Targeted Therapeutics, Department of Biomaterials Science and Technology, MIRA Institute for Biomedical Technology and Technical Medicine, Faculty of Science and Technology, University of Twente, Enschede, The Netherlands.
Department of Pharmaceutics, Utrecht Institute of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands.
Sci Rep. 2017 Mar 14;7:44545. doi: 10.1038/srep44545.
Hepatic fibrosis, a progressive chronic disease mainly caused by hepatitis viral infections, alcohol abuse or metabolic syndrome leading to liver dysfunction and is the growing cause of mortality worldwide. Tyrosine kinase inhibitor BIBF1120 (Nintedanib) has been evaluated in clinical trials for idiopathic pulmonary fibrosis and advanced Hepatocellular carcinoma, but has not been explored for liver fibrosis yet. In this study, we aimed to investigate the therapeutic effects and mechanism of BIBF1120 in liver fibrogenesis. The effects of BIBF1120 were evaluated in TGFβ-activated mouse 3T3 fibroblasts, LX2 cells, primary human hepatic stellate cells (HSCs) and CCl-induced liver fibrogenesis mouse model. Fibroblasts-conditioned medium studies were performed to assess the paracrine effects on macrophages and endothelial cells. In-vitro in TGFβ-activated fibroblasts, BIBF1120 significantly inhibited expression of major fibrotic parameters, wound-healing and contractility. In vivo in CCl-induced acute liver injury model, post-disease BIBF1120 administration significantly attenuated collagen accumulation and HSC activation. Interestingly, BIBF1120 drastically inhibited intrahepatic inflammation and angiogenesis. To further elucidate the mechanism of action, 3T3-conditioned medium studies demonstrated increased 3T3-mediated macrophage chemotaxis and endothelial cells tube formation and activation, which was significantly decreased by BIBF1120. These results suggests that BIBF1120 can be a potential therapeutic approach for the treatment of liver fibrosis.
肝纤维化是一种进行性慢性疾病，主要由肝炎病毒感染、酒精滥用或代谢综合征引起，导致肝功能障碍，是全球死亡率不断上升的主要原因。酪氨酸激酶抑制剂 BIBF1120（尼达尼布）已在特发性肺纤维化和晚期肝细胞癌的临床试验中进行了评估，但尚未探索其在肝纤维化中的作用。在本研究中，我们旨在研究 BIBF1120 在肝纤维化发生中的治疗作用和机制。在 TGFβ 激活的小鼠 3T3 成纤维细胞、LX2 细胞、原代人肝星状细胞（HSCs）和 CCl 诱导的肝纤维化小鼠模型中评估了 BIBF1120 的作用。进行了成纤维细胞条件培养基研究，以评估对巨噬细胞和内皮细胞的旁分泌作用。在 TGFβ 激活的成纤维细胞中，BIBF1120 显著抑制主要纤维化参数、伤口愈合和收缩的表达。在 CCl 诱导的急性肝损伤模型中，疾病后给予 BIBF1120 可显著减轻胶原积累和 HSC 激活。有趣的是，BIBF1120 明显抑制肝内炎症和血管生成。为了进一步阐明作用机制，3T3 条件培养基研究表明，3T3 介导的巨噬细胞趋化和内皮细胞管形成和激活增加，而 BIBF1120 可显著降低这些作用。这些结果表明，BIBF1120 可能是治疗肝纤维化的一种有潜力的治疗方法。
