ISCHEMIA/REPERFUSION INDUCED CAPILLARY FILTRATION

描述：（改编自申请人的摘要） 本项目的目的是确定如何临床问题， 缺血-再灌注（I/R）诱导液体从 微血管，以及这种微血管功能障碍是如何 在存在心血管风险因素的情况下恶化 高胆固醇血症 I/R诱导的组织损伤被认为是 由嗜酸性粒细胞-内皮细胞相互作用和一氧化氮介导 抑制，并通过试剂，如氧自由基和蛋白水解 内切酶 探讨这些介质对微静脉的作用 内皮细胞正在进行中，但关于它们如何影响 毛细血管内皮，无论是在正常人或那些 高胆固醇血症 在拟议的研究中，大鼠将被喂食 正常或高胆固醇饮食，因此， 可以在缺血后毛细血管中评估心血管风险。 结扎肠系膜上上级血管可造成肠系膜血管缺血 肠系膜动脉持续不同时间。 之前和之后 在缺血时，将通过阻塞选择的 毛细管与微量移液器，并确定流体过滤速率 (Jv/S）从血管内红血 闭塞部位上游的细胞。初步实验表明， 高胆固醇血症增强I/R诱导的Jv/S， 主要负责。 三个具体目标中的第一个 建议的项目是建立I/R诱导的时间过程 增加Jv/S，并确定 高胆固醇血症改变了这种过滤反应。 第二 具体目的是确定中性粒细胞的作用方式， 参与高胆固醇血症增强的Jv/S增加， I/R。 可能包括1）与毛细管直接相互作用 2）由于毛细血管后的上游传播反应 粘附，3）嗜中性粒细胞衍生的产物通过 间质液，和4）嗜中性粒细胞衍生产物的再循环 通过血液循环 第三个具体目标是确定是否 粘附分子、氧化剂、蛋白酶和一氧化氮抑制 包括在嗜中性粒细胞介导的Jv/S增加中， I/R后高胆固醇血症。 确定调解人 I/R引起的毛细血管滤过增强可能有助于发展 治疗策略，以降低相关的高死亡率 缺血性心脏病的危险因素。

DESCRIPTION: (Adapted from the Applicant's Abstract) The long-term objective of this project is to determine how the clinical problem of ischemia-reperfusion (I/R) induces fluid filtration from the microvasculature, and also how such microvascular dysfunction is exacerbated in the presence of the cardiovascular risk factor hypercholesterolemia. I/R-induced tissue injury is thought to be mediated by neutrophil-endothelial cell interactions and nitric oxide suppression, and by agents such as oxygen radicals and proteolytic enzymes. Investigation on the effects of these mediators on the venular endothelium is well underway, but knowledge is scarce on how they affect capillary endothelium, either in normal individuals or those with hypercholesterolemia. In the proposed studies, rats will be fed either a normal or high cholesterol diet, so that the effect of this cardiovascular risk can be evaluated in postischemic capillaries. Ischemia of mesenteric vessels will be produced by ligating the superior mesenteric artery for various durations. Prior to and following ischemia, measurements of filtration will be made by occluding a selected capillary with a micropipette, and determining the fluid filtration rate (Jv/S) from the decreasing distance between intravascular red blood cells upstream of the occlusion site. Preliminary experiments demonstrate that hypercholesterolemia enhances I/R-induced Jv/S and that neutrophils are primarily responsible. The first of three specific aims of the proposed project is to establish the time course of I/R-induced increases in Jv/S and to determine the extent to which hypercholesterolemia modifies this filtration response. The second specific aim is to determine the mode of action whereby neutrophils are involved in hypercholesterolemia-enhanced increases in Jv/S following I/R. Possibilities include 1) direct interaction with the capillary endothelium, 2) an upstream propagated response due to postcapillary adhesion, 3) diffusion of neutrophil-derived products through interstitial fluid, and 4) recirculation of neutrophil-derived products through the bloodstream. The third specific aim is to determine whether adhesion molecules, oxidants, proteases, and nitric oxide suppression are included in the neutrophil-mediated increase in Jv/S associated with hypercholesterolemia following I/R. Identification of the mediators of the enhanced capillary filtration elicited by I/R may help in developing therapeutic strategies to reduce the higher mortality rates associated with risk factors of ischemic heart disease.