title: PI3K-γ inhibition ameliorates acute lung injury through regulation of IκBα/NF-κB pathway and innate immune responses.
abstract: BACKGROUND
  Acute lung injury (ALI) is a devastating disorder of the lung by various causes and its cardinal features are tissue inflammation, pulmonary edema, low lung compliance, and widespread capillary leakage. Among phosphoinositide 3-kinases (PI3Ks), PI3K-γ isoform has been shown to play an important role in a number of immune/inflammatory responses.
  
  
  METHODS
  We investigated the role of PI3K-γ and its molecular basis in lipopolysaccharide (LPS)-induced ALI using a selective inhibitor for PI3K-γ, AS 605240, and LPS-treated C57BL/6 mice.
  
  
  RESULTS
  Treatment of mice with LPS showed an increase of lung inflammation and vascular leakage. Production of reactive oxygen species (ROS), interleukin (IL)-1β, tumor necrosis factor-α, and IL-4, adhesion molecule, and vascular endothelial growth factor (VEGF) was also increased. Administration of AS 605240 to LPS-treated mice markedly reduced the pathophysiological features of ALI and the increased production of ROS, cytokines, adhesion molecule, and VEGF in the lung. Our results also showed that treatment of mice with LPS activates nuclear factor-κB (NF-κB) and degradation of inhibitory κBα (IκBα) through PI3K-γ. Additionally, infiltration of dendritic cells (DCs) and expression of toll-like receptor 4 (TLR4) were significantly increased in the lung of LPS-treated mice, and inhibition of PI3K-γ reduced the infiltration of DCs and TLR4 expression in the lung.
  
  
  CONCLUSIONS
  These results indicate that PI3K-γ is critically involved in LPS-induced ALI by regulating IκBα/NF-κB pathway and innate immune responses. Based on our data, we suggest that PI3K-γ isoform is a promising target for the treatment of ALI.
authors.affiliation: Department of Internal Medicine, Research Center for Pulmonary Disorders, Chonbuk National University Medical School, San 2-20, Geumam-dong, Deokjin-gu, Jeonju 561-180, South Korea.
authors.forename: Dong Im
authors.initials: DI
authors.lastname: Kim
authors.forename: So Ri
authors.initials: SR
authors.lastname: Kim
authors.forename: Hee Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Su Jeong
authors.initials: SJ
authors.lastname: Lee
authors.forename: Heung Bum
authors.initials: HB
authors.lastname: Lee
authors.forename: Seoung Ju
authors.initials: SJ
authors.lastname: Park
authors.forename: Mie-Jae
authors.initials: MJ
authors.lastname: Im
authors.forename: Yong Chul
authors.initials: YC
authors.lastname: Lee
mesh_terms: D055371:Acute Lung Injury / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D058544:Class Ib Phosphatidylinositol 3-Kinase; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D005260:Female; D020672:I-kappa B Proteins / Q000378:metabolism*; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D021381:Protein Transport; D011810:Quinoxalines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C505144:5-quinoxalin-6-ylmethylenethiazolidine-2,4-dione; D016207:Cytokines; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011810:Quinoxalines; D017382:Reactive Oxygen Species; D045162:Thiazolidinediones; D051197:Toll-Like Receptor 4; D042461:Vascular Endothelial Growth Factor A; D018799:Intercellular Adhesion Molecule-1; D000072000:NF-KappaB Inhibitor alpha; D009195:Peroxidase; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse