Hepatic congestion leads to fibrosis: findings in a newly developed murine model.
Hepatic congestion leads to fibrosis: findings in a newly developed murine model.
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肝充血导致纤维化：新开发的小鼠模型的发现。
DOI：
10.1002/hep.27550
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Iwakiri,Yasuko
中科院分区：
文献类型：
--
作者：
Hidaka,Hisashi;Iwakiri,Yasuko
被动肝充血，又称充血性肝病（CH），是肝流出梗阻的结果，最常见于充血性心力衰竭。慢性肝充血最终可导致肝纤维化。肝充血患者的肝脏标本在组织学上表现为肝腺泡周围静脉窦充血和出血性坏死，导致肝窦纤维化，最终在邻近的中心静脉之间桥接纤维化。1,2我们对CH中纤维发生的理解主要来自于人类样本的病理检查。其机制仍不清楚，部分原因是缺乏适当的实验模型。在最新一期的《HEPATOLOGY》杂志上，Simonetto等3通过部分结扎下腔静脉（pIVCL）建立了小鼠CH模型。通过该模型和体外细胞培养系统，他们证明了慢性肝充血导致窦状血栓形成和窦状静脉拉伸，这两者都促进了肝星状细胞（hsc）的纤维连接蛋白（FN）原纤维的组装，这是细胞外基质（ECM）沉积的早期步骤，最终导致肝纤维化。这项工作新颖而重要，特别是因为开发了一种相对简单的手术方法来产生啮齿动物的肝脏充血，这使他们能够研究CH和纤维化之间的机制联系。在他们的pIVCL模型中，下腔静脉（IVC）用直径0.6 mm的无菌钢丝结扎。金属丝放置在IVC旁边，并将两者结扎在一起，金属丝充当结扎的间隔或占位符。结扎后立即取出金属丝，使下腔静脉直径缩小了约70%。研究人员对该模型进行了深入的表征，并证实给予pIVCL的小鼠表现出与CH患者相似的病理特征，包括纤维化的发展。心输出量是个例外。虽然患者的心输出量减少，但在该小鼠模型中未观察到减少。在他们的pIVCL模型中有两个关键的观察结果。一个是肝脏的炎症活动最小，尽管发生了纤维化。鉴于慢性炎症在大多数纤维化病例中起关键作用，这是一种独特的特征，表明纤维化发生的非炎症机制。事实上，在Fontan循环患者中观察到最小的肝脏炎症，Fontan循环是心脏病相关肝脏充血的另一个原因，这表明在这种情况下纤维化可以独立于炎症发展。另一种是窦状血栓形成，pIVCL小鼠和CH患者的肝脏标本中存在纤维蛋白，这一点很明显。研究人员检查了药理学（华法林治疗）和遗传（组织因子途径抑制剂[TFPI]过表达小鼠）措施对凝血过程的破坏是否减少了pIVCL模型中的纤维化（图1）。TFPI是外源性凝血途径的内源性抑制剂5，因此过表达TFPI的小鼠可以预防血栓形成。这两种方法显著降低肝内纤维蛋白水平和纤维化，表明血栓形成对肝纤维化的影响。
Passive hepatic congestion, known as congestive hepatopathy (CH), occurs as a result of hepatic outflow obstruction, a condition most commonly observed in congestive heart failure. Chronic hepatic congestion can eventually result in hepatic fibrosis. Liver specimens of patients with hepatic congestion are histologically characterized by sinusoidal engorgement and hemorrhagic necrosis in the perivenular areas of the hepatic acini, which leads to sinusoidal fibrosis and ultimately to bridging fibrosis between adjacent central veins. 1, 2 Our understanding of fibrogenesis in CH has largely come from pathological examinations of human samples. The mechanisms have remained unclear partly as a result of the lack of appropriate experimental models. In the current issue of HEPATOLOGY, Simonetto et al. 3 developed a murine model of CH through partial ligation of the inferior vena cava (pIVCL). Using this model and an in vitro cell culture system, they demonstrated that chronic hepatic congestion causes sinusoidal thrombus formation as well as sinusoidal stretch, which both facilitate fibronectin (FN) fibril assembly by hepatic stellate cells (HSCs), an early step in extracellular matrix (ECM) deposition, and, eventually, hepatic fibrosis. 3 This work is novel and important, particularly because of the development of a relatively easy surgical procedure to generate hepatic congestion in rodents, which allowed them to investigate a mechanistic link between CH and fibrosis. In their pIVCL model, the inferior vena cava (IVC) was ligated along with a sterile steel wire of 0.6 mm in diameter. The wire was placed alongside the IVC and the two ligated together, with the wire acting as a spacer or placeholder for the ligature. The wire was removed immediately after the ligation, which reduced the IVC diameter by approximately 70%. The investigators characterized this model intensively and verified that mice given pIVCL presented pathological features similar to those observed in patients with CH, including the development of fibrosis. An exception was cardiac output. Though reduced cardiac output was reported in patients, no reductions were observed in this mouse model.There were two key observations in their pIVCL model. One was minimal inflammatory activity in the liver, despite the development of fibrosis. Given that chronic inflammation has a pivotal role in the majority of fibrotic cases, this was a unique feature and suggested a noninflammatory mechanism of fibrogenesis. In fact, minimal hepatic inflammation was observed in patients with the Fontan circulation, another cause of cardiac disease-related hepatic congestion, suggesting that fibrosis can develop independently of inflammation in this condition. 4 The other was sinusoidal thrombus formation, which was evident by the presence of fibrin in liver specimens of pIVCL mice as well as those of patients with CH. The investigators examined whether disruption of the coagulation process by pharmacological (warfarin treatment) and genetic (tissue factor pathway inhibitor [TFPI]-overexpressing mice) measures reduces fibrosis in the pIVCL model (Fig. 1). TFPI is an endogenous inhibitor of the extrinsic coagulation pathway, 5 and thus mice overexpressing TFPI prevent thrombosis. These two approaches significantly reduced intrahepatic fibrin levels and fibrosis, indicating an effect of thrombosis on fibrogenesis in CH.