代偿期肝硬化患者及大鼠模型中病因特异性炎症模式

Aetiology-specific inflammation patterns in patients and rat models of compensated cirrhosis.

作者信息

Hofer Benedikt Silvester, Simbrunner Benedikt, Königshofer Philipp, Brusilovskaya Ksenia, Petrenko Oleksandr, Taru Vlad, Sorz Thomas, Zinober Kerstin, Semmler Georg, Kauschke Stefan G, Pfisterer Larissa, Trauner Michael, Mandorfer Mattias, Schwabl Philipp, Reiberger Thomas

机构信息

Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria.

出版信息

Dig Liver Dis. 2025 Feb;57(2):450-458. doi: 10.1016/j.dld.2024.09.006. Epub 2024 Sep 28.

DOI:10.1016/j.dld.2024.09.006

PMID:39343656

Abstract

BACKGROUND

Cirrhosis is associated with a proinflammatory environment.

AIMS

To analyse aetiology-specific inflammation patterns in compensated cirrhosis in animal models and patients.

METHODS

Portal pressure (PP), fibrosis (collagen proportionate area [CPA]) and hepatic inflammation were measured in cirrhotic rat models (thioacetamide [TAA;n = 12]; choline-deficient high-fat diet [CDHFD;n = 12]; bile duct ligation [BDL;n = 16]). Compensated cirrhotic patients (alcohol-related liver disease [ALD;n = 67]; metabolic dysfunction-associated steatohepatitis [MASH;n = 50]; cholestatic liver disease [primary biliary cholangitis [PBC]/primary sclerosing cholangitis [PSC];n = 22]) undergoing hepatic venous pressure gradient (HVPG) measurement were included.

RESULTS

In rats, hepatic proinflammatory gene expression was highest in CDHFD and lowest in TAA, despite comparable PP levels. Across all animal models, Tnfa/Il6 correlated positively with CPA, and Mcp1 with elevated PP. Mcp1 was also associated with increased CPA in TAA/CDHFD. Mcp1/Cxcl1 showed a model-independent positive correlation to transaminases. Il1b correlated positively with CPA/PP in BDL and with transaminases in CDHFD. In patients, CRP/IL-6 were lower in MASH compared to ALD or PBC/PSC, regardless of hepatic function. IgA/IgG were highest and complement factors lowest in ALD. More pronounced systemic inflammation was linked to higher HVPG primarily in ALD/MASH.

CONCLUSION

Proinflammatory pathways are upregulated across all liver disease aetiologies, yet their association with fibrosis and portal hypertension can vary.

摘要

背景

肝硬化与促炎环境相关。

目的

分析动物模型和患者代偿期肝硬化中病因特异性炎症模式。

方法

在肝硬化大鼠模型（硫代乙酰胺 [TAA；n = 12]；胆碱缺乏高脂饮食 [CDHFD；n = 12]；胆管结扎 [BDL；n = 16]）中测量门静脉压力（PP）、纤维化（胶原比例面积 [CPA]）和肝脏炎症。纳入接受肝静脉压力梯度（HVPG）测量的代偿期肝硬化患者（酒精性肝病 [ALD；n = 67]；代谢功能障碍相关脂肪性肝炎 [MASH；n = 50]；胆汁淤积性肝病 [原发性胆汁性胆管炎 [PBC]/原发性硬化性胆管炎 [PSC]；n = 22]）。

结果

在大鼠中，尽管PP水平相当，但肝脏促炎基因表达在CDHFD中最高，在TAA中最低。在所有动物模型中，Tnfa/Il6与CPA呈正相关，Mcp1与升高的PP呈正相关。Mcp1在TAA/CDHFD中也与CPA增加有关。Mcp1/Cxcl1与转氨酶呈模型无关的正相关。Il1b在BDL中与CPA/PP呈正相关，在CDHFD中与转氨酶呈正相关。在患者中，无论肝功能如何，MASH患者的CRP/IL-6均低于ALD或PBC/PSC患者。ALD患者的IgA/IgG最高，补体因子最低。更明显的全身炎症主要与ALD/MASH中较高的HVPG相关。