Abstract
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 alphavbeta5 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 beta5 subunit were also protected from lung vascular permeability in VILI. In pulmonary endothelial cells, both the genetic absence and blocking of alphavbeta5 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 alphavbeta5, suggesting that alphavbeta5 regulates induced pulmonary endothelial permeability by facilitating interactions with the actin cytoskeleton. These results identify integrin alphavbeta5 as a central regulator of increased pulmonary vascular permeability and a potentially attractive therapeutic target in ALI.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amides / pharmacology
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Animals
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Antibodies / immunology
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Blood-Air Barrier / drug effects
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Blood-Air Barrier / metabolism*
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Capillary Permeability / drug effects
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Capillary Permeability / physiology*
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Cattle
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Endothelial Cells / cytology
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Endothelial Cells / drug effects
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / metabolism*
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Enzyme Activation / drug effects
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Humans
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Integrins / antagonists & inhibitors
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Integrins / immunology
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Integrins / metabolism*
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Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
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Lung Diseases / chemically induced
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Lung Diseases / pathology
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Mice
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Pulmonary Artery / cytology
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Pulmonary Artery / drug effects
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Pyridines / pharmacology
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Rats
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Rats, Sprague-Dawley
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Receptors, Vitronectin / antagonists & inhibitors
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Receptors, Vitronectin / immunology
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Receptors, Vitronectin / metabolism*
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Reperfusion Injury
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Stress Fibers / drug effects
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Ventilators, Mechanical
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rho-Associated Kinases
Substances
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Amides
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Antibodies
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Integrins
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Intracellular Signaling Peptides and Proteins
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Pyridines
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Receptors, Vitronectin
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integrin alphaVbeta5
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Y 27632
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Protein Serine-Threonine Kinases
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rho-Associated Kinases