Phosphoinositide 3-kinase γ required for lipopolysaccharide-induced transepithelial neutrophil trafficking in the lung

Phosphoinositide 3-kinase gamma(PI3K gamma) is a critical mediator of directional cell movement. Here, we sought to characterise the role of PI3K gamma in mediating the different steps of polymorphonuclear leukocyte (PMN) trafficking in the lung. In a murine model of lipopolysaccharide (LPS)-induced lung injury, PMN migration into the different lung compartments was determined in PI3K gamma gene-deficient (PI3K gamma(-/-)) and wild-type mice. Bone marrow chimeras were created to characterise the role of PI3K gamma on haematopoietic versus nonhaematopoietic cells. A small-molecule PI3K gamma inhibitor was tested in vitro and in vivo. PMN adhesion to the pulmonary endothelium and transendothelial migration into the lung interstitium was enhanced in PI3K gamma(-/-) mice. However, transepithelial migration into the alveolar space was reduced in these mice. When irradiated PI3K gamma(-/-) mice were reconstituted with bone marrow from wild-type mice, migratory activity into the alveolar space was restored partially. A small-molecule PI3K gamma inhibitor reduced chemokine-induced PMN migration in vitro when PMNs or epithelial cells, but not when endothelial cells, were treated. The inhibitor also reduced LPS-induced PMN migration in vivo. We conclude that PI3K gamma is required for transepithelial but not for transendothelial migration in LPS-induced lung injury. Inhibition of PI3K gamma activity may be effective at curbing excessive PMN infiltration in lung injury.