Phosphoinositide 3-kinase gamma inhibitor ameliorates concanavalin A-induced hepatic injury in mice.
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.
Wang
Zhen-ling
ZL
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
Wu
Xiao-hua
XH
Song
Li-fang
LF
Wang
Yong-sheng
YS
Hu
Xiao-hong
XH
Luo
You-fu
YF
Chen
Zhi-zhi
ZZ
Ke
Jin
J
Peng
Xiao-dong
XD
He
Chun-mei
CM
Zhang
Wei
W
Chen
Li-juan
LJ
Wei
Yu-qua
YQ
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*
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