Hemodynamics and hepatic remodeling

摘要 本研究旨在了解血流动力学改变对肝脏结构和功能的影响。 功能，重点是门静脉高压症。门静脉高压症是慢性肝病的主要并发症 疾病。肝硬变是其最常见的原因，但也可在非肝硬变的情况下发展。在门户中 高血压，门静脉流量减少，而肝动脉(HA)流量增加，因为 肝动脉缓冲反应和内脏动脉血管扩张的结合。这些变化是如何发生的 对肝脏结构和功能的影响在很大程度上是未知的。 我们的初步数据显示，部分门静脉结扎(PPVL；一种门静脉外科模型)的大鼠 高血压)发展为门静脉纤维化症。PPVL部分阻断肝前部位的门静脉， 导致门脉高压和HA-Flow增加。患有PPVL的大鼠也表现出更多的 汇管区的巨噬细胞和T细胞。此外，已知血流增加会导致心脏重塑。 动脉壁，由血管周围巨噬细胞和T细胞的瞬时聚集和激活所介导。 因此，我们假设门静脉高压症中HA流量的增加通过以下方式促进门静脉系统纤维化 通过机械转导介导的信号来招募巨噬细胞和T细胞。肝 通过增强HA血流进行重塑也可能是放大肝纤维化/肝硬变的第二个打击。此外， 我们假设脾是渗入的免疫细胞的重要来源。 为了检验这些假设，我们建议检验以下三个目标：1)确定 HA-FLOW在门静脉纤维化发展中的作用及流行性门静脉纤维化的意义 肝纤维化/肝硬变的进展，2)决定HA-Flow增加引起的机制 免疫细胞浸润和门静脉纤维化；3)决定免疫细胞的机制。 调节肝门部纤维化。

SUMMARY The goal of this study is to understand the effects of hemodynamic changes on liver structure and function with a focus on portal hypertension. Portal hypertension is a major complication of chronic liver disease. Liver cirrhosis is its most common cause, but it develops in non-cirrhotic conditions as well. In portal hypertension, portal venous flow decreases, while hepatic arterial (HA) flow increases because of a combination of a hepatic arterial buffer response and vasodilation of splanchnic arteries. How these changes influence liver structure and function is largely unknown. Our preliminary data show that rats with partial portal vein ligation (PPVL; a surgical model of portal hypertension) develop portal tract fibrosis. PPVL partially occludes the portal vein at a pre-hepatic site and leads to portal hypertension and increased HA-flow. Rats with PPVL also showed increased infiltration of macrophages and T-cells in portal tracts. Further, increased blood flow is known to cause remodeling of arterial walls, mediated by transient accumulation and activation of perivascular macrophages and T-cells. Therefore, we hypothesize that increased HA-flow in portal hypertension facilitates portal tract fibrosis by recruiting macrophages and T-cells through signals that are mediated by mechano-transduction. Liver remodeling through enhanced HA-flow could also be a second hit that amplifies liver fibrosis/cirrhosis. Further, we hypothesize that the spleen is an important source of the infiltrating immune cells. To test these hypotheses, we propose to examine the following three aims: 1) Determine the role of HA-flow in the development of portal tract fibrosis and the significance of flow-induced portal tract fibrosis in the progression of liver fibrosis/cirrhosis, 2) Determine the mechanism by which increased HA-flow causes immune cell infiltration and portal tract fibrosis, and 3) Determine the mechanism by which immune cells regulate portal tract fibrosis.