Centre for Liver Research, School of Digestive & Liver Diseases, Institute of Post Graduate Medical Education & Research, Kolkata, India.
Toxicol Appl Pharmacol. 2011 Feb 15;251(1):59-69. doi: 10.1016/j.taap.2010.11.016. Epub 2010 Dec 4.
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.
砷是一种环境毒物和致癌物质。通过不明确的机制，暴露于砷会导致肝纤维化和门静脉高压的发展。我们在一种小鼠模型中评估了长期砷暴露后肝纤维化的发生。BALB/c 小鼠通过每日灌胃 6μg/gm 体重的砷暴露 1 年，并在 9 个月和 12 个月时评估肝脏氧化应激和纤维化的标志物以及促炎、促凋亡和促纤维化因子。随着肝脏氧化应激的发展，砷暴露后肝 NADPH 氧化酶活性逐渐增加。在砷暴露 9 个月后，观察到的主要肝脏病变为肝脂肪变性，偶尔伴有单核炎性细胞聚集和轻度门脉纤维化，而在 12 个月时，病变包括轻度肝脂肪变性、炎症、坏死和肝门脉周围区域的显著纤维化。肝脏的病理变化与肝星状细胞（HSCs）激活、基质重排和纤维化的标志物相关，包括α-平滑肌肌动蛋白、转化生长因子-β1、血小板衍生生长因子受体-β、促炎细胞因子和组织金属蛋白酶抑制剂-1 和前（α）胶原 I 的表达增强。此外，在砷暴露小鼠的肝脏中，Bax 表达增加，Bcl-2 下调，TUNEL 阳性肝细胞数量增加，提示存在促凋亡作用。此外，在体内砷暴露后观察到的肝脏氧化应激增加导致 HSCs 激活，这在分离的 HSCs 和肝细胞共培养模型中暴露于砷时得到了重现。这些发现不仅对理解砷相关性肝纤维化的病理学具有重要意义，而且对慢性砷中毒的预防策略的设计也具有重要意义。
