VASCULAR RESPONSE TO HEMORRHAGE IN PORTAL HYPERTENSION

门静脉高压症(PHT)的多变表现导致 每年有超过10万名美国人死亡， 不成比例地瞄准少数族裔和女性，因为他们的 更容易患上肝病。出血性休克是 门静脉高压症最常见和最致命的并发症 患者对大出血的耐受性很差， 肾功能衰竭和成人呼吸窘迫综合征。当前 治疗方法和方式实际上可能会加剧潜在的 出血的原因。在最初的门静脉阻塞之后 血流，门脉压力的升高是由于 明显的内脏和全身动脉充血 (~高动力循环~)。出血量和出血量 复苏，口腔压力实际上上升到高于 基线，重建持续出血的危险因素。这 提案寻求确定机械设备之间的关系 力量，内脏血流的假定媒介(否， 前列环素、血管紧张素II和内皮素)与异常血管 门静脉高压症对出血的反应。我们的中心假设是 管腔内机械力的变化(剪应力和 腔内压力)增加血管内皮生长因子的表达和/或活性 慢性调节升压激素的血管扩张物质 PHT中的受体跨膜信号最终 确定充血血管系统对 失血性休克和复苏。具体来说，我们假设 机械力导致特定的生理和 PHT血管的解剖学变化包括表达 和内皮抑制鸟嘌呤核苷酸的功能 控制NO产生的调节蛋白(Gipha) 和来自血管内皮细胞的PGI2。我们进一步假设 内源性血管紧张剂引起的血管反应改变 门静脉高压症患者基线和入院时的刺激物(抗原素II、内皮素) 失血性休克后是由于慢性调节或 升压激素受体跨膜信号转导增强 血管扩张剂生产。使用PHT的两种活体模型， 或无肝硬变(部分门静脉结扎(PVL)和胆汁 失血性休克后胆管结扎(BDL) 复苏，结合体外灌流 跨毛细血管内皮细胞与血管平滑肌共培养 系统(模拟体内结构和流量/压力 参数)，我们将确定机械力的作用， 血管活性物质与肝实质功能障碍 血管信号机制促进和/或维持 PHT的血管病变。这些实验将提供 对我们理解门静脉高压症和出血性疾病至关重要的信息 冲击，并应进一步直接导致发展 有效的治疗方案。

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.