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.
Reutershan
J
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Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA. joerg.reutershan@uni-tuebingen.de
Saprito
M S
MS
Wu
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D
Rückle
T
T
Ley
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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