title: Phosphoinositide 3-kinase gamma inhibitor ameliorates concanavalin A-induced hepatic injury in mice.
abstract: A pivotal role of phosphoinositide 3-kinase-gamma (PI3Kgamma) in inflammatory cell activation and recruitment makes it an attractive target for immunomodulatory therapy. In present study we investigated the therapeutic efficiency of AS605240, a selective PI3Kgamma inhibitor, on hepatitis and liver fibrosis in murine models induced by concanavalin A (ConA). Orally administration of AS605240 significantly improved survival, decreased the serum levels of alanine aminotransaminase (ALT), prevented inflammatory infiltration to liver in ConA-induced hepatitis. TNF-alpha and IFN-gamma at protein levels in serum and mRNA levels in liver were markedly reduced. Downregulated phospho-Akt level of inflammatory cells infiltrating the liver by AS605240 treatment was detected by immunohistochemistry analysis in liver and further confirmed by Western blotting analysis in splenocytes. In ConA-induced chronic liver fibrosis model, accumulation of smooth-muscle actin (SMA)-expressing cells was partially inhibited by AS605240 treatment. These observations suggest that AS605240 might be of therapeutic value for the treatment of ConA-induced hepatic injury.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
authors.forename: Zhen-ling
authors.initials: ZL
authors.lastname: Wang
authors.forename: Xiao-hua
authors.initials: XH
authors.lastname: Wu
authors.forename: Li-fang
authors.initials: LF
authors.lastname: Song
authors.forename: Yong-sheng
authors.initials: YS
authors.lastname: Wang
authors.forename: Xiao-hong
authors.initials: XH
authors.lastname: Hu
authors.forename: You-fu
authors.initials: YF
authors.lastname: Luo
authors.forename: Zhi-zhi
authors.initials: ZZ
authors.lastname: Chen
authors.forename: Jin
authors.initials: J
authors.lastname: Ke
authors.forename: Xiao-dong
authors.initials: XD
authors.lastname: Peng
authors.forename: Chun-mei
authors.initials: CM
authors.lastname: He
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Li-juan
authors.initials: LJ
authors.lastname: Chen
authors.forename: Yu-qua
authors.initials: YQ
authors.lastname: Wei
mesh_terms: D000208:Acute Disease; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D058544:Class Ib Phosphatidylinositol 3-Kinase; D003208:Concanavalin A / Q000633:toxicity; D016207:Cytokines / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008103:Liver Cirrhosis / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008934:Mitogens / Q000633:toxicity; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011810:Quinoxalines / Q000627:therapeutic use*; D045162:Thiazolidinediones / Q000627:therapeutic use*
chemical_list: C505144:5-quinoxalin-6-ylmethylenethiazolidine-2,4-dione; D016207:Cytokines; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D008934:Mitogens; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011810:Quinoxalines; D045162:Thiazolidinediones; D003208:Concanavalin A; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse; D051057:Proto-Oncogene Proteins c-akt