Vascular Response to Hemmorhage in Portal Hyprtension

描述(申请人提供)：门户的多变表现 高血压每年导致超过10万美国人死亡，而且 不成比例地以少数族裔和女性为目标，因为他们的 对肝病的易感性。失血性休克是最常见的致死原因 患者耐受大出血时门脉高压的并发症 很差。目前的治疗方式实际上可能会加剧潜在的 出血的原因，是由于对其发病机制认识不清。 生理异常。我们的实验室在阐明这些因素方面发挥了重要作用。 对PHT的发展至关重要，包括确定 内脏血流量增加的可能介质(NO、PGI2、血管紧张素 [AngII]、内皮素[ET]，以及在PHT中改变的跨膜信号 是出血后血管反应改变的基础。这项建议旨在 确定机械力之间的关系(增加流量， 压力和压力)，以及内脏血液增加的可能介质 血流量(NO、PGI2、AngII、ET)和出血后异常血管反应 PHT。我们的中心假设是管腔内机械力的变化 (压力和切应力)增加血管扩张的内皮表达 慢性调节升压激素受体跨膜的物质 决定PHT异常的信号和血管结构变化 充血血管对出血和复苏的反应性。我们 将使用PHT合并和不合并肝硬变(胆管结扎)的体内模型 [BDL]和部分门静脉结扎[PVL])和iNOS、eNOS、COX 1、COX-2基因敲除小鼠联合体外灌流模型 跨毛细血管内皮细胞(EC)和血管平滑肌细胞(VSMC) 共培养系统和FlexWork细胞株系统(模拟体内 血管结构和流体、压力和应变的机械力)。我们 将评估机械力对EC一氧化氮合酶的影响 一氧化氮合酶(NOS)和环氧合酶(COX)的表达/活性与VSMC升压激素 血管紧张素转换酶受体(AngII、ET)表达与跨膜信号转导与VSMC 扩散和迁徙。我们将确定：1)内皮细胞的变化 一氧化氮合酶和环氧合酶在流量、压力或应变变化中的表达； 2)VSMC受体和跨膜信号转导的变化 增殖和迁移的改变；3)如果剪切、压力或应变 诱导性改变受肝病的存在或不存在的调节 (肝硬变)；以及4)机械力是否引起EC血管活性的变化 物质表达或VSMC变化导致血管异常反应 出血和休克。总而言之，我们将确定阻碍 门静脉血流及机械力和肝硬变对门静脉血流的影响 对出血和复苏的异常血管反应。这些实验 将为我们理解PHT提供重要的新信息， 并直接导致有效的治疗方案。

DESCRIPTION (Provided by Applicant): The protean manifestations of portal hypertension (PHT) lead to the deaths of over 100,000 Americans each year, and disproportionately target minorities and women due to their greater susceptibility to liver disease. Hemorrhagic shock is the most common lethal complication of portal hypertension where patients tolerate massive hemorrhage poorly. Current treatment modalities may actually aggravate the underlying cause of bleeding, due to the poor understanding of the pathogenesis of the abnormal physiology. Our lab has been instrumental in elucidating the factors critical to the development of PHT, including the identification of the putative mediators of increased splanchnic blood flow (NO, PGI2, angiotensin [ANGII], endothelin [ET), and an altered transmembrane signaling in PHT that underlies the altered vascular response to hemorrhage. This proposal seeks to determine the relationship between the mechanical forces (increased flow, pressure and strain), and the putative mediators of increased splanchnic blood flow (NO, PGI2, ANGII, ET), and the abnormal vascular response to hemorrhage in PHT. Our central hypothesis is that changes in intraluminal mechanical forces (pressure and shear stress) increase endothelial expression of vasodilatory substances that chronically regulate pressor hormone receptor transmembrane signaling and vessel structural changes in PHT that determines the abnormal responsiveness of the hyperemic vasculature to hemorrhage and resuscitation. We will use in vivo models of PHT with and without cirrhosis (bile duct ligated [BDL] and partial portal vein ligated [PVL]) in wild type and iNOS, eNOS, COX 1, COX 2 knockout mice, in conjunction with in vitro models of perfused transcapillary endothelial cell (EC) and vascular smooth muscle cell (VSMC) co-culture system, and the Flexercell Strain System (mimicking the in vivo vascular architecture and mechanical forces of flow, pressure and strain). We will evaluate the effect of mechanical force upon EC nitric oxide synthase (NOS) and cyclooxygenase (COX) expression/activity and VSMC pressor hormone receptor (ANGII, ET) expression and transmembrane signaling and VSMC proliferation and migration. We will determine: 1) changes in endothelial expression of NOS and COX in response to changes in flow, pressure, or strain; 2) changes in VSMC receptor and transmembrane signal transduction as well as alterations in proliferation and migration; 3) if shear, pressure, or strain induced alterations are modulated by the presence or absence of liver disease (cirrhosis); and 4) if mechanical force induced changes in EC vasoactive substance expression or VSMC changes result in abnormal vascular response to hemorrhage and shock. In summary, we will determine the role of obstruction to portal flow and the influence of mechanical forces and cirrhosis upon the abnormal vascular response to hemorrhage and resuscitation. These experiments will provide significant new information central to our understanding of PHT, and lead directly to effective treatment programs.