Portal hypertension is one of the most important cirrhosis-associated complications of chronic liver disease, leading to significant morbidity and mortality. After chronic liver injury, hepatic stellate cells reside in the perisinusoidal space activted and acquire a myofibroblast-like phenotype. The activated hepatic stellate cells act as both sources as well as the target for a potent vasoconstrictor endothelin-1. Activation of hepatic stellate cells plays a vital role in the onset of cirrhosis by way of increased extracellular matrix production and the enhanced contractile response to vasoactive mediators such as endothelin-1. In fibrotic/cirrhotic liver, activated hepatic stellate cells produce endothelin-1 leading to an imbalance between pro and antifibrotic factors responsible for enormous extracellular matrix synthesis. Thus, extracellular matrix deposition in the perisinusoidal space further augments liver stiffness and elevates the vascular tone and portal hypertension. Portal hypertension is a complex process modulated by several cell types like hepatic stellate cells, liver sinusoidal endothelial cells, Kupffer cells, injured hepatocytes, immune cells, and biliary epithelial cells. Therefore, targeting a single cell type may not be useful for regression of cirrhosis and portal hypertension. Nevertheless, numerous findings indicate that functionally liver sinusoidal endothelial cells and hepatic stellate cells closely regulate the sinusoidal blood flow via synthesis of several vasoactive molecules including endothelin-1, and hence targeting these cells with novel pharmacological agents may offer promising results.

Impact statement

Portal hypertension is pathologically defined as increase of portal venous pressure, mainly due to chronic liver diseases such as fibrosis and cirrhosis. In fibrotic liver, activated hepatic stellate cells increase their contraction in response to endothelin-1 (ET-1) via autocrine and paracrine stimulation from liver sinusoidal endothelial cells and injured hepatocytes. Clinical studies are limited with ET receptor antagonists in cirrhotic patients with portal hypertension. Hence, studies are needed to find molecules that block ET-1 synthesis. Accumulation of extracellular matrix proteins in the perisinusoidal space, tissue contraction, and alteration in blood flow are prominent during portal hypertension. Therefore, novel matrix modulators should be tested experimentally as well as in clinical studies. Specifically, tumor necrosis factor-α, transforming growth factor-β1, Wnt, Notch, rho-associated protein kinase 1 signaling antagonists, and peroxisome proliferator-activated receptor α and γ, interferon-γ and sirtuin 1 agonists should be tested elaborately against cirrhosis patients with portal hypertension.

中文翻译：

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Endothelin-1 在门静脉高压症中的作用：肝星状细胞的复杂作用。

门脉高压是慢性肝病最重要的肝硬化相关并发症之一，导致显着的发病率和死亡率。慢性肝损伤后，肝星状细胞驻留在窦周空间被激活并获得肌成纤维细胞样表型。活化的肝星状细胞既是有效血管收缩剂内皮素 1 的来源，也是其靶点。肝星状细胞的激活通过增加细胞外基质的产生和增强对血管活性介质（如内皮素-1）的收缩反应，在肝硬化的发生中起着至关重要的作用。在纤维化/肝硬化肝脏中，活化的肝星状细胞产生内皮素-1，导致促纤维化因子和抗纤维化因子之间的失衡，导致大量细胞外基质合成。因此，窦周间隙中的细胞外基质沉积进一步增加了肝脏硬度，并提高了血管张力和门脉高压。门脉高压是一个复杂的过程，由多种细胞类型调节，如肝星状细胞、肝窦内皮细胞、库普弗细胞、受损肝细胞、免疫细胞和胆道上皮细胞。因此，靶向单一细胞类型可能对肝硬化和门静脉高压症的消退没有帮助。然而，许多研究结果表明，功能性肝窦内皮细胞和肝星状细胞通过合成包括内皮素-1 在内的几种血管活性分子来密切调节肝窦血流，因此用新型药物靶向这些细胞可能会提供有希望的结果。

影响陈述

门静脉高压症在病理学上被定义为门静脉压力升高，主要由肝纤维化、肝硬化等慢性肝病引起。在纤维化肝脏中，活化的肝星状细胞通过来自肝窦内皮细胞和受损肝细胞的自分泌和旁分泌刺激，响应内皮素-1（ET-1）而增加收缩。ET 受体拮抗剂在肝硬化门脉高压患者中的临床研究受到限制。因此，需要进行研究以找到阻止 ET-1 合成的分子。在门静脉高压症期间，细胞外基质蛋白在窦周隙中的积累、组织收缩和血流改变是突出的。因此，应在实验和临床研究中测试新型基质调节剂。具体来说，肿瘤坏死因子-α，