Oxidative stress and hepatic stellate cell activation are key events in arsenic induced liver fibrosis in mice

Abstract

Arsenic is an environmental toxicant and carcinogen. Exposure to arsenic is associated with development of liver fibrosis and portal hypertension through ill defined mechanisms. We evaluated hepatic fibrogenesis after long term arsenic exposure in a murine model. BALB/c mice were exposed to arsenic by daily gavages of 6 μg/ gm body weight for 1 year and were evaluated for markers of hepatic oxidative stress and fibrosis, as well as pro-inflammatory, pro-apoptotic and pro-fibrogenic factors at 9 and 12 months. Hepatic NADPH oxidase activity progressively increased in arsenic exposure with concomitant development of hepatic oxidative stress. Hepatic steatosis with occasional collection of mononuclear inflammatory cells and mild portal fibrosis were the predominant liver lesion observed after 9 months of arsenic exposure, while at 12 months, the changes included mild hepatic steatosis, inflammation, necrosis and significant fibrosis in periportal areas. The pathologic changes in the liver were associated with markers of hepatic stellate cells (HSCs) activation, matrix reorganization and fibrosis including α-smooth muscle actin, transforming growth factor-β1, PDGF-Rβ, pro-inflammatory cytokines and enhanced expression of tissue inhibitor of metalloproteinase-1 and pro (α) collagen type I. Moreover, pro-apoptotic protein Bax was dominantly expressed and Bcl-2 was down-regulated along with increased number of TUNEL positive hepatocytes in liver of arsenic exposed mice. Furthermore, HSCs activation due to increased hepatic oxidative stress observed after in vivo arsenic exposure was recapitulated in co-culture model of isolated HSCs and hepatocytes exposed to arsenic. These findings have implications not only for the understanding of the pathology of arsenic related liver fibrosis but also for the design of preventive strategies in chronic arsenicosis.

Oxidative stress-related liver dysfunction by sodium arsenite: Alleviation byPistacia lentiscusoil

“…As a result the accumulated hydroperoxides in this organ could cause cytotoxicity associated with membrane phospholipids peroxidation, the basis of liver damage. Such results agree with the previous findings (Ghatak et al, 2011;Messarah et al, 2012).…”

“…Epidemiology studies have indicated that chronic arsenic exposure causes abnormal liver function, hepatomegaly, liver fibrosis and cirrhosis (Santra et al, 2000). Subsequent studies of Santra et al (2000) and Ghatak et al (2011) on chronic arsenic toxicity have revealed that oxidative stress and hepatic stellate cell activation are key events in arsenic-induced liver fibrosis.…”

Epigenetic Modifications in Hepatic Stellate Cells Contribute to Liver Fibrosis

“…These cytokines can enhance the oxidative stress and inflammation, which in return mediate cell differentiation and permeates through whole fibrogenesis process. The modulating mechanisms of genes coding cytokines in HSCs are underlined (Ghatak et al 2011;Ramachandran and Iredale 2012).…”

Hepatoprotective Effects of Phloridzin on Hepatic Fibrosis Induced by Carbon Tetrachloride against Oxidative Stress-Triggered Damage and Fibrosis in Rats

“…2) In recent years, considerably clinical and experimental evidences show that oxidative stress caused by an imbalance between the oxidant and antioxidant systems of the body in favor of the oxidants should be a major apoptotic stimulus in the different types of acute and chronic liver injury and hepatic fibrosis. 3) Carbon tetrachloride (CCl 4 ) is a xenobiotic used extensively to induce oxidative stress. The rats treated with CCl 4 are frequently used to produce an experimental model to study hepatic fibrosis.…”