Poly (ADP-ribose) polymerase-1 is a key mediator of liver inflammation and fibrosis.

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Version: author
Serval ID
serval:BIB_19EAC92AF60E
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Poly (ADP-ribose) polymerase-1 is a key mediator of liver inflammation and fibrosis.
Journal
Hepatology
Author(s)
Mukhopadhyay P., Rajesh M., Cao Z., Horváth B., Park O., Wang H., Erdelyi K., Holovac E., Wang Y., Liaudet L., Hamdaoui N., Lafdil F., Haskó G., Szabo C., Boulares A.H., Gao B., Pacher P.
ISSN
1527-3350 (Electronic)
ISSN-L
0270-9139
Publication state
Published
Issued date
2014
Peer-reviewed
Oui
Volume
59
Number
5
Pages
1998-2009
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural Publication Status: ppublish
Abstract
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 (CCl4 )-induced liver injury and fibrosis, a model of bile duct ligation (BDL)-induced hepatic fibrosis in vivo, and isolated liver-derived cells ex vivo. Pharmacological inhibition of PARP with structurally distinct inhibitors or genetic deletion of PARP-1 markedly attenuated CCl4 -induced hepatocyte death, inflammation, and fibrosis. Interestingly, the chronic CCl4 -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 CCl4 -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.
CONCLUSION: 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.
Keywords
Animals, Carbon Tetrachloride/toxicity, Hepatic Stellate Cells/physiology, Hepatitis/drug therapy, Hepatitis/etiology, Humans, Liver Cirrhosis, Experimental/drug therapy, Liver Cirrhosis, Experimental/etiology, Male, Mice, Mice, Inbred C57BL, Poly(ADP-ribose) Polymerases/antagonists & inhibitors, Poly(ADP-ribose) Polymerases/physiology
Pubmed
Web of science
Open Access
Yes
Create date
11/07/2014 17:14
Last modification date
20/08/2019 12:51
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