Selective bromodomain and extra-terminal bromodomain inhibitor inactivates macrophages and hepatic stellate cells to inhibit liver inflammation and fibrosis

Liver fibrosis occurs following inflammation triggered by the integrated actions of activated liver-resident macrophages (Kupffer cells) and hepatic stellate cells (HSCs), and the multiplicity of these mechanisms complicates drug therapy. Here, we demonstrate that the selective bromodomain and extra-terminal (BET) bromodomain inhibitor compound38 can block both the Janus kinase-signal transducer and activator of transcription and mitogen-activated protein kinase signaling pathways in macrophages, which decreased their secretion of proinflammatory cytokines in a dose-dependent manner. The inactivation of macrophages attenuated lipopolysaccharide-induced injurious inflammation concurrent with a reduction in F4/80+ cells, proinflammatory cytokine levels, and neutrophil infiltration. Moreover, compound 38 inhibited the Wnt/β-catenin and transforming growth factor-beta/SMAD signaling pathways to abolish the activation of HSCs. <i>In vivo</i>, compound 38 significantly decreased the collagen deposition and fibrotic area of a CCl₄-induced liver fibrosis model, and restored the deficiency of activated HSCs and the upregulation of liver inflammation. These results highlight the potential role of compound 38 in treating liver fibrosis considering its simultaneous inhibitory effects on liver inflammation and related fibrosis.

肝纤维化多发生于活化的肝脏驻留巨噬细胞（库普弗细胞，Kupffer cells）与肝星状细胞（hepatic stellate cells, HSCs）协同作用所触发的炎症反应之后，此类机制的多样性使得药物治疗面临诸多挑战。本研究证实，选择性溴结构域与额外末端结构域（bromodomain and extra-terminal, BET）溴结构域抑制剂化合物38，可同时阻断巨噬细胞中的贾纳斯激酶-信号转导与转录激活因子（Janus kinase-signal transducer and activator of transcription）与丝裂原活化蛋白激酶（mitogen-activated protein kinase）信号通路，进而以剂量依赖性方式抑制巨噬细胞分泌促炎细胞因子（proinflammatory cytokines）。巨噬细胞的失活可减轻脂多糖（lipopolysaccharide, LPS）诱导的损伤性炎症，同时减少F4/80阳性细胞数量、降低促炎细胞因子水平并抑制中性粒细胞浸润。此外，化合物38可抑制Wnt/β-连环蛋白（Wnt/β-catenin）与转化生长因子-β（transforming growth factor-beta, TGF-β）/SMAD信号通路，从而阻断肝星状细胞的活化。在体内（in vivo）实验中，化合物38可显著降低四氯化碳（CCl₄）诱导的肝纤维化模型中的胶原沉积与纤维化面积，并逆转活化肝星状细胞的异常增多及肝脏炎症的过度激活。综上，鉴于化合物38可同时抑制肝脏炎症与相关纤维化进程，其在肝纤维化治疗中具备潜在应用价值。