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Role of phosphatidylinositol 3-kinase- in mediating lung neutrophil sequestration and vascular injury induced by E. coli sepsis

Department of Pharmacology and The Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, Illinois

Submitted 20 April 2005 ; accepted in final form 6 July 2005

We addressed the in vivo role of phosphatidylinositol 3-kinase- (PI3K-) in signaling the sequestration of polymorphonuclear leukocytes (PMNs) in lungs and in the mechanism of inflammatory lung vascular injury. We studied mice with deletion of the p110 catalytic subunit of PI3K- (PI3K-^–/– mice). We measured lung tissue PMN sequestration, microvascular permeability, and edema formation after bacteremia induced by intraperitoneal Escherichia coli challenge. PMN infiltration into the lung interstitium in PI3K-^–/– mice as assessed morphometrically was increased 100% over that in control mice within 1 h after bacterial challenge. PI3K-^–/– mice also developed a greater increase in lung microvascular permeability after E. coli challenge, resulting in edema formation. The augmented lung tissue PMN sequestration in PI3K-^–/– mice was associated with increased expression of the PMN adhesive proteins CD47 and ₃-integrins. We observed increased association of CD47 and ₃-integrins with the extracellular matrix protein vitronectin in lungs of PI3K-^–/– mice after E. coli challenge. PMNs from these mice also showed increased ₃-integrin expression and augmented ₃-integrin-dependent PMN adhesion to vitronectin. These results point to a key role of PMN PI3K- in negatively regulating CD47 and ₃-integrin expression in gram-negative sepsis. PI3K- activation in PMNs induced by E. coli may modulate the extent of lung tissue PMN sequestration secondary to CD47 and ₃-integrin expression. Therefore, the level of PI3K- activation may be an important determinant of PMN-dependent lung vascular injury.

₃-integrins; CD47; polymorphonuclear leukocyte sequestration; sepsis-induced lung vascular injury

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