Integrin Beta 4 in Vascular Inflammatory Responses

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DESCRIPTION (provided by applicant): Acute inflammatory lung injury (ALI) is a challenging clinical problem that is commonly encountered in the intensive care unit and is associated with significant morbidity and mortality. A cardinal feature of ALI is an increase in lung vascular permeability, often precipitated by an exuberant inflammatory response with subsequent endothelial barrier disruption. Strategies designed to attenuate vascular permeability could provide attractive novel therapeutic targets and approaches. We previously identified the protective effects of simvastatin, an HMG CoA-reductase inhibitor, in a murine model of ALI and defined potent anti-inflammatory effects of statins including augmentation of endothelial cell (EC) barrier function. Genomic studies of simvastatin-mediated EC gene expression identified the dramatic upregulation of integrin ¿4, a laminin receptor expressed in numerous cell types including EC, suggesting a potentially novel ALI target. While information is limited as to the role of integrin ¿4 in EC, integrins are known to serve as mediators of inflammatory signaling and we have recently confirmed the attenuation of lung inflammation associated with the inhibition of integrin ¿4 in separate models of murine ALI and ventilator-induced lung injury (VILI). Accordingly, we now hypothesize that integrin ¿4 mediates EC inflammatory responses in ALI and may serve as a highly novel therapeutic target in this setting. PUBLIC HEALTH RELEVANCE: Acute inflammatory lung injury (ALI) is a challenging clinical problem that is commonly encountered in the intensive care unit and is associated with significant morbidity and mortality. Although treatment options for ALI are severely limited we previously identified the protective effects of simvastatin, a drug commonly used to lower serum cholesterol levels, in an animal model of ALI and our subsequent genomic studies identified the dramatic increase in the protein integrin ¿4 in response to simvastatin treatment. Accordingly, we now hypothesize that integrin ¿4 mediates vascular inflammatory responses in ALI and may serve as a highly novel therapeutic target in this setting.