Phosphoinositide 3-kinase gamma required for lipopolysaccharide-induced transepithelial neutrophil trafficking in the lung.
Phosphoinositide 3-kinase gamma(PI3Kgamma) is a critical mediator of directional cell movement. Here, we sought to characterise the role of PI3Kgamma 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 PI3Kgamma gene-deficient (PI3Kgamma(-/-)) and wild-type mice. Bone marrow chimeras were created to characterise the role of PI3Kgamma on haematopoietic versus nonhaematopoietic cells. A small-molecule PI3Kgamma inhibitor was tested in vitro and in vivo. PMN adhesion to the pulmonary endothelium and transendothelial migration into the lung interstitium was enhanced in PI3Kgamma(-/-) mice. However, transepithelial migration into the alveolar space was reduced in these mice. When irradiated PI3Kgamma(-/-) mice were reconstituted with bone marrow from wild-type mice, migratory activity into the alveolar space was restored partially. A small-molecule PI3Kgamma 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 PI3Kgamma is required for transepithelial but not for transendothelial migration in LPS-induced lung injury. Inhibition of PI3Kgamma activity may be effective at curbing excessive PMN infiltration in lung injury.
Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA. joerg.reutershan@uni-tuebingen.de
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Reutershan
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Saprito
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Wu
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Rückle
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Ley
D055371:Acute Lung Injury / Q000276:immunology*; D000704:Analysis of Variance; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002465:Cell Movement / Q000187:drug effects; D002678:Chimera; D058544:Class Ib Phosphatidylinositol 3-Kinase; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology; D007527:Isoenzymes / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000276:immunology*; D008297:Male; D008565:Membrane Proteins / Q000276:immunology; D051379:Mice; D009504:Neutrophils / Q000276:immunology*; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology*; D011810:Quinoxalines / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology
C505144:5-quinoxalin-6-ylmethylenethiazolidine-2,4-dione; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D008070:Lipopolysaccharides; D008565:Membrane Proteins; C513303:Ptprcap protein, mouse; D011810:Quinoxalines; D045162:Thiazolidinediones; D019869:Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546760:PIK3CG protein, human; C546764:Pik3cg protein, mouse