Cyclooxygenase-1 serves a vital hepato-protective function in chemically induced acute liver injury

• Published in: Toxicological sciences 2015-02, Vol.143 (2), p.430-440
• Main Authors: Xiao, Jia, Liong, Emily C, Huang, Hai, On Tse, Wing, Lau, Kam Shing, Pan, Jingfei, Nanji, Amin A, Fung, Man Lung, Xing, Feiyue, Tipoe, George L
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; Carbon Tetrachloride - toxicity; Chemical and Drug Induced Liver Injury - enzymology; Chemical and Drug Induced Liver Injury - immunology; Chemical and Drug Induced Liver Injury - pathology; Chemical and Drug Induced Liver Injury - prevention & control; Cyclooxygenase 1 - deficiency; Cyclooxygenase 1 - genetics; Cytokines - biosynthesis; Dinoprostone - biosynthesis; Dinoprostone - pharmacology; Heterozygote; Homozygote; In Situ Nick-End Labeling; Liver Function Tests; Mice, Knockout; Oxidative Stress - drug effects
• ISSN: 1096-6080; 1096-0929
• DOI: 10.1093/toxsci/kfu244

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.