Nonselective inhibition of prostaglandin-endoperoxide synthases by naproxen ameliorates acute or chronic liver injury in animals.
The rising prevalence of hepatic injury due to toxins, metabolites, viruses, etc., necessitates development of further mechanisms for protecting the liver and for treating acute or chronic liver diseases. To examine whether inhibition of inflammation is directed by cyclo-oxygenase pathways, we performed animal studies with naproxen, which inhibits prostaglandin-endoperoxide synthases 1 and 2 and is in extensive clinical use. We administered carbon tetrachloride to induce acute liver injury and ligated the common bile duct to induce chronic liver injury in adult rats. These experimental manipulations produced abnormalities in liver tests, tissue necrosis, compensatory hepatocyte or biliary proliferation, and onset of fibrosis, particularly after bile duct ligation. After carbon tetrachloride-induced acute injury, naproxen decreased liver test abnormalities, tissue necrosis and compensatory hepatocellular proliferation. After bile duct ligation-induced chronic injury, naproxen decreased liver test abnormalities, tissue injury and compensatory biliary hyperplasia. Moreover, after bile duct ligation, naproxen-treated rats showed more periductular oval liver cells, which have been classified as hepatic progenitor cells. In naproxen-treated rats, we found greater expression in hepatic stellate cells and mononuclear cells of cytoprotective factors, such as vascular endothelial growth factor. The ability of naproxen to induce expression of vascular endothelial growth factor was verified in cell culture studies with CFSC-8B clone of rat hepatic stellate cells. Whereas assays for carbon tetrachloride toxicity using cultured primary hepatocytes established that naproxen was not directly cytoprotective, we found conditioned medium containing vascular endothelial growth factor from naproxen-treated CFSC-8B cells protected hepatocytes from carbon tetrachloride toxicity. Therefore, naproxen was capable of ameliorating toxic liver injury, which involved naproxen-induced release of physiological cytoprotective factors in nonparenchymal liver cells. Such drug-induced release of endogenous cytoprotectants will advance therapeutic development for hepatic injury.
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA; Surgical Research, Department of General and Visceral Surgery, University Hospital, Muenster, Germany.
Ralf
R
Bahde
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
Sorabh
S
Kapoor
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA; Department of Pathology, Marion Bessin Liver Research Center, Diabetes Center, Cancer Center, Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, and Institute for Clinical and Translational Research, Albert Einstein College of Medicine, Bronx, NY, USA. Electronic address: sanjeev.gupta@einstein.yu.edu.
Sanjeev
S
Gupta
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D015153:Blotting, Western; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000737:chemistry* / Q000378:metabolism; D058625:End Stage Liver Disease / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D007249:Inflammation / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009288:Naproxen / Q000494:pharmacology*; D009336:Necrosis; D051381:Rats; D011916:Rats, Inbred F344
D000894:Anti-Inflammatory Agents, Non-Steroidal; D008565:Membrane Proteins; D009288:Naproxen; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496513:Ptgs1 protein, rat; C489691:Ptgs2 protein, rat
Drug; Injury; Liver; Protection; Soluble factors