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Integrin v5 Regulates Lung Vascular Permeability and Pulmonary Endothelial Barrier Function

Lung Biology Center, Division of Pulmonary and Critical Care Medicine, Laboratory of Surgical Research, Departments of Anesthesia and Surgery, and Cardiovascular Research Institute, University of California, San Francisco; and Veterans Administration Medical Center, San Francisco, California

Correspondence and requests for reprints should be addressed to Dean Sheppard, Lung Biology Center, UCSF, Rock Hall, Room 545, 1550 4th Street, San Francisco, CA 94158. E-mail: dean.sheppard{at}ucsf.edu

Increased lung vascular permeability is an important contributor to respiratory failure in acute lung injury (ALI). We found that a function-blocking antibody against the integrin v5 prevented development of lung vascular permeability in two different models of ALI: ischemia-reperfusion in rats (mediated by vascular endothelial growth factor [VEGF]) and ventilation-induced lung injury (VILI) in mice (mediated, at least in part, by transforming growth factor- [TGF-]). Knockout mice homozygous for a null mutation of the integrin 5 subunit were also protected from lung vascular permeability in VILI. In pulmonary endothelial cells, both the genetic absence and blocking of v5 prevented increases in monolayer permeability induced by VEGF, TGF-, and thrombin. Furthermore, actin stress fiber formation induced by each of these agonists was attenuated by blocking v5, suggesting that v5 regulates induced pulmonary endothelial permeability by facilitating interactions with the actin cytoskeleton. These results identify integrin v5 as a central regulator of increased pulmonary vascular permeability and a potentially attractive therapeutic target in ALI.

Key Words: integrin v5 • lung vascular permeability • pulmonary endothelial barrier function

CLINICAL RELEVANCE We describe a novel role for integrin v5 in regulating lung vascular permeability and agonist-induced endothelial permeability. Furthermore, we suggest that v5 regulation of the actin-cytoskeleton may be a mechanism responsible for these effects.

 

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