Fibrosis is an important wound‐healing process in injured tissues, but excessive fibrosis is often observed in patients with chronic inflammation. Although oncostatin M (OSM) has been reported to play crucial roles for recovery from acute liver injury by inducing tissue inhibitor of metalloproteinase 1 (Timp1) expression, the role of OSM in chronic liver injury (CLI) is yet to be elucidated. Here, we show that OSM exerts powerful fibrogenic activity by regulating macrophage activation during CLI. Genetic ablation of the OSM gene alleviated fibrosis in a mouse model of chronic hepatitis. Conversely, continuous expression of OSM in a normal mouse liver by hydrodynamic tail vein injection (HTVi) induced severe fibrosis without necrotic damage of hepatocytes, indicating that OSM is involved in the fundamental process of liver fibrosis (LF) after hepatitis. In a primary coculture of hepatic stellate cells (HSCs) and hepatic macrophages (HMs), OSM up‐regulated the expression of fibrogenic factors, such as transforming growth factor‐β and platelet‐derived growth factor in HMs, while inducing Timp1 expression in HSCs, suggesting the synergistic roles of OSM for collagen deposition in the liver. Fluorescence‐activated cell sorting analyses using OSM‐HTVi and OSM knockout mice have revealed that bone‐marrow–derived monocyte/macrophage are responsive to OSM for profibrotic activation. Furthermore, depletion or blocking of HMs by administration of clodronate liposome or chemokine inhibitor prevented OSM‐induced fibrosis. Conclusion: OSM plays a crucial role in LF by coordinating the phenotypic change of HMs and HSCs. Our data suggest that OSM is a promising therapeutic target for LF. (Hepatology 2018;67:296‐312).

中文翻译：

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制瘤素 M 通过调节小鼠肝星状细胞和巨噬细胞之间的合作导致肝纤维化

纤维化是受伤组织中重要的伤口愈合过程，但在慢性炎症患者中经常观察到过度纤维化。尽管据报道制瘤素 M (OSM) 通过诱导金属蛋白酶 1 (Timp1) 表达的组织抑制剂在急性肝损伤的恢复中发挥关键作用，但 OSM 在慢性肝损伤 (CLI) 中的作用仍有待阐明。在这里，我们表明 OSM 通过在 CLI 期间调节巨噬细胞活化发挥强大的纤维化活性。OSM 基因的遗传消融减轻了慢性肝炎小鼠模型中的纤维化。相反，通过流体动力学尾静脉注射（HTVi）在正常小鼠肝脏中连续表达 OSM 诱导严重纤维化，而没有肝细胞坏死损伤，表明 OSM 参与了肝炎后肝纤维化 (LF) 的基本过程。在肝星状细胞 (HSCs) 和肝巨噬细胞 (HMs) 的原代共培养中，OSM 上调纤维生成因子的表达，如 HMs 中的转化生长因子-β 和血小板衍生生长因子，同时诱导 HSCs 中的 Timp1 表达，表明 OSM 对肝脏中胶原沉积的协同作用。使用 OSM-HTVi 和 OSM 敲除小鼠的荧光激活细胞分选分析表明，骨髓来源的单核细胞/巨噬细胞对 OSM 有促纤维化激活的反应。此外，通过施用氯膦酸盐脂质体或趋化因子抑制剂来消耗或阻断 HMs 可防止 OSM 诱导的纤维化。结论：OSM 通过协调 HMs 和 HSCs 的表型变化在 LF 中发挥关键作用。我们的数据表明 OSM 是 LF 的有希望的治疗靶点。（肝病学 2018 年；67：296-312）。