Liver Center, Yale University School of Medicine, New Haven, CT, USA.
Allergan plc, South San Francisco, CA, USA.
Liver Int. 2018 Jun;38(6):1128-1138. doi: 10.1111/liv.13698. Epub 2018 Feb 13.
BACKGROUND & AIMS: Cholestatic liver injury is mediated by bile acid-induced inflammatory responses. We hypothesized that superior therapeutic effects might be achieved by combining treatments that reduce the bile acid pool size with one that blocks inflammation.
Bile duct-ligated (BDL) rats and Mdr2(Abcb4) mice were treated with all-trans retinoic acid (atRA), a potent inhibitor of bile acid synthesis, 5 mg/kg/d by gavage, or Cenicriviroc (CVC), a known antagonist of CCR2 and CCR5, 50 mg/kg/d alone or in combination for 14 days and 1 month respectively.
All-trans retinoic acid alone reduced bile acid pool size and liver necrosis in BDL rats. However, the combination with CVC further reduced liver to body weight ratio, bile acid pool size, plasma liver enzyme, bilirubin, liver necrosis and fibrosis when compared to the atRA treatment. The assessment of hepatic hydroxyproline content further confirmed the reduced liver injury concurrent with reduction of pro-inflammatory cytokines emphasizing the synergistic effects of these two agents. Profiling of hepatic inflammatory cells revealed that combination therapy reduced neutrophils and T cells but not macrophages. The superior therapeutic effects of combination treatment were also confirmed in Mdr2 mice where a significant reduction in plasma liver enzymes, bilirubin, liver fibrosis, bile duct proliferation and hepatic infiltration of neutrophils and T cells and expression of cytokines were found.
Multitargeted therapy is an important paradigm for treating cholestatic liver injury. The combination of CVC with atRA or other FXR activators may warrant a clinical trial in patients with cholestatic liver disease.
胆汁淤积性肝损伤是由胆汁酸诱导的炎症反应介导的。我们假设，通过将减少胆汁酸池大小的治疗方法与阻断炎症的治疗方法相结合，可能会取得更好的治疗效果。
胆管结扎（BDL）大鼠和 Mdr2(Abcb4) 小鼠分别用全反式视黄酸（atRA）和西尼利福昔（CVC）进行治疗。atRA 通过灌胃以 5mg/kg/d 的剂量给药，是一种有效的胆汁酸合成抑制剂；CVC 是 CCR2 和 CCR5 的已知拮抗剂，单独或联合使用 50mg/kg/d 分别治疗 14 天和 1 个月。
atRA 单独使用可减少 BDL 大鼠的胆汁酸池大小和肝坏死。然而，与 atRA 治疗相比，联合 CVC 进一步降低了肝/体重比、胆汁酸池大小、血浆肝酶、胆红素、肝坏死和纤维化。肝羟脯氨酸含量的评估进一步证实了肝损伤的减少与促炎细胞因子的减少同时发生，强调了这两种药物的协同作用。对肝炎性细胞的分析表明，联合治疗减少了中性粒细胞和 T 细胞，但不减少巨噬细胞。在 Mdr2 小鼠中也证实了联合治疗的更好疗效，发现血浆肝酶、胆红素、肝纤维化、胆管增生和中性粒细胞和 T 细胞在肝内浸润以及细胞因子的表达均显著减少。
多靶点治疗是治疗胆汁淤积性肝损伤的重要策略。CVC 与 atRA 或其他 FXR 激动剂联合使用可能值得在胆汁淤积性肝病患者中进行临床试验。
