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(Circulation Research. 2008;102:804.)
© 2008 American Heart Association, Inc.

Molecular Medicine

Interleukin-1β Causes Acute Lung Injury via vβ5 and vβ6 Integrin–Dependent Mechanisms

Michael T. Ganter^*, Jérémie Roux^*, Byron Miyazawa, Marybeth Howard, James A. Frank, George Su, Dean Sheppard, Shelia M. Violette, Paul H. Weinreb, Gerald S. Horan, Michael A. Matthay, Jean-François Pittet

From the Laboratory of Surgical Research, Departments of Anesthesia and Surgery (M.T.G., J.R., B.M., M.H., J.-F.P.), Department of Medicine, The Cardiovascular Research Institute (J.A.F., M.A.M., J.-F.P.), Lung Biology Center (G.S., D.S.), University of California, San Francisco; and Department of Exploratory Biology (S.M.V., P.H.W., G.S.H.), Biogen Idec, Cambridge, Mass.

Correspondence to Jean-François Pittet, MD, Department of Anesthesia, San Francisco General Hospital, 1001 Potrero Ave, Room 3C-38, San Francisco, CA 94110. E-mail pittetj{at}anesthesia.ucsf.edu

Interleukin (IL)-1β has previously been shown to be among the most biologically active cytokines in the lungs of patients with acute lung injury (ALI). Furthermore, there is experimental evidence that lung vascular permeability increases after short-term exposure to IL-1 protein, although the exact mechanism is unknown. Therefore, the objective of this study was to determine the mechanisms of IL-1β–mediated increase in lung vascular permeability and pulmonary edema following transient overexpression of this cytokine in the lungs by adenoviral gene transfer. Lung vascular permeability increased with intrapulmonary IL-1β production with a maximal effect 7 days after instillation of the adenovirus. Furthermore, inhibition of the vβ6 integrin and/or transforming growth factor-β attenuated the IL-1β–induced ALI. The results of in vitro studies indicated that IL-1β caused the activation of transforming growth factor-β via RhoA/vβ6 integrin–dependent mechanisms and the inhibition of the vβ6 integrin and/or transforming growth factor-β signaling completely blocked the IL-1β–mediated protein permeability across alveolar epithelial cell monolayers. In addition, IL-1β increased protein permeability across lung endothelial cell monolayers via RhoA- and vβ5 integrin–dependent mechanisms. The final series of in vivo experiments demonstrated that pretreatment with blocking antibodies to both the vβ5 and vβ6 integrins had an additive protective effect against IL-1β–induced ALI. In summary, these results demonstrate a critical role for the vβ5/β6 integrins in mediating the IL-1β–induced ALI and indicate that these integrins could be a potentially attractive therapeutic target in ALI.

Key Words: lung • cytokines • inflammation • endothelial cells • epithelial cells • rodents

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