as-605240 and Liver-Cirrhosis

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.

Topics: Acute Disease; Animals; Chemical and Drug Induced Liver Injury; Class Ib Phosphatidylinositol 3-Kinase; Concanavalin A; Cytokines; Enzyme Inhibitors; Isoenzymes; Liver; Liver Cirrhosis; Mice; Mitogens; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Proto-Oncogene Proteins c-akt; Quinoxalines; Thiazolidinediones