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

Journal Article · Tue Feb 15 00:00:00 EST 2011 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2010.11.016· OSTI ID:21535238

Ghatak, Subhadip; Biswas, Ayan; Dhali, Gopal Krishna ^[1]; Chowdhury, Abhijit ^[1]; Boyer, James L ^[2]; Santra, Amal ^[1]

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1. Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata (India)
2. Yale Liver Center, Yale University School of Medicine, New Haven (United States)

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 {mu}g/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 {alpha}-smooth muscle actin, transforming growth factor-{beta}1, PDGF-R{beta}, pro-inflammatory cytokines and enhanced expression of tissue inhibitor of metalloproteinase-1 and pro({alpha}) 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.

• OSTI ID: 21535238
• Journal Information: Toxicology and Applied Pharmacology, Vol. 251, Issue 1; Other Information: DOI: 10.1016/j.taap.2010.11.016; PII: S0041-008X(10)00448-5; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
• Country of Publication: United States
• Language: English

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60 APPLIED LIFE SCIENCES
ACTIN
AMINOTRANSFERASES
ARSENIC
CARCINOGENS
CYSTEINE
FIBROSIS
GLUTATHIONE
HEMATOXYLIN
IN VIVO
INFLAMMATION
LIVER
LIVER CELLS
LYMPHOKINES
MICE
MUSCLES
OXIDASES
PATHOLOGY
POLYMERASE CHAIN REACTION
SUPEROXIDE DISMUTASE
AMINO ACIDS
ANIMAL CELLS
ANIMALS
AROMATICS
BODY
CARBOXYLIC ACIDS
DIGESTIVE SYSTEM
DRUGS
DYES
ELEMENTS
ENZYMES
GENE AMPLIFICATION
GLANDS
GROWTH FACTORS
HETEROCYCLIC COMPOUNDS
HETEROCYCLIC OXYGEN COMPOUNDS
HYDROXY COMPOUNDS
MAMMALS
MITOGENS
NITROGEN TRANSFERASES
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
ORGANIC SULFUR COMPOUNDS
ORGANS
OXIDOREDUCTASES
PATHOLOGICAL CHANGES
PEPTIDES
PHENOLS
POLYPEPTIDES
POLYPHENOLS
PROTEINS
PYRANS
RADIOPROTECTIVE SUBSTANCES
RESPONSE MODIFYING FACTORS
RODENTS
SEMIMETALS
SOMATIC CELLS
SYMPTOMS
THIOLS
TRANSFERASES
VERTEBRATES