TY - JOUR T1 - Phosphoinositide 3-kinase γ required for lipopolysaccharide-induced transepithelial neutrophil trafficking in the lung JF - European Respiratory Journal JO - Eur Respir J SP - 1137 LP - 1147 DO - 10.1183/09031936.00085509 VL - 35 IS - 5 AU - J. Reutershan AU - M. S. Saprito AU - D. Wu AU - T. Rückle AU - K. Ley Y1 - 2010/05/01 UR - http://erj.ersjournals.com/content/35/5/1137.abstract N2 - 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. ER -