肝纤维化的分子和细胞机制及其消退

StephenW

Molecular and cellular mechanisms of liver fibrosis and its regression

    Tatiana Kisseleva & David Brenner

Nature Reviews Gastroenterology & Hepatology volume 18, pages151–166(2021)Cite this article

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Abstract

Chronic liver injury leads to liver inflammation and fibrosis, through which activated myofibroblasts in the liver secrete extracellular matrix proteins that generate the fibrous scar. The primary source of these myofibroblasts are the resident hepatic stellate cells. Clinical and experimental liver fibrosis regresses when the causative agent is removed, which is associated with the elimination of these activated myofibroblasts and resorption of the fibrous scar. Understanding the mechanisms of liver fibrosis regression could identify new therapeutic targets to treat liver fibrosis. This Review summarizes studies of the molecular mechanisms underlying the reversibility of liver fibrosis, including apoptosis and the inactivation of hepatic stellate cells, the crosstalk between the liver and the systems that orchestrate the recruitment of bone marrow-derived macrophages (and other inflammatory cells) driving fibrosis resolution, and the interactions between various cell types that lead to the intracellular signalling that induces fibrosis or its regression. We also discuss strategies to target hepatic myofibroblasts (for example, via apoptosis or inactivation) and the myeloid cells that degrade the matrix (for example, via their recruitment to fibrotic liver) to facilitate fibrosis resolution and liver regeneration.
Key points

    Most chronic liver diseases, such as hepatitis C virus infection or non-alcoholic hepatic steatohepatitis, can progress to liver fibrosis with the formation of a fibrous scar.

    Experimental and clinical liver fibrosis regresses with the removal of the aetiological agent or with new therapeutic interventions.

    Chronic liver injury leads to activation of hepatic stellate cells, the major source of the fibrous scar in liver fibrosis.

    Hepatic stellate cells have four known phenotypes — quiescent, activated, inactivated and senescent — each of which has a critical role in liver fibrosis and its regression.

    During regression of liver fibrosis, activated hepatic stellate cells can undergo apoptosis or revert to an inactivated phenotype; the inactivated cells have a phenotype that is similar to but distinct from quiescent hepatic stellate cells.

    Macrophages can promote fibrogenesis by the secretion of TGFβ and other agonists, but they also support the regression of fibrosis through the secretion of collagenases that resorb the fibrous scar.

StephenW

肝纤维化的分子和细胞机制及其消退

    塔蒂亚娜·基塞列娃（Tatiana Kisseleva）和大卫·布伦纳（David Brenner）

自然评论，胃肠病和肝病，第18卷，第151–166页（2021），引用本文

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抽象的

慢性肝损伤导致肝脏发炎和纤维化，肝脏中活化的成纤维细胞通过其分泌细胞外基质蛋白，从而产生纤维性瘢痕。这些成肌纤维细胞的主要来源是常驻肝星状细胞。当去除病原体后，临床和实验性肝纤维化就会消退，这与这些活化的成纤维细胞的消除和纤维疤痕的吸收有关。了解肝纤维化消退的机制可以确定治疗肝纤维化的新治疗靶标。这篇综述总结了对肝纤维化可逆性的分子机制的研究，包括细胞凋亡和肝星状细胞的失活，肝脏与协调募集骨髓来源的巨噬细胞（和其他炎性细胞）驱动系统的相互作用。纤维化的解决，以及导致细胞内信号传导的各种细胞类型之间的相互作用，从而诱导纤维化或其消退。我们还将讨论靶向肝肌成纤维细胞（例如，通过凋亡或失活）和降解基质（例如，通过募集到纤维化肝）的髓样细胞以促进纤维化消退和肝再生的策略。
关键点

    大多数慢性肝脏疾病，例如丙型肝炎病毒感染或非酒精性肝脂肪性肝炎，都可以发展为肝纤维化并形成纤维性瘢痕。

    实验性和临床性肝纤维化会随着病因的去除或新的治疗手段的发展而消退。

    慢性肝损伤导致肝星状细胞活化，这是肝纤维化中纤维疤痕的主要来源。

    肝星状细胞具有四种已知的表型-静止，活化，失活和衰老-每种在肝纤维化及其消退中都起关键作用。

    在肝纤维化消退期间，活化的肝星状细胞可发生凋亡或恢复为失活的表型。灭活的细胞具有与静止的肝星状细胞相似但又不同的表型。

    巨噬细胞可通过分泌TGFβ和其他激动剂来促进纤维发生，但它们也通过吸收可吸收纤维疤痕的胶原酶的分泌来支持纤维化的消退。