lysophosphatidylethanolamine and Chemical-and-Drug-Induced-Liver-Injury

Excessive apoptosis and leukocyte-dependent inflammation mediated by pro-inflammatory cytokines, such as TNFα, are cardinal features of acute liver injury. This study evaluated the ability of the newly designed bile acid-phospholipid conjugate ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE) to protect from hepatocellular injury in comparison to the known hepatoprotectant ursodeoxycholic acid (UDCA) and phosphatidylcholine (PC).. Anti-apoptotic and anti-inflammatory properties of UDCA-LPE were evaluated after TNFα treatment of embryonic human hepatocyte cell line CL48 as well as of primary human hepatocytes. Acute liver injury was induced in C57BL/6 mice with d-galactosamine/lipopolysaccharide (GalN/LPS) in order to determine in vivo efficacy of the conjugate.. UDCA-LPE inhibited TNFα-induced apoptosis and inflammation in hepatocytes in vitro and markedly ameliorated GalN/LPS-mediated fulminant hepatitis in mice, whereas UDCA or PC failed to show protection. The conjugate was able to decrease injury-induced elevation of phospholipase A(2) activity as well as its product lysophosphatidylcholine. Analysis of hepatic gene expression showed that UDCA-LPE treatment led to favourable inhibitory effects on expression profiles of key pro-inflammatory cytokines and chemokines, which are crucial for leukocyte recruitment and activation thereby inhibiting chemokine-mediated aggravation of parenchymal damage.. Thus, UDCA-LPE as a synthetic bile acid-phospholipid conjugate may represent a potent anti-inflammatory agent that is more effective than UDCA and PC for treatment of liver diseases.

Topics: Animals; Apoptosis; Cell Line; Chemical and Drug Induced Liver Injury; Cholagogues and Choleretics; Cytokines; Galactosamine; Gene Expression; Humans; Inflammation Mediators; Lipopolysaccharides; Lysophospholipids; Male; Mice; Mice, Inbred C57BL; Phosphatidylcholines; Phospholipases A2; Phospholipids; Tumor Necrosis Factor-alpha; Ursodeoxycholic Acid