title: Src tyrosine kinases mediate activations of NF-kappaB and integrin signal during lipopolysaccharide-induced acute lung injury.
abstract: Src tyrosine kinases (TKs) are signaling proteins involved in cell signaling pathways toward cytoskeletal, membrane and nuclear targets. In the present study, using a selective Src TK inhibitor, PP1, we investigated the roles of Src TKs in the key pulmonary responses, NF-kappaB activation, and integrin signaling during acute lung injury in BALB/C mice intratracheally treated with LPS. LPS resulted in c-Src phosphorylation in lung tissue and the phospho-c-Src was predominantly localized in recruited neutrophils and alveolar macrophages. PP1 inhibited LPS-induced increases in total protein content in bronchoalveolar lavage fluid, neutrophil recruitment, and increases in the production or activity of TNF-alpha and matrix metalloproteinase-9. PP1 also blocked LPS-induced NF-kappaB activation, and phosphorylation and degradation of IkappaB-alpha. The inhibition of NF-kappaB activation by PP1 correlated with a depression of LPS-induced integrin signaling, which included increases in the phosphorylations of integrin beta(3), and of the focal adhesion kinase (FAK) family members, FAK and Pyk2, in lung tissue, and reductions in the fibrinogen-binding activity of alveolar macrophages. Moreover, treatment with anti-alpha(v), anti-beta(3), or Arg-Gly-Asp-Ser (RGDS), inhibited LPS-induced NF-kappaB activation. Taken together, our findings suggest that Src TKs play a critical role in LPS-induced activations of NF-kappaB and integrin (alpha(v)beta(3)) signaling during acute lung injury. Therefore, Src TK inhibition may provide a potential means of ameliorating inflammatory cascade-associated lung injury.
authors.affiliation: Department of Physiology, Ewha Medical Research Center, School of Medicine, Ewha Womans University, Seoul, South Korea.
authors.forename: Hui S
authors.initials: HS
authors.lastname: Lee
authors.forename: Changsuk
authors.initials: C
authors.lastname: Moon
authors.forename: Hye W
authors.initials: HW
authors.lastname: Lee
authors.forename: Eun-Mi
authors.initials: EM
authors.lastname: Park
authors.forename: Min-Sun
authors.initials: MS
authors.lastname: Cho
authors.forename: Jihee L
authors.initials: JL
authors.lastname: Kang
mesh_terms: D000818:Animals; D051417:Focal Adhesion Kinase 1 / Q000276:immunology / Q000378:metabolism; D051418:Focal Adhesion Kinase 2 / Q000276:immunology / Q000378:metabolism; D020672:I-kappa B Proteins / Q000276:immunology / Q000378:metabolism; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000276:immunology* / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D017476:Receptors, Neuropeptide Y / Q000276:immunology / Q000378:metabolism; D012128:Respiratory Distress Syndrome / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D019061:src-Family Kinases / Q000276:immunology* / Q000378:metabolism
chemical_list: D020672:I-kappa B Proteins; D039302:Integrin alphaVbeta3; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D009842:Oligopeptides; D010975:Platelet Aggregation Inhibitors; D017476:Receptors, Neuropeptide Y; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; C109491:neuropeptide Y4 receptor; C046617:arginyl-glycyl-aspartyl-serine; D051417:Focal Adhesion Kinase 1; D051418:Focal Adhesion Kinase 2; C496051:Ptk2 protein, mouse; C496053:Ptk2b protein, mouse; D019061:src-Family Kinases; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse