Poly (ADP‐ribose) polymerase‐1 is a key mediator of liver inflammation and fibrosis. Issue 5 (1st April 2014)

• Record Type: Journal Article
• Authors: Mukhopadhyay, Partha; Rajesh, Mohanraj; Cao, Zongxian; Horváth, Béla; Park, Ogyi; Wang, Hua; Erdelyi, Katalin; Holovac, Eileen; Wang, Yuping; Liaudet, Lucas; Hamdaoui, Nabila; Lafdil, Fouad; Haskó, György; Szabo, Csaba; Boulares, A. Hamid; Gao, Bin; Pacher, Pal
• Is Part Of: Hepatology. Volume 59:Issue 5(2014:May)
• Page Start: 1998
• Page End: 2009
• Publication Date: 2014-04-01
• Subjects: Heart -- Diseases -- Nursing -- Periodicals; Lungs -- Diseases -- Nursing -- Periodicals; Intensive care nursing -- Periodicals; Foie -- Maladies -- Périodiques; 616.362
• DOI: 10.1002/hep.26763
• Languages: English
• ISSNs: 0270-9139

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>Poly (ADP‐ribose) polymerase 1 (PARP‐1) is a constitutive enzyme, the major isoform of the PARP family, which is involved in the regulation of DNA repair, cell death, metabolism, and inflammatory responses. Pharmacological inhibitors of PARP provide significant therapeutic benefits in various preclinical disease models associated with tissue injury and inflammation. However, our understanding the role of PARP activation in the pathophysiology of liver inflammation and fibrosis is limited. In this study we investigated the role of PARP‐1 in liver inflammation and fibrosis using acute and chronic models of carbon tetrachloride (CCl<sub>4</sub>)‐induced liver injury and fibrosis, a model of bile duct ligation (BDL)‐induced hepatic fibrosis <italic>in vivo</italic>, and isolated liver‐derived cells <italic>ex vivo</italic>. Pharmacological inhibition of PARP with structurally distinct inhibitors or genetic deletion of PARP‐1 markedly attenuated CCl<sub>4</sub>‐induced hepatocyte death, inflammation, and fibrosis. Interestingly, the chronic CCl<sub>4</sub>‐induced liver injury was also characterized by mitochondrial dysfunction and dysregulation of numerous genes involved in metabolism. Most of these pathological changes were attenuated by PARP inhibitors. PARP inhibition not only prevented CCl<sub>4</sub>‐induced chronic liver inflammation and fibrosis, but was also able to reverse these pathological processes. PARP inhibitors also attenuated the development of BDL‐induced hepatic fibrosis in mice. In liver biopsies of subjects with alcoholic or hepatitis B‐induced cirrhosis, increased nitrative stress and PARP activation was noted. <italic>Conclusion</italic>: The reactive oxygen/nitrogen species‐PARP pathway plays a pathogenetic role in the development of liver inflammation, metabolism, and fibrosis. PARP inhibitors are currently in clinical trials for oncological indications, and the current results indicate that liver inflammation and liver fibrosis may be additional clinical indications where PARP inhibition may be of translational potential. (H<sc>epatology</sc> 2014;59:1998–2009)</p> </abstract>