Role of Sinusoidal Pressure and Arterialization in Driving Fibrosis Progression
Role of Sinusoidal Pressure and Arterialization in Driving Fibrosis Progression
复制标题
正弦压力和动脉化在驱动纤维化进展中的作用
DOI：
10.1007/978-3-030-40542-7_57
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
S. Mueller
中科院分区：
文献类型：
--
作者：
S. Mueller
窦压假说（SPH）最近已被引入，其确定窦压（SP）升高是纤维化和肝硬化的原因。正常情况下，肝硬化背景下的压力变化与肝硬化导致的门静脉高压相关。然而，根据SPH，升高的SP是启动纤维化的主要上游事件（起始）。在健康肝脏中，肝硬度（LS）对应于SP，并响应于许多促纤维化刺激（如炎症、胆汁淤积或肝充血）而增加。SPH假设细胞外基质是响应于升高的SP而产生的，以承受潜在的压力。SP/LS升高的持续时间（>4周）和程度（>12 mmHg或>12 kPa）都是关键的。虽然如果消除SP升高的根本原因，纤维化仍然可以逆转，但增加的基质沉积导致通过肝动脉的血液供应增加。这种升高的肝动脉流量和肝脏的最终动脉化永久地引起病理性高压。恶性循环开始与进一步的基质沉积和动脉压升高。因此，动脉化定义了具有不可逆纤维化进展的所谓“不归点”。在细胞水平，SP是通过窦周细胞的拉伸、组织硬度的压力相关增加以及经由细胞和细胞间生物力学信号转导的拉伸力来产生胶原的实际驱动力。SPH能够解释硬化肝脏的宏观变化（轨迹力），对各种病因的一致纤维化反应，以及尽管消除了病因但在晚期阶段不返回的点。根据SPH的说法，未来的治疗方案应该以降低正弦压力为目标。
The Sinusoidal Pressure Hypothesis (SPH) has been recently introduced which identifies an elevation of sinusoidal pressure (SP) as cause of fibrosis and liver cirrhosis. Normally, pressure changes in the context of cirrhosis are associated with portal hypertension which is a consequence of cirrhosis. According to the SPH, however, an elevated SP is the major upstream event that initiates fibrosis (initiation). In healthy liver, liver stiffness (LS) corresponds to SP and increases in response to many pro-fibrogenic stimuli such as inflammation, cholestasis, or liver congestion. SPH postulates that extracellular matrix is produced in response to elevated SP to withstand the underlying pressure. Both duration (>4 weeks) and degree (>12 mmHg or >12 kPa) of SP/LS elevation are critical. While fibrosis can still reverse if the underlying cause of SP elevation is eliminated, the increased matrix deposition causes an increasing blood supply through the hepatic artery. This elevated hepatic arterial flow and the final arterialization of the liver permanently cause pathologically high pressures. A vicious cycle is initiated with further matrix deposition and increased arterial pressure. Thus, arterialization defines the so-called “point of no return” with irreversible fibrosis progression. At the cellular level, SP is the actual driving force for the production of collagen by stretching of perisinusoidal cells, pressure-related increase in tissue stiffness, and stretch forces transduced via cellular and intercellular biomechanic signaling. SPH is able to explain the macroscopic changes of the cirrhotic liver (trajectory forces), the uniform fibrotic response to various etiologies, and the point of no return in advanced stages despite elimination of the cause. According to SPH, future treatment options should be targeted at lowering the sinusoidal pressure.
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