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Published ahead of print on November 1, 2006, doi:10.1165/rcmb.2006-0238OC

Am. J. Respir. Cell Mol. Biol., Volume 36, Number 3, March 2007, 377-386

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Submitted on July 4, 2006
Revised on November 1, 2006

Integrin {alpha}v{beta}5 Regulates Lung Vascular Permeability and Pulmonary Endothelial Barrier Function

George Su1, Maki Hodnett2, Nanyan Wu3, Amha Atakilit3, Cynthia Kosinski3, Mika Godzich2, Xiao Zhu Huang3, Jiyeun K Kim3, James A Frank4, Michael A Matthay5, Dean Sheppard6*, and Jean-Francois Pittet7

1 Lung Biology Center, University of California San Francisco, San Francisco, CA, USA; Division of Pulmonary and Critical Care Medicine, University of California San Francisco, San Francisco, CA, USA, 2 Laboratory of Surgical Research, University of California San Francisco, San Francisco, CA, USA, 3 Lung Biology Center, University of California San Francisco, San Francisco, CA, USA, 4 Division of Pulmonary and Critical Care Medicine, University of California San Francisco, San Francisco, CA, USA; Veterans Administration Medical Center, San Francisco, CA, USA, 5 Division of Pulmonary and Critical Care Medicine, University of California San Francisco, San Francisco, CA, USA; Departments of Anesthesia and Surgery, University of California San Francisco, San Francisco, CA, USA; Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA, 6 Lung Biology Center, University of California San Francisco, San Francisco, CA, USA; Division of Pulmonary and Critical Care Medicine, University of California San Francisco, San Francisco, CA, USA; Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA, 7 Laboratory of Surgical Research, University of California San Francisco, San Francisco, CA, USA; Departments of Anesthesia and Surgery, University of California San Francisco, San Francisco, CA, USA; Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA

* To whom correspondence should be addressed. 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 {alpha}v{beta}5 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-{beta} (TGF-{beta})). Knockout mice homozygous for a null mutation of the integrin {beta}5 subunit were also protected from lung vascular permeability in VILI. In pulmonary endothelial cells, both the genetic absence and blocking of {alpha}v{beta}5 prevented increases in monolayer permeability induced by VEGF, TGF-{beta}, and thrombin. Furthermore, actin stress fiber formation induced by each of these agonists was attenuated by blocking {alpha}v{beta}5, suggesting that {alpha}v{beta}5 regulates induced pulmonary endothelial permeability by facilitating interactions with the actin cytoskeleton. These results identify integrin {alpha}v{beta}5 as a central regulator of increased pulmonary vascular permeability and a potentially attractive therapeutic target in ALI.




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