Kongphat Wanthita, Pudgerd Arnon, Sridurongrit Somyoth
Graduate Program of Toxicology, Faculty of Science, Mahidol University, Bangkok, Thailand.
Department of Anatomy, Faculty of Science, Mahidol University, Bangkok, Thailand.
Heliyon. 2017 May 19;3(5):e00305. doi: 10.1016/j.heliyon.2017.e00305. eCollection 2017 May.
While Transforming growth factor-βs (Tgf-βs) have been known to play an important role in liver fibrosis through an activation of Hepatic Stellate Cells (HSC), their fibrotic role on hepatocytes in liver damage has not been addressed thoroughly. To shed more light on the hepatocyte-specific role of Tgf-β signaling during liver fibrosis, we generated transgenic mice expressing constitutively active Tgf-β type I receptor Alk5 under the control of albumin promoter. Uninjured mice with increased Tgf-β/Alk5 signaling in hepatocytes ( mice) did not show characteristics related to hepatocyte death, fibrosis and inflammation. When subjected to thioacetamide (TAA) treatment, mice exhibited more severe liver injury, when compared to control littermates. After TAA administration for 12 weeks, an increase in pathological changes was evident in livers, with higher number of infiltrating cells in the portal and periportal area. Immunohistochemistry for F4/80, myeloperoxidase and CD3 showed that there was an increased accumulation of macrophages, neutrophils and T-lymphocytes, respectively, in livers. Coincidently, we observed an exacerbated liver damage as seen by increases in serum aminotransferase level and number of apoptotic hepatocytes in mice. Sirius staining of collagen demonstrated that the fibrotic response was worsened in mice. The enhanced fibrosis in mutant livers was associated with marked production of α-SMA-positive myofibroblast. Hepatic expression of genes indicative of HSC activation was greater in mice. In conclusion, our data indicated that elevation of Tgf-β signaling via Alk5 in hepatocytes is not sufficient to induce liver pathology but plays an important role in amplifying TAA-induced liver damage.
虽然已知转化生长因子-β（Tgf-β）通过激活肝星状细胞（HSC）在肝纤维化中发挥重要作用，但其在肝损伤中对肝细胞的纤维化作用尚未得到充分研究。为了更深入了解肝纤维化过程中Tgf-β信号在肝细胞中的特异性作用，我们构建了在白蛋白启动子控制下组成型表达活性Tgf-β I型受体Alk5的转基因小鼠。肝细胞中Tgf-β/Alk5信号增加的未受伤小鼠（小鼠）未表现出与肝细胞死亡、纤维化和炎症相关的特征。与对照同窝小鼠相比，用硫代乙酰胺（TAA）处理时，小鼠表现出更严重的肝损伤。给予TAA 12周后，小鼠肝脏的病理变化明显增加，门脉和门脉周围区域的浸润细胞数量更多。F4/80、髓过氧化物酶和CD3的免疫组织化学显示，小鼠肝脏中巨噬细胞、中性粒细胞和T淋巴细胞的积累分别增加。巧合的是，我们观察到小鼠血清转氨酶水平升高和凋亡肝细胞数量增加，肝损伤加剧。天狼星胶原染色显示，小鼠的纤维化反应恶化。突变肝脏中增强的纤维化与α-SMA阳性肌成纤维细胞的大量产生有关。小鼠肝脏中指示HSC激活的基因表达更高。总之，我们的数据表明，肝细胞中通过Alk-5升高的Tgf-β信号不足以诱导肝脏病变，但在放大TAA诱导的肝损伤中起重要作用。
