Hemodynamics and hepatic remodeling

血流动力学和肝脏重塑

• 批准号: 9920142
• 负责人: YASUKO IWAKIRI
• 金额: $ 37.69万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-05 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9920142
• 关键词: Area; Arteries; Biology; Blood Vessels; Blood flow; Buffers; Cells; Cirrhosis; Complication; Data; Defect; Development; Endothelial Cells; Experimental Models; Fibrosis; Goals; Hepatic; Hepatic artery; Immune; Infiltration; KDR gene; Ligands; Ligation; Light; Liver; Liver Cirrhosis; Liver Fibrosis; Mediating; MicroRNAs; Mus; Mutation; Myofibroblast; Operative Surgical Procedures; Organ; Partial Hepatectomy; Pharmacology; Portal Hypertension; Portal vein structure; Rattus; Research; Role; Signal Transduction; Site; Source; Spleen; Splenectomy; Structure; Surgical Models; T-Lymphocyte; Testing; Thrombosis; Transmembrane Domain; Transplantation; Tumor-infiltrating immune cells; Vascular Cell Adhesion Molecule-1; Vasodilation; Venous; arterial remodeling; cadherin 5; chronic liver disease; exosome; hemodynamics; hepatic vein; liver transplantation; macrophage; mechanotransduction; novel; recruit; response

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.

概括 本研究的目的是了解血流动力学变化对肝脏结构和功能的影响。 重点关注门脉高压的功能。门脉高压是慢性肝病的主要并发症 疾病。肝硬化是其最常见的原因，但在非肝硬化情况下也会发生。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舒张的结合。这些变化是如何发生的 对肝脏结构和功能的影响尚不清楚。 我们的初步数据表明，部分门静脉结扎（PPVL；一种门静脉结扎手术模型）的大鼠 高血压）发展为门静脉纤维化。 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 的大鼠也表现出细胞浸润增加 汇管束中的巨噬细胞和 T 细胞。此外，已知血流量增加会导致 动脉壁，由血管周围巨噬细胞和 T 细胞的短暂积累和激活介导。 因此，我们假设门静脉高压症中 HA 流量增加可通过以下方式促进门静脉纤维化： 通过机械转导介导的信号招募巨噬细胞和 T 细胞。肝 通过增强HA流动进行重塑也可能是加剧肝纤维化/肝硬化的第二个打击。更远， 我们假设脾脏是浸润免疫细胞的重要来源。 为了检验这些假设，我们建议检查以下三个目标：1）确定 HA-流在门管纤维化发展中的作用以及流诱导门管纤维化在门管束纤维化中的意义 肝纤维化/肝硬化的进展，2) 确定 HA 流量增加导致的机制 免疫细胞浸润和门静脉纤维化，3) 确定免疫细胞的机制 调节门静脉纤维化。