REGULATION OF SINUSOIDAL PERFUSION IN SHOCK

描述（来自申请人摘要的逐字描述） 肝脏微循环的反应是肝脏微循环的主要决定因素。 氧化或炎症应激反应。这种血管反应是 主要由应激相关的血管调节基因的诱导介导： 内皮素、内皮素受体和一氧化氮合酶（NOS）。的 本提案的长期目标是阐明 改变的血管反应调节临床相关的肝损伤后， 内毒素血症和败血症等应激。短期目标是测试 假设肝血管对内毒素或脓毒症的反应 是由内皮素B受体的上调和 这些受体与一氧化氮合酶。为了验证这一假设，四 具体目标是：1。定义内皮素的相对贡献 受体亚型在应激后微血管反应中的作用这一目标将 使用一系列特异性内皮素激动剂和拮抗剂， 内皮素受体亚型对生理性 答复2.确定改变的表达的细胞类型分布 内皮素、内皮素受体和NOS亚型。 这一目的将阐明特定的细胞类型（内皮细胞，枯否细胞， 细胞、星状细胞、肝细胞和中性粒细胞）表达特异性 内皮素受体此外，表达的腺泡分布在 将确定具体的细胞类型。3.检验假设， eNOS的调节有助于对内皮素的高反应性。 这一目标将首先表征eNOS在人乳腺癌中的表达和活性。 特定的细胞类型和腺泡位置，然后测试生理反应 过度表达（使用辛伐他汀或腺病毒基因转移）或 缺失（使用具有靶向突变的小鼠），以确定NOS在 调节内毒素或脓毒症后内皮素敏感性。4.测试是否 操纵特异性肝血管应激的表达或作用 蛋白质导致O2供应和 需求和肝细胞损伤。这一目的将评估生理 缩张平衡关系的意义 其特征在于目标1-3。这将使用新的方法来实现 在上一个资助期内开发，以量化空间分布 氧输送和代谢反应在肝脏中的高分辨率， vivo.

DESCRIPTION (Verbatim from the applicant's abstract) Alterations in vascular response of the liver microcirculation is a major determinant of the liver's response to oxidative or inflammatory stress. This vascular response is mediated largely by the induction of the stress-related vasoregulatory genes: the endothelins and endothelin receptors and nitric oxide synthase (NOS). The long term objective of this proposal is to elucidate the mechanisms by which altered vascular responses modulate hepatic injury after clinically relevant stresses such as endotoxemia and sepsis. The short term objective is to test the hypothesis that that the hepatic vascular response to endotoxin or sepsis is mediated by upregulation of endothelin B receptors and the interaction of these receptors with nitric oxide synthase. To test this hypothesis, four specific aims are proposed: 1. Define the relative contribution of endothelin receptor subtypes in the microvascular response following stress. This aim will use a series of specific endothelin agonists and antagonists to dissect out the specific contributions of endothelin receptor subtypes to the physiologic response 2. Determine cell-type distribution of altered expression of endothelins, endothelin receptors and NOS isoforms following stress conditions. This aim will elucidate the specific cell types (endothelial cell, Kupffer cell, stellate cell, hepatocyte and neutrophil) that express specific endothelin receptors. Additionally, the acinar distribution of expression in specific cell types will be determined. 3. Test the hypothesis that altered regulation of eNOS contributes to the hyperse aboutzsitivity to endothelins. This aim will first characterize the expression and activity of eNOS in specific cell types and acinar locations and then test the physiologic response to either over expression (using simvastatin or adenovirus gene transfer) or deletion (using mice with targeted mutations) to determine the role of NOS in modulating endothelin sensitivity follow endotoxin or sepsis. 4. Test whether manipulation of the expression or action of specific hepatic vascular stress proteins results in disruption of microregional balance between O2 supply and demand and hepatocellular injury. This aim will evaluate the physiologic significance of the relationships among the constrictor / dilator balance characterized in aims 1-3. This will be accomplished using novel methodologies developed in the previous funding period to quantify the spatial distribution of oxygen delivery and metabolic response in the liver with high resolution in vivo.