Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut; Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut.
Am J Pathol. 2023 Dec;193(12):2182-2202. doi: 10.1016/j.ajpath.2023.08.004. Epub 2023 Sep 4.
Liver is the largest lymph-producing organ. In cirrhotic patients, lymph production significantly increases concomitant with lymphangiogenesis. The aim of this study was to determine the mechanism of lymphangiogenesis in liver and its implication in liver fibrosis. Liver biopsies from portal hypertensive patients with portal-sinusoidal vascular disease (n = 22) and liver cirrhosis (n = 5) were evaluated for lymphangiogenesis and compared with controls (n = 9 and n = 6, respectively). For mechanistic studies, rats with partial portal vein ligation (PPVL) and bile duct ligation (BDL) were used. A gene profile data set (GSE77627), including 14 histologically normal liver, 18 idiopathic noncirrhotic portal hypertension, and 22 cirrhotic patients, was analyzed. Lymphangiogenesis was significantly increased in livers from patients with portal-sinusoidal vascular disease, cirrhotic patients, as well as PPVL and BDL rats. Importantly, Schwann cells of sympathetic nerves highly expressed vascular endothelial growth factor-C in PPVL rats. Vascular endothelial growth factor-C neutralizing antibody or sympathetic denervation significantly decreased lymphangiogenesis in livers of PPVL and BDL rats, which resulted in progression of liver fibrosis. Liver specimens from cirrhotic patients showed a positive correlation between sympathetic nerve/Schwann cell-positive areas and lymphatic vessel numbers, which was supported by gene set analysis from patients with noncirrhotic portal hypertension and cirrhotic patients. Sympathetic nerves promote hepatic lymphangiogenesis in noncirrhotic and cirrhotic livers. Increased hepatic lymphangiogenesis can be protective against liver fibrosis.
肝脏是最大的淋巴生成器官。在肝硬化患者中，伴随淋巴管生成，淋巴生成显著增加。本研究旨在确定肝脏淋巴管生成的机制及其在肝纤维化中的意义。评估了门静脉高压伴门腔静脉血管疾病患者（n=22）和肝硬化患者（n=5）的肝活检以确定淋巴管生成，并与对照组（n=9 和 n=6）进行比较。对于机制研究，使用部分门静脉结扎（PPVL）和胆管结扎（BDL）大鼠。分析了包括 14 例组织学正常肝、18 例特发性非肝硬化性门静脉高压和 22 例肝硬化患者的基因谱数据集（GSE77627）。在门腔静脉血管疾病、肝硬化患者以及 PPVL 和 BDL 大鼠的肝脏中，淋巴管生成显著增加。重要的是，PPVL 大鼠交感神经施万细胞高表达血管内皮生长因子-C。血管内皮生长因子-C 中和抗体或交感神经去神经显著减少了 PPVL 和 BDL 大鼠肝脏中的淋巴管生成，导致肝纤维化进展。肝硬化患者的肝组织标本显示交感神经/施万细胞阳性区域与淋巴管数量之间存在正相关，这得到了非肝硬化性门静脉高压和肝硬化患者基因集分析的支持。交感神经促进非肝硬化和肝硬化肝脏的肝淋巴管生成。增加的肝淋巴管生成可能对肝纤维化具有保护作用。
