Transgenic expression of cyclooxygenase-2 in hepatocytes accelerates endotoxin-induced acute liver failure.
Bacterial LPS (endotoxin) is implicated in the pathogenesis of acute liver failure and several chronic inflammatory liver diseases. To evaluate the effect of hepatocyte cyclooxygenase (COX)-2 in LPS-induced liver injury, we generated transgenic mice with targeted expression of COX-2 in the liver by using the albumin promoter-enhancer driven vector and the animals produced were subjected to a standard experimental protocol of LPS-induced acute fulminant hepatic failure (i.p. injection of low dose of LPS in combination with d-galactosamine (d-GalN)). The COX-2 transgenic mice exhibited earlier mortality, higher serum aspartate aminotransferase and alanine aminotransferase levels and more prominent liver tissue damage (parenchymal hemorrhage, neutrophilic inflammation, hepatocyte apoptosis, and necrosis) than wild-type mice. Western blot analysis of the liver tissues showed that LPS/d-GalN treatment for 4 h induced much higher cleavage of poly(ADP-ribose) polymerase, caspase-3, and caspase-9 in COX-2 transgenic mice than in wild-type mice. Increased hepatic expression of JNK-2 in COX-2 transgenic mice suggest that up-regulation of JNK-2 may represent a potential mechanism for COX-2-mediated exacerbation of liver injury. Blocking the prostaglandin receptor, EP(1), prevented LPS/d-GalN-induced liver injury and hepatocyte apoptosis in COX-2 transgenic mice. Accordingly, the mice with genetic ablation of EP(1) showed less LPS/d-GalN-induced liver damage and less hepatocyte apoptosis with prolonged survival when compared with the wild-type mice. These findings demonstrate that COX-2 and its downstream prostaglandin receptor EP(1) signaling pathway accelerates LPS-induced liver injury. Therefore, blocking COX-2-EP(1) pathway may represent a potential approach for amelioration of LPS-induced liver injury.
Han
Chang
C
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. changhan@pitt.edu
Li
Guiying
G
Lim
Kyu
K
DeFrances
Marie C
MC
Gandhi
Chandrashekhar R
CR
Wu
Tong
T
D000410:Alanine Transaminase / Q000097:blood / Q000235:genetics / Q000276:immunology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D001219:Aspartate Aminotransferases / Q000097:blood / Q000235:genetics / Q000276:immunology; D053148:Caspase 3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053453:Caspase 9 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002908:Chronic Disease; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005688:Galactosamine / Q000633:toxicity; D015870:Gene Expression; D006470:Hemorrhage / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology; D006505:Hepatitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity*; D017114:Liver Failure, Acute / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D048056:Mitogen-Activated Protein Kinase 9 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009336:Necrosis / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology; D009928:Organ Specificity / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D058306:Receptors, Prostaglandin E, EP1 Subtype; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D019076:Transgenes / Q000235:genetics / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology
D008070:Lipopolysaccharides; C545635:PTGER1 protein, human; C545636:Ptger1 protein, mouse; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D005688:Galactosamine; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011065:Poly(ADP-ribose) Polymerases; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D048056:Mitogen-Activated Protein Kinase 9; C505409:Casp3 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053453:Caspase 9