title: Cyclooxygenase-1 serves a vital hepato-protective function in chemically induced acute liver injury.
abstract: Cyclooxygenase-1 (COX-1) is the constitutive form of the COX enzyme family, which produces bioactive lipids called prostanoids. Although the role of COX-2 in liver diseases has been studied, little is known about the function of COX-1 in liver injury. We aimed to investigate the role and mechanism of COX-1 in acute liver injury. Carbon tetrachloride (CCl(4)) was administered to induce acute liver injury in wild-type or COX-1-deficient mice. Both genetic (partially or completely) deletion of COX-1 expression and pharmacological inhibition of COX-1 activity in mice exacerbated acute liver injury induced by CCl(4), revealing the (1) histopathological changes and increased serum levels of aminotransferases; (2) oxidative stress in the liver partly through the action of cytochrome P450 2E1-dependent pathway; (3) enhanced inflammatory and chemoattractive responses with increased number of activated macrophages; and (4) increased apoptosis through both intrinsic and extrinsic apoptotic pathways. These pathological changes were partly through the modulation of transcription factor-dependent pathways (eg, NF-κB and C/EBP-α). Pre-treatment with prostaglandin E2 (PGE(2)) or 5-lipoxygenase (5-LO) inhibitor in homozygous COX-1 knockout mice significantly ameliorated CCl(4)-induced hepatic injury. In addition, level of hepato-protective molecules (eg, OSM and OSMR) and associated liver regeneration pathway were significantly inhibited by the deficiency of COX-1 but restored by the addition of PGE(2) or the inhibition of 5-LO. Furthermore, the alternative arachidonic acid metabolism pathway of 5-LO, which induced additional inflammation in the liver, was activated in response to the deficiency of COX-1. In conclusion, basal expression of COX-1 is essential for the protection of liver against chemical-induced hepatotoxicity and required for hepatic homeostatic maintenance.
authors.affiliation: *Department of Immunobiology, Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, 510632 China, Department of Anatomy and Department of Physiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China and Department of Pathology and Laboratory Medicine, Dalhousie University School of Medicine, Halifax, B3H 4R2 Canada *Department of Immunobiology, Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, 510632 China, Department of Anatomy and Department of Physiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China and Department of Pathology and Laboratory Medicine, Dalhousie University School of Medicine, Halifax, B3H 4R2 Canada.
authors.forename: Jia
authors.initials: J
authors.lastname: Xiao
authors.affiliation: *Department of Immunobiology, Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, 510632 China, Department of Anatomy and Department of Physiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China and Department of Pathology and Laboratory Medicine, Dalhousie University School of Medicine, Halifax, B3H 4R2 Canada.
authors.forename: Emily C
authors.initials: EC
authors.lastname: Liong
authors.affiliation: *Department of Immunobiology, Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, 510632 China, Department of Anatomy and Department of Physiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China and Department of Pathology and Laboratory Medicine, Dalhousie University School of Medicine, Halifax, B3H 4R2 Canada.
authors.forename: Hai
authors.initials: H
authors.lastname: Huang
authors.affiliation: *Department of Immunobiology, Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, 510632 China, Department of Anatomy and Department of Physiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China and Department of Pathology and Laboratory Medicine, Dalhousie University School of Medicine, Halifax, B3H 4R2 Canada.
authors.forename: Wing
authors.initials: W
authors.lastname: On Tse
authors.affiliation: *Department of Immunobiology, Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, 510632 China, Department of Anatomy and Department of Physiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China and Department of Pathology and Laboratory Medicine, Dalhousie University School of Medicine, Halifax, B3H 4R2 Canada.
authors.forename: Kam Shing
authors.initials: KS
authors.lastname: Lau
authors.affiliation: *Department of Immunobiology, Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, 510632 China, Department of Anatomy and Department of Physiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China and Department of Pathology and Laboratory Medicine, Dalhousie University School of Medicine, Halifax, B3H 4R2 Canada.
authors.forename: Jingfei
authors.initials: J
authors.lastname: Pan
authors.affiliation: *Department of Immunobiology, Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, 510632 China, Department of Anatomy and Department of Physiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China and Department of Pathology and Laboratory Medicine, Dalhousie University School of Medicine, Halifax, B3H 4R2 Canada.
authors.forename: Amin A
authors.initials: AA
authors.lastname: Nanji
authors.affiliation: *Department of Immunobiology, Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, 510632 China, Department of Anatomy and Department of Physiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China and Department of Pathology and Laboratory Medicine, Dalhousie University School of Medicine, Halifax, B3H 4R2 Canada.
authors.forename: Man Lung
authors.initials: ML
authors.lastname: Fung
authors.affiliation: *Department of Immunobiology, Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, 510632 China, Department of Anatomy and Department of Physiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China and Department of Pathology and Laboratory Medicine, Dalhousie University School of Medicine, Halifax, B3H 4R2 Canada.
authors.forename: Feiyue
authors.initials: F
authors.lastname: Xing
authors.affiliation: *Department of Immunobiology, Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, 510632 China, Department of Anatomy and Department of Physiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China and Department of Pathology and Laboratory Medicine, Dalhousie University School of Medicine, Halifax, B3H 4R2 Canada tgeorge@hku.hk.
authors.forename: George L
authors.initials: GL
authors.lastname: Tipoe
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002251:Carbon Tetrachloride / Q000633:toxicity; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology* / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D051545:Cyclooxygenase 1 / Q000172:deficiency / Q000235:genetics*; D016207:Cytokines / Q000096:biosynthesis; D015232:Dinoprostone / Q000096:biosynthesis / Q000494:pharmacology; D006579:Heterozygote; D006720:Homozygote; D020287:In Situ Nick-End Labeling; D008111:Liver Function Tests; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects
chemical_list: D016207:Cytokines; D002251:Carbon Tetrachloride; D051545:Cyclooxygenase 1; D015232:Dinoprostone
keywords: 5-lipoxygenase; acute liver injury; carbon tetrachloride; cyclooxygenase; prostaglandin