Hemodynamics and hepatic remodeling

总结 本研究的目的是了解血流动力学变化对肝脏结构的影响， 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 疾病肝硬化是其最常见的原因，但它也会在非肝硬化情况下发生。门脉 高血压，门静脉血流量减少，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舒张的组合。这些变化如何 对肝脏结构和功能影响在很大程度上是未知的。 我们的初步数据表明，大鼠部分门静脉结扎（PPVL;门静脉结扎的外科模型）， 高血压）发展成门脉纤维化。PPVL在肝前部位部分闭塞门静脉， 导致门静脉高压和HA流量增加。患有PPVL的大鼠也显示了 巨噬细胞和T细胞。此外，已知增加的血流量会引起骨骼肌的重塑。 动脉壁，由血管周围巨噬细胞和T细胞的瞬时积聚和活化介导。 因此，我们假设门静脉高压症HA-流量增加通过以下途径促进门脉纤维化： 通过机械转导介导的信号募集巨噬细胞和T细胞。肝 通过增强的HA流的重塑也可能是放大肝纤维化/肝硬化的第二次打击。此外，本发明还 我们假设脾脏是浸润免疫细胞的重要来源。 为了验证这些假设，我们提出了以下三个目标：1）确定的作用， 肝动脉血流在门脉纤维化形成中的作用及血流诱导的门脉纤维化在肝硬化中的意义 肝纤维化/肝硬化的进展，2）确定HA-流量增加引起肝纤维化/肝硬化的机制， 免疫细胞浸润和门脉纤维化，以及3）确定免疫细胞 调节门脉纤维化。

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.