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

Abstract

Poly (ADP-ribose) polymerase 1 (PARP-1) is a constitutive enzyme, the major isoform of 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 have investigated the role of PARP-1 in the liver inflammation and fibrosis using acute and chronic models of 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 hepatic cell 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. These results, taken together, suggest that the reactive oxygen/nitrogen species-PARP pathway plays a pathogenetic role in the development of liver inflammation, metabolism and fibrosis. Several PARP inhibitors are currently in clinical trials for oncological indications. The current results indicate that liver inflammation and liver fibrosis may be additional clinical indications where PARP inhibition may be of translational potential.

Puerarin protects against CCl4-induced liver fibrosis in mice: possible role of PARP-1 inhibition

“…The mechanism of the anti-fibrotic effects of puerarin involves its ability to inhibited expression of PARP-1, which is a novel mediator of CCl 4 -induced chronic liver fibrosis as demonstrated recently [43]. The certain role between PARP-1 activation and the profibrotic gene expression such as TGF-b and CTGF has been reported in vascular smooth muscle cells [44].…”

Hybrid inhibitor of peripheral cannabinoid-1 receptors and inducible nitric oxide synthase mitigates liver fibrosis

“…Ligation of the common bile duct was performed as described previously (67). Average survival was 18–20 days after the surgery.…”

“…Tissues were cut at 4-μm thickness for staining, and staining was performed as described previously (67). …”

Antioxidant and Hepatoprotective Effect of Swertiamarin on Carbon Tetrachloride-Induced Hepatotoxicity via the Nrf2/HO-1 Pathway

“…In acute liver injury induced by CCl 4 , there were drastic decreases in the activities of the main liver P450 isoenzymes such as CYP1A2, CYP2C6, CYP2E1 and CYP3A2, as well as their protein expressions due to oxidative stress [30]. And chronic CCl 4 -induced liver injury was also characterized by dysregulation of numerous genes involved in metabolism [31]. In this study, considerable decreases in hepatic CYP3A and CYP2E1 protein level were found in rats treated with CCl 4 alone.…”