VASCULAR RESPONSE TO HEMORRHAGE IN PORTAL HYPERTENSION

门脉高压出血的血管反应

• 批准号: 2905582
• 负责人: JAMES V SITZMANN
• 金额: $ 25.13万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2905582
• 关键词: angiotensin II; bile ducts; biological signal transduction; blood pressure; blood volume; disease /disorder model; endothelin; gene expression; guanine nucleotide binding protein; hemodynamics; hemorrhagic shock; hormone receptor; hormone regulation /control mechanism; injection /infusion; laboratory rat; liver cirrhosis; mesenteric artery; nitric oxide; polymerase chain reaction; portal hypertension; portal vein; prostacyclins; prostaglandin endoperoxide synthase; prostaglandin receptor; radioimmunoassay; resuscitation; tissue /cell culture; vascular endothelium; vasoconstriction; vasodilation

The protean manifestations of portal hypertension (PHT) leads to the death of over 100,000 Americans annually, and disproportionately targets minorities and women due to their greater susceptibility to liver disease. Hermorrhagic shock is the most common and lethal complication of portal hypertension where patients tolerate massive hemorrhage poorly, developing renal failure and adult respiratory distress syndrome. Current treatments and modalities may actually aggravate the underlying cause of the bleeding. Following the initial obstruction to portal blood flow, an elevation in portal pressure is maintained due to a marked splanchnic and systemic arterial hyperemia (~hyperdynamic circulation~). During hemorrhage and volume resuscitation, ortal pressure actually rises to levels higher than baseline, recreating the risk factors for continued bleeding. This proposal seeks to determine the relationship between mechanical forces, the putative mediators of splanchnic blood flow (NO, PGI2, angiotensiin II and endothelin) and the abnormal vasular response to hemorrhage in PHT. Our central hypothesis is that changes in intraluminal mechanical forces (shear stress and intraluminal pressure) increase the expression and/or activity of vasodilator substances which chronically regulate pressor hormone receptor transmembrane signaling in PHT that ultimately determines the responsiveness of the hyperemic vasculature to hemorrhagic shock and resuscitation. Specifically, we hypothesize that mechanical forces induce specific physiological and anatomical alterations in the PHT vessel including the expression and function of endothelial inhibitory guanine nucleotide regulatory proteins (Gialpha) that the control the production of NO and PGI2 from the vascular endothelium. we further hypothesize that the altered vascular response to endogenous vasoconstrictor stimuli (antiogensin II, endothelin) in PHT at baseline and following hemorrhagic shock is due to chronic regulation or pressor hormone receptor transmembrane signaling by increased vasodilator production. Using both in vivo models of PHT, with or without cirrhosis (partial portal vein ligated (PVL) and bile duct-ligated (BDL) following hemmorrhagic shock and resuscitation, in conjunction with an in vitro perfused transcapillary endothelial and vascular smooth muscle co-culture system (which mimics the in vivo architecture and flow/pressure parameters), we will determine the role of mechanical forces, vasoactrive substances, and hepatic parenchymal dysfunction on vascular signal mechanisms that contribute to and/or maintain the vasculopathy of PHT. These experiments will provide information central to our understanding of PHT and hemorrhagic shock, and should further lead directly to the development of effective treatment programs.

门静脉高压症（PHT）的多变表现导致 每年有超过10万美国人死亡， 不成比例地针对少数群体和妇女，因为他们 更易患肝病。 出血性休克是 门静脉高压症最常见且致命的并发症 患者对大出血耐受性差， 肾衰竭和成人呼吸窘迫综合征。 电流 治疗和方式实际上可能会加剧潜在的 因为出血。 在最初的入口阻塞之后 血液流动，门静脉压力的升高是由于 内脏和全身动脉明显充血 （~hyperdynamic circulation~）。 出血和出血量 复苏时，门压实际上上升到高于 基线，重新创建持续出血的风险因素。 这 建议旨在确定机械之间的关系， 力，内脏血流量的假定介质（NO， 血管紧张素II和内皮素）与异常的血管紧张素转换酶（VEGF） 对PHT出血的反应。 我们的核心假设是， 管腔内机械力（剪切应力和 管腔内压力）增加以下的表达和/或活性： 长期调节升压激素的血管扩张物质 受体跨膜信号转导，最终 确定充血脉管系统对 失血性休克和复苏。 具体来说，我们假设 机械力诱导特定的生理和 PHT血管中的解剖学改变，包括表达 内皮抑制鸟嘌呤核苷酸的功能 控制NO产生的调节蛋白（G1 α） 和血管内皮的PGI 2。 我们进一步假设 血管对内源性血管收缩剂的反应改变 刺激（抗原素II，内皮素）在PHT中的基线和 失血性休克后是由于慢性调节或 升压激素受体跨膜信号通过增加 血管扩张剂的产生。 使用体内PHT模型， 或无肝硬化（部分门静脉结扎（PVL）和胆汁 失血性休克后导管结扎（BDL）， 复苏，结合体外灌注 跨毛细血管内皮和血管平滑肌共培养 系统（其模拟体内结构和流量/压力 参数），我们将确定机械力的作用， 血管活性物质和肝实质功能障碍 血管信号机制，有助于和/或维持 PHT血管病变 这些实验将提供 信息中心，我们的理解PHT和出血 冲击，并应进一步直接导致发展 有效的治疗方案。