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: Zhen-ling Wang, Xiao-hua Wu, Li-fang Song, Yong-sheng Wang, Xiao-hong Hu, You-fu Luo, Zhi-zhi Chen, Jin Ke, Xiao-dong Peng, Chun-mei He, Wei Zhang, Li-juan Chen, Yu-qua Wei
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 386 Issue 4 Pg. 569-74 (Sep 04 2009) ISSN: 1090-2104 [Electronic] United States
• PMID: 19538942 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 5-quinoxalin-6-ylmethylenethiazolidine-2,4-dione
• Cytokines
• Enzyme Inhibitors
• Isoenzymes
• Mitogens
• Phosphoinositide-3 Kinase Inhibitors
• Quinoxalines
• Thiazolidinediones
• Concanavalin A
• Class Ib Phosphatidylinositol 3-Kinase
• Pik3cg protein, mouse
• Proto-Oncogene Proteins c-akt

Topics

• Acute Disease
• Animals
• Chemical and Drug Induced Liver Injury (complications, drug therapy, pathology)
• Class Ib Phosphatidylinositol 3-Kinase
• Concanavalin A (toxicity)
• Cytokines (biosynthesis)
• Enzyme Inhibitors (therapeutic use)
• Isoenzymes (antagonists & inhibitors)
• Liver (drug effects, enzymology, pathology)
• Liver Cirrhosis (etiology, pathology, prevention & control)
• Mice
• Mitogens (toxicity)
• Phosphoinositide-3 Kinase Inhibitors
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• Quinoxalines (therapeutic use)
• Thiazolidinediones (therapeutic use)