Oxidative stress and hepatic stellate cell activation are key events in arsenic induced liver fibrosis in mice.
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.
Centre for Liver Research, School of Digestive & Liver Diseases, Institute of Post Graduate Medical Education & Research, Kolkata, India.
Subhadip
S
Ghatak
Ayan
A
Biswas
Gopal Krishna
GK
Dhali
Abhijit
A
Chowdhury
James L
JL
Boyer
Amal
A
Santra
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D018053:Arsenites / Q000633:toxicity*; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000139:chemically induced / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D015227:Lipid Peroxidation; D008103:Liver Cirrhosis / Q000139:chemically induced* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D017670:Sodium Compounds / Q000633:toxicity*; D013997:Time Factors
D051017:Apoptosis Regulatory Proteins; D018053:Arsenites; D016207:Cytokines; D018836:Inflammation Mediators; D017670:Sodium Compounds; C017947:sodium arsenite; D019255:NADPH Oxidases