ISCHEMIA/REPERFUSION INDUCED CAPILLARY FILTRATION

描述：(改编自申请者摘要)长期 这个项目的目标是确定临床问题是如何 缺血再灌注(I/R)诱导液体滤过 微血管系统，以及这种微血管功能障碍是如何 在存在心血管危险因素的情况下加重 高胆固醇血症。I/R诱导的组织损伤被认为是 中性粒细胞-内皮细胞相互作用和一氧化氮的介导 抑制，以及氧自由基和蛋白水解剂 酵素。这些介质对静脉曲张的影响 内皮功能进展顺利，但关于它们如何影响的知识却很少。 毛细血管内皮细胞，无论是在正常人还是在那些 高胆固醇血症。在拟议的研究中，老鼠将被喂食 正常或高胆固醇饮食，所以这一影响 心血管风险可以在缺血后毛细血管中进行评估。 结扎肠系膜上动脉可造成肠系膜血管缺血。 肠系膜动脉持续时间各不相同。之前和之后 缺血时，将通过闭塞选定的 毛细管和微吸管，并测定液体的过滤速度 (JV/S)从血管内红血球之间的距离递减 闭塞部位上游的细胞。初步实验证明 高胆固醇血症增强I/R诱导的JV/S和中性粒细胞 对此负有主要责任。三个具体目标中的第一个 提出的方案是建立I/R诱导的时间进程 增加合资企业/S，并确定以下程度 高胆固醇血症会改变这种滤过反应。第二 具体目的是确定中性粒细胞的作用模式 参与高胆固醇血症-JV/S以下增加 I/R的可能性包括1)与毛细管直接相互作用 内皮，2)毛细血管后引起的上游传播反应 黏附，3)中性粒细胞衍生产物通过 间质液体，以及4)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 黏附分子、氧化剂、蛋白酶与一氧化氮抑制 包括在中性粒细胞介导的JV/S相关的增加中 脑缺血再灌注后高胆固醇血症的研究 I/R引起的毛细管过滤增强可能有助于发展 降低相关较高死亡率的治疗策略 与缺血性心脏病的危险因素有关。

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.