Targeted disruption of Smad3 confers resistance to the development of dimethylnitrosamine-induced hepatic fibrosis in mice
Targeted disruption of Smad3 confers resistance to the development of dimethylnitrosamine-induced hepatic fibrosis in mice
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DOI：
10.1111/j.1478-3231.2009.02011.x
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发表时间：
2009-08-01
影响因子：
6.7
通讯作者：
Gaudio, Eugenio
中科院分区：
文献类型：
--
作者：
Latella, Giovanni;Vetuschi, Antonella;Gaudio, Eugenio
背景肝纤维化是以胶原等纤维细胞外基质（ECM）蛋白的进行性积聚为特征的疾病，常发生于多种慢性肝病。转化生长因子-β（TGF-β）/Smad 3信号传导在组织纤维发生中起中心作用，目的探讨Smad 3基因缺失对二甲基亚硝胺（DMN）诱导小鼠肝纤维化的保护作用。方法在13只Smad 3基因缺失小鼠和13只野生型（WT）小鼠中诱导慢性肝炎相关性纤维化。通过腹膜内给予DMN（10 μ g/g体重/天），每周连续三天，持续6周。切除肝脏进行肉眼检查和组织学、形态测定和免疫组织化学（IHC）分析。对于IHC，α-平滑肌肌动蛋白（α-SMA），胶原蛋白I-III型，TGF-β 1，结缔组织生长因子（CTGF），Smad 3，Smad 7和CD 3 antibodies were used.ResultsAt macroscopic examination，DMN处理的Smad 3 WT的肝脏出现较硬的深棕色着色和坏死区域相比，从null小鼠。组织学和形态学评价显示，与裸小鼠相比，Smad 3 WT小鼠的肝纤维化和结缔组织积聚程度显著更高。免疫组化评价显示，α-SMA，CTGF，胶原蛋白I-III，TGF-β和Smad 3染色的Smad 3 WT与null小鼠相比，显着增加，而Smad 7增加只有在null mice.ConclusionsThe结果表明，Smad 3损失赋予抵抗DMN诱导的肝纤维化的发展。减少的纤维化反应似乎是由于纤维化肌成纤维细胞活化和ECM产生和积累的减少。Smad 3可能成为治疗慢性肝炎肝纤维化的新靶点。
BackgroundHepatic fibrosis is characterized by a progressive accumulation of fibrillar extracellular matrix (ECM) proteins including collagen, which occurs in most types of chronic liver diseases. Transforming growth factor-beta (TGF-beta)/Smad3 signalling plays a central role in tissue fibrogenesis, acting as a potent stimulus of ECM accumulation.AimTo evaluate the potential protective role of Smad3 deficiency in the pathogenesis of liver fibrosis induced by dimethylnitrosamine (DMN) in Smad3 null mice.MethodsChronic hepatitis-associated fibrosis was induced in 13 Smad3 null and 13 wild-type (WT) mice by intraperitoneal DMN administration (10 mu g/g body weight/day) for three consecutive days per week for 6 weeks. The liver was excised for macroscopic examination and histological, morphometric and immunohistochemical (IHC) analyses. For IHC, alpha-smooth muscle actin (alpha-SMA), collagen types I-III, TGF-beta 1, connective tissue growth factor (CTGF), Smad3, Smad7 and CD3 antibodies were used.ResultsAt macroscopic examination, the liver of DMN-treated Smad3 WT appeared harder with a dark brown colouring and necrotic areas compared with that from null mice. Histological and morphometric evaluation revealed a significantly higher degree of hepatic fibrosis and accumulation of connective tissue in the Smad3 WT compared with null mice. IHC evaluation showed a marked increase in alpha-SMA, CTGF, collagen I-III, TGF-beta and Smad3 staining in the liver of Smad3 WT compared with that in null mice, whereas Smad7 was increased only in null mice.ConclusionsThe results indicate that Smad3 loss confers resistance to the development of DMN-induced hepatic fibrosis. The reduced fibrotic response appears to be due to a reduction of fibrogenic myofibroblast activation and ECM production and accumulation. Smad3 could be a novel target for potential treatment of fibrosis complicating chronic hepatitis.