Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
Laboratory of Stem Cell Regulation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan.
Hepatology. 2018 Jan;67(1):296-312. doi: 10.1002/hep.29421. Epub 2017 Nov 15.
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.
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).
纤维化是受伤组织中重要的愈合过程，但慢性炎症患者常出现过度纤维化。虽然已有报道称孤啡肽（OSM）通过诱导金属蛋白酶组织抑制剂 1（Timp1）的表达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）中的作用尚未阐明。在这里，我们表明 OSM 通过调节 CLI 期间的巨噬细胞活化发挥强大的纤维生成活性。OSM 基因缺失减轻了慢性肝炎小鼠模型的纤维化。相反，通过尾静脉高压注射（HTVi）在正常小鼠肝脏中持续表达 OSM 会诱导严重的纤维化而不会导致肝细胞坏死损伤，这表明 OSM 参与了肝炎后的基本肝纤维化（LF）过程。在肝星状细胞（HSCs）和肝巨噬细胞（HMs）的原代共培养物中，OSM 上调了 HM 中纤维生成因子的表达，如转化生长因子-β和血小板衍生生长因子，同时诱导 HSCs 中 Timp1 的表达，这表明 OSM 在肝脏胶原沉积中具有协同作用。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 有反应，以促进纤维发生。此外，通过氯膦酸盐脂质体或趋化因子抑制剂给药耗尽或阻断 HMs 可防止 OSM 诱导的纤维化。
OSM 通过协调 HMs 和 HSCs 的表型变化在 LF 中起关键作用。我们的数据表明，OSM 是 LF 的一个有前途的治疗靶点。（《肝脏病学》2018；67：296-312）。
