Cui Binbin, Yu Chao, Zhang Shenglei, Hou Xiying, Wang Yi, Wang Jun, Zhuang Shougang, Liu Feng
Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, Rhode Island, USA.
Kidney Dis (Basel). 2022 Apr 11;8(4):319-333. doi: 10.1159/000523852. eCollection 2022 Jul.
A multiple-target tyrosine kinase inhibitor, nintedanib, which is approved for treatment of interstitial pulmonary disease, has been demonstrated to have anti-fibrotic activity outside of the lungs. We explored its therapeutic effect in a murine model of peritoneal fibrosis.
Daily intraperitoneal injections of chlorhexidine gluconate (CG) induced peritoneal fibrosis in mice. The effects of delayed administration of nintedanib (given at day 21 after CG injection and then given daily for 14 days) were determined by immunohistochemical staining, ELISA, and immunoblot analysis.
Delayed administration of nintedanib significantly inhibited peritoneal fibrosis progression as indicated by decreasing deposition and expression of extracellular matrix (ECM) proteins (fibronectin and type I collagen). Treatment with nintedanib also upregulated MMP-2 and reciprocally downregulated TIMP-2, along with reducing expression of α-SMA, β-vimentin, and two transcription factors (Snail and Twist), and retaining E-cadherin expression. Nintedanib also inhibited co-expression of β-vimentin with Snail or Twist as shown by immunofluorescent staining. Moreover, nintedanib decreased the number of CD31-positive blood vessels and CD31 expression in the injured peritoneum. Moreover, delayed application of nintedanib inhibited the expression of several cytokines/chemokines, including monocyte chemoattractant protein-1, tumor necrosis factor-α, interleukin-1β (IL-1β), and IL-6, and infiltration of CD68 macrophages to the injured peritoneum. Finally, nintedanib blocked phosphorylation of STAT3, NF-κB, and Smad3 during the development of peritoneal fibrosis.
Delayed administration of nintedanib inhibits progression of peritoneal fibrosis and partially reverses established peritoneal fibrosis by attenuating epithelial-mesenchymal transition, inflammation, and angiogenesis, as well as promoting ECM degradation. We conclude that nintedanib has a therapeutic potential to treat peritoneal fibrosis.
尼达尼布是一种多靶点酪氨酸激酶抑制剂，已被批准用于治疗间质性肺疾病，并且已被证明在肺部以外具有抗纤维化活性。我们在小鼠腹膜纤维化模型中探究了其治疗效果。
每日腹腔注射葡萄糖酸氯己定（CG）诱导小鼠腹膜纤维化。通过免疫组织化学染色、酶联免疫吸附测定（ELISA）和免疫印迹分析来确定尼达尼布延迟给药（在CG注射后第21天给药，然后每日给药14天）的效果。
尼达尼布延迟给药显著抑制了腹膜纤维化进展，表现为细胞外基质（ECM）蛋白（纤连蛋白和I型胶原）的沉积和表达减少。尼达尼布治疗还上调了基质金属蛋白酶-2（MMP-2）并相应地下调了金属蛋白酶组织抑制剂-2（TIMP-2），同时降低了α-平滑肌肌动蛋白（α-SMA）、β-波形蛋白以及两种转录因子（Snail和Twist）的表达，并维持了E-钙黏蛋白的表达。免疫荧光染色显示，尼达尼布还抑制了β-波形蛋白与Snail或Twist的共表达。此外，尼达尼布减少了损伤腹膜中CD31阳性血管的数量和CD31的表达。此外，尼达尼布延迟应用抑制了几种细胞因子/趋化因子的表达，包括单核细胞趋化蛋白-1、肿瘤坏死因子-α、白细胞介素-1β（IL-1β）和IL-6，以及CD68巨噬细胞向损伤腹膜的浸润。最后，尼达尼布在腹膜纤维化发展过程中阻断了信号转导和转录激活因子3（STAT3）、核因子-κB（NF-κB）和Smad3的磷酸化。
尼达尼布延迟给药可抑制腹膜纤维化进展，并通过减弱上皮-间质转化、炎症和血管生成以及促进ECM降解来部分逆转已形成的腹膜纤维化。我们得出结论，尼达尼布具有治疗腹膜纤维化的潜力。
