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

Phosphoinositide 3-kinase γ(PI3Kγ) is a critical mediator of directional cell movement. Here, we sought to characterise the role of PI3Kγ 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 PI3Kγ gene-deficient (PI3Kγ^-/-) and wild-type mice. Bone marrow chimeras were created to characterise the role of PI3Kγ on haematopoietic versus nonhaematopoietic cells. A small-molecule PI3Kγ inhibitor was tested in vitro and in vivo. PMN adhesion to the pulmonary endothelium and transendothelial migration into the lung interstitium was enhanced in PI3Kγ^-/-mice. However, transepithelial migration into the alveolar space was reduced in these mice. When irradiated PI3Kγ^-/- mice were reconstituted with bone marrow from wild-type mice, migratory activity into the alveolar space was restored partially. A small-molecule PI3Kγ 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 PI3Kγ is required for transepithelial but not for transendothelial migration in LPS-induced lung injury. Inhibition of PI3Kγ activity may be effective at curbing excessive PMN infiltration in lung injury. Copyright