REGULATION OF SINUSOIDAL PERFUSION IN SHOCK

描述(逐字摘自申请人的摘要)血管改变 肝脏微循环的反应是肝脏的一个主要决定因素 对氧化或炎症应激的反应。这种血管反应是 主要由应激相关血管调节基因的诱导所介导： 内皮素及其受体和一氧化氮合酶(NOS)。这个 这项提议的长期目标是阐明通过什么机制 临床相关后血管反应改变对肝损伤的调节作用 应激，如内毒素血症和败血症。短期目标是测试 假设肝血管对内毒素或脓毒症的反应 是通过上调内皮素B受体和相互作用介导的 这些受体与一氧化氮合酶有关。为了检验这一假设，有四个 提出了具体的目标：1.确定内皮素的相对贡献 应激后微血管反应中的受体亚型。这一目标将 使用一系列特异的内皮素激动剂和拮抗剂来解剖 内皮素受体亚型对生理学的特殊贡献 回答2.确定改变的表达的细胞类型分布 应激条件下的内皮素、内皮素受体和一氧化氮合酶亚型。 这一目标将阐明特定的细胞类型(内皮细胞、库普弗细胞 细胞、星状细胞、肝细胞和中性粒细胞) 内皮素受体。此外，腺泡状细胞的表达分布 具体的细胞类型将被确定。3.测试更改后的假设 内皮型一氧化氮合酶(ENOS)的调节参与了内皮素活性的升高。 这一目标将首先表征eNOS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)以确定一氧化氮合酶在 内毒素或脓毒症后调节内皮素敏感性。4.测试是否 特异性肝血管应激的表达或作用的调控 蛋白质导致氧气供应和氧气供应之间的微区域平衡中断 需求与肝细胞损伤。这一目的将评估生理 收缩/扩张平衡关系的意义 以目标1-3为特征。这将使用新的方法来实现 在上一次筹资期间开发，以量化空间分布 肝脏中氧输送和代谢反应的高分辨率 活着。

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.