-050k, Queen Wing, Terrence Donnelly Heart Centre, St. Michael's Hospital, 30 Bond Street, Toronto, ON, M5B 1W8 Canada. E-mail: stewartd{at}smh.toronto.on.ca

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.

Key Words: acute lung injury (ALI) • acute respiratory distress syndrome (ARDS) • angiopoietin-1 • cell-based gene transfer • LPS • Tie2

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject It has been reported that neutrophil infiltration, capillary leakage, and lung edema in experimental acute lung injury are associated with decreased angiopoietin (Ang)-1 and that pretreatment with an adenoviral construct encoding Ang-1 reduced mortality in mice with endotoxic shock. What This Study Adds to the Field Cell-based Ang-1 gene transfer improved indices of LPS-induced acute lung injury. 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 is a potential new strategy for the treatment and/or prevention of acute lung injury.

 

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