Pathobiology of inherited biliary diseases: a roadmap to understand acquired liver diseases.,Nature Reviews Gastroenterology & Hepatology

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Pathobiology of inherited biliary diseases: a roadmap to understand acquired liver diseases.
Nature Reviews Gastroenterology & Hepatology ( IF 45.9 ) Pub Date : 2019-06-05 , DOI: 10.1038/s41575-019-0156-4
Luca Fabris _{1,

2} , Romina Fiorotto ₁ , Carlo Spirli ₁ , Massimiliano Cadamuro ₂ , Valeria Mariotti ₂ , Maria J Perugorria _{3,

4,

5} , Jesus M Banales _{3,

4,

5} , Mario Strazzabosco _{1,

2}

Affiliation

Bile duct epithelial cells, also known as cholangiocytes, regulate the composition of bile and its flow. Acquired, congenital and genetic dysfunctions in these cells give rise to a set of diverse and complex diseases, often of unknown aetiology, called cholangiopathies. New knowledge has been steadily acquired about genetic and congenital cholangiopathies, and this has led to a better understanding of the mechanisms of acquired cholangiopathies. This Review focuses on findings from studies on Alagille syndrome, polycystic liver diseases, fibropolycystic liver diseases (Caroli disease and congenital hepatic fibrosis) and cystic fibrosis-related liver disease. In particular, knowledge on the role of Notch signalling in biliary repair and tubulogenesis has been advanced by work on Alagille syndrome, and investigations in polycystic liver diseases have highlighted the role of primary cilia in biliary pathophysiology and the concept of biliary angiogenic signalling and its role in cyst growth and biliary repair. In fibropolycystic liver disease, research has shown that loss of fibrocystin generates a signalling cascade that increases β-catenin signalling, activates the NOD-, LRR- and pyrin domain-containing 3 inflammasome, and promotes production of IL-1β and other chemokines that attract macrophages and orchestrate the process of pericystic and portal fibrosis, which are the main mechanisms of progression in cholangiopathies. In cystic fibrosis-related liver disease, lack of cystic fibrosis transmembrane conductance regulator increases the sensitivity of epithelial Toll-like receptor 4 that sustains the secretion of nuclear factor-κB-dependent cytokines and peribiliary inflammation in response to gut-derived products, providing a model for primary sclerosing cholangitis. These signalling mechanisms may be targeted therapeutically and they offer a possibility for the development of novel treatments for acquired cholangiopathies.

中文翻译：

遗传性胆道疾病的病理学：了解获得性肝病的路线图。

胆管上皮细胞，也称为胆管细胞，调节胆汁的成分及其流动。这些细胞的后天性、先天性和遗传性功能障碍会导致一系列多样且复杂的疾病，通常病因不明，称为胆管病。关于遗传性和先天性胆管病的新知识不断获得，这使得人们更好地了解获得性胆管病的机制。本综述重点关注 Alagille 综合征、多囊肝病、纤维多囊性肝病（Caroli 病和先天性肝纤维化）和囊性纤维化相关肝病的研究结果。特别是，通过对 Alagille 综合征的研究，人们对 Notch 信号在胆道修复和肾小管生成中的作用有了更深入的了解，对多囊肝病的研究强调了初级纤毛在胆道病理生理学中的作用以及胆道血管生成信号的概念及其作用囊肿生长和胆道修复。在纤维多囊性肝病中，研究表明，纤囊蛋白的缺失会产生信号级联反应，增加 β-连环蛋白信号传导，激活包含 NOD-、LRR- 和 Pyrin 结构域的 3 炎症小体，并促进 IL-1β 和其他吸引趋化因子的产生巨噬细胞并协调囊周和门静脉纤维化的过程，这是胆管病进展的主要机制。在囊性纤维化相关的肝病中，囊性纤维化跨膜电导调节因子的缺乏会增加上皮 Toll 样受体 4 的敏感性，该受体维持核因子 κB 依赖性细胞因子的分泌和胆周炎症对肠源性产物的反应，从而提供了原发性硬化性胆管炎模型。这些信号传导机制可以作为治疗目标，并且为开发获得性胆管病的新疗法提供了可能性。

更新日期：2019-06-05

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