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(Circulation Research. 2009;105:549.)
© 2009 American Heart Association, Inc.

Integrative Physiology

LIM Kinase 1 Promotes Endothelial Barrier Disruption and Neutrophil Infiltration in Mouse Lungs

Matvey Gorovoy, Jingyan Han, Haiyun Pan, Emily Welch, Radu Neamu, Zhengping Jia, Dan Predescu, Stephen Vogel, Richard D. Minshall, Richard D. Ye, Asrar B. Malik, Tatyana Voyno-Yasenetskaya

From the Department of Pharmacology (M.G., J.H., H.P., E.W., R.N., D.P., S.V., R.M., R.D.Y., A.B.M., T.V.-Y.) and the Center for Lung and Vascular Biology (D.P., S.V., R.M., A.B.M., T.V.-Y.), University of Illinois, Chicago; and the Neuroscience and Mental Health Program (Z.J.), The Hospital for Sick Children, Toronto, Ontario, Canada.

Correspondence to Tatyana Voyno-Yasenetskaya, Department of Pharmacology (MC 868), University of Illinois at Chicago, 909 S Wolcott Ave, Chicago, IL 60612. E-mail tvy{at}uic.edu

Rationale: Disruption of endothelial barrier function and neutrophil-mediated injury are two major mechanisms underlying the pathophysiology of sepsis-induced acute lung injury (ALI). Recently we reported that endotoxin induced activation of RhoA in mice lungs that led to the disruption of endothelial barrier and lung edema formation; however, the molecular mechanism of this phenomenon remained unknown.

Objective: We reasoned that LIMK1, which participates in the regulation of endothelial cell contractility and is activated by RhoA/Rho kinase pathway, could mediate RhoA-dependent disruption of endothelial barrier function in mouse lungs during ALI. And if that is the case, then attenuation of endothelial cell contractility by downregulating LIMK1 may lead to the enhancement of endothelial barrier function, which could protect mice from endotoxin-induced ALI.

Methods and Results: Here we report that LIMK1 deficiency in mice significantly reduced mortality induced by endotoxin. Data showed that lung edema formation, lung microvascular permeability, and neutrophil infiltration into the lungs were suppressed in limk1^–/– mice.

Conclusions: We identified that improvement of endothelial barrier function along with impaired neutrophil chemotaxis were the underlying mechanisms that reduced severity of ALI in limk1^–/– mice, pointing to a new therapeutic target for diseases associated with acute inflammation of the lungs.

Key Words: LIMK1 • RhoA • endothelial barrier function • inflammation • acute lung injury • neutrophil infiltration • actin cytoskeleton