Antifibrotic Effects of the Dual CCR2/CCR5 Antagonist Cenicriviroc in Animal Models of Liver and Kidney Fibrosis.
Antifibrotic Effects of the Dual CCR2/CCR5 Antagonist Cenicriviroc in Animal Models of Liver and Kidney Fibrosis.
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DOI：
10.1371/journal.pone.0158156
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Friedman SL
中科院分区：
文献类型：
--
作者：
Lefebvre E;Moyle G;Reshef R;Richman LP;Thompson M;Hong F;Chou HL;Hashiguchi T;Plato C;Poulin D;Richards T;Yoneyama H;Jenkins H;Wolfgang G;Friedman SL
C-C 趋化因子受体 2 型 (CCR2) 和 5 (CCR5) 及其配体（包括 CCL2 和 CCL5）之间的相互作用，通过促进单核细胞/巨噬细胞募集和组织浸润以及肝星状细胞活化来介导纤维形成。 Cenicriviroc (CVC) 是一种口服双重 CCR2/CCR5 拮抗剂，对两种受体具有纳摩尔效力。 CVC 的抗炎和抗纤维化作用在一系列炎症和纤维化的临床前模型中进行了评估。在硫代乙醇酸盐诱导的腹膜炎小鼠模型中体内评估单核细胞/巨噬细胞的募集。在小鼠单核细胞上离体评估 CCL2 诱导的趋化性。在硫代乙酰胺诱导的肝纤维化大鼠模型和饮食诱导的非酒精性脂肪性肝炎 (NASH) 和肾纤维化小鼠模型中评估了 CVC 的抗纤维化作用。研究评估包括身体和肝/肾重量、肝功能测试、肝/肾形态和胶原沉积、纤维形成基因和蛋白质表达以及药代动力学分析。 CVC 在剂量≥20 mg/kg/天时显着减少体内单核细胞/巨噬细胞的募集 (p < 0.05)。在这些剂量下，CVC 显示出抗纤维化作用，三种纤维化动物模型中的胶原蛋白沉积 (p < 0.05) 以及 1 型胶原蛋白和 mRNA 表达显着减少。在 NASH 模型中，CVC 显着降低非酒精性脂肪肝疾病活动评分（与对照组相比，p < 0.05）。 CVC 治疗对身体或肝/肾重量没有显着影响。 CVC 在一系列动物纤维化模型中显示出有效的抗炎和抗纤维化活性，支持纤维化疾病的人体测试。需要进一步的实验研究来阐明 CVC 抗纤维化作用的潜在机制。针对患有 NASH 和肝纤维化的成人的 2b 期研究已全部入组（CENTAUR 研究 652-2-203；NCT02217475）。
Interactions between C-C chemokine receptor types 2 (CCR2) and 5 (CCR5) and their ligands, including CCL2 and CCL5, mediate fibrogenesis by promoting monocyte/macrophage recruitment and tissue infiltration, as well as hepatic stellate cell activation. Cenicriviroc (CVC) is an oral, dual CCR2/CCR5 antagonist with nanomolar potency against both receptors. CVC’s anti-inflammatory and antifibrotic effects were evaluated in a range of preclinical models of inflammation and fibrosis. Monocyte/macrophage recruitment was assessed in vivo in a mouse model of thioglycollate-induced peritonitis. CCL2-induced chemotaxis was evaluated ex vivo on mouse monocytes. CVC’s antifibrotic effects were evaluated in a thioacetamide-induced rat model of liver fibrosis and mouse models of diet-induced non-alcoholic steatohepatitis (NASH) and renal fibrosis. Study assessments included body and liver/kidney weight, liver function test, liver/kidney morphology and collagen deposition, fibrogenic gene and protein expression, and pharmacokinetic analyses. CVC significantly reduced monocyte/macrophage recruitment in vivo at doses ≥20 mg/kg/day (p < 0.05). At these doses, CVC showed antifibrotic effects, with significant reductions in collagen deposition (p < 0.05), and collagen type 1 protein and mRNA expression across the three animal models of fibrosis. In the NASH model, CVC significantly reduced the non-alcoholic fatty liver disease activity score (p < 0.05 vs. controls). CVC treatment had no notable effect on body or liver/kidney weight. CVC displayed potent anti-inflammatory and antifibrotic activity in a range of animal fibrosis models, supporting human testing for fibrotic diseases. Further experimental studies are needed to clarify the underlying mechanisms of CVC’s antifibrotic effects. A Phase 2b study in adults with NASH and liver fibrosis is fully enrolled (CENTAUR Study 652-2-203; NCT02217475).