ENDOTHELIAL INJURY IN TRAUMA AND ISCHEMIA-REPERFUSION

这个项目的主要目标是描述时间的特征 创伤后内皮细胞损伤的过程、严重程度和来源 或冠状血管和内脏血管的缺血+再灌注。 人物塑造将采取生理性、幽默性和 血管内皮细胞完整性的形态学评估。生理学 评估将侧重于EDRF依赖和非EDRF依赖的血管扩张剂 个人资料；体液评估将与确定 二十烷类化合物的产生(例如，前列环素释放)；以及形态 评估将集中在传输和扫描电子 内皮细胞显微镜。的三个实验设置 有待研究的潜在内皮损伤包括(A)心肌缺血+ 再灌注，(B)内脏缺血+再灌注，以及(C)创伤性 令人震惊。体外发现(例如，分离的血管环制剂 将与在体内进行的研究相关联。 完好无损的动物。我们将特别注意准确的时间 所有模型再灌流后血管内皮细胞损伤的过程。 此外，还将进行研究，以确定氧气的作用 使用适当的衍生自由基(例如，超氧化物、羟基离子) 自由基清除剂，以及其他自由基清除剂的作用 内皮损伤，包括细胞因子(例如，肿瘤坏死因子α)和粘附性 蛋白质和随后的脂质过氧化分析 氧自由基的作用。合适的封闭剂 包括人超氧化物歧化酶(h-SOD)对超氧离子的保护作用 (例如N-2-硫代甘氨酸)，对抗羟基离子， 转化生长因子(TGF-β)对细胞因子的作用 肿瘤坏死因子α和抗整合素的表达 (RI5.7)针对LFA-1的共同亚基(CD/18) 黏附蛋白异源二聚体家族，作用于中性粒细胞和 内皮细胞黏附蛋白。此外，我们还将研究 中性粒细胞与血管内皮细胞相互作用的研究 心脏和分离的冠状动脉和肠系膜动脉环存在 通过检测髓过氧化物酶，一种特异的 中性粒细胞标志物在完整动物脑缺血和再灌注后的变化 再灌流。这些发现应该会提供关于 心肌缺血、肠缺血和创伤的病理生理学 休克，并应开辟治疗这些潜在的新方法 致命的循环系统疾病。

The primary objective of this project is to characterize the time course, severity and source of endothelial cell Injury following trauma or ischemia + reperfusion of the coronary and splanchnic vasculatures. Characterization will take the form of physiological, humoral and morphological assessment of endothelial integrity. The physiological assessment will focus on EDRF-dependent and EDRF-independent vasodilator profiles; the humoral evaluation will be related to determining eicosanoid production (e.g., prostacyclin release); and the morphological assessment will concentrate on transmission and scanning electron microscopy of endothelial cells. The three experimental settings of potential endothelial injury to be studied are (a) myocardial ischemia + reperfusion, (b) splanchnic ischemia + reperfusion, and (c) traumatic shock. In vitro findings (e.g., vascular ring preparations, isolated perfused organs) will be correlated with in vivo studies performed in the intact animal. Particular attention will be paid to the precise time course of endothelial injury following reperfusion in all models. Moreover, studies will be conducted to determine the role of oxygen derived free radicals (e.g., superoxide, hydroxyl ions) using appropriate free radical scavengers, as well as the role of other mediators of endothelial injury including cytokines (e.g., TNFalpha) and adhesive proteins and analysis of subsequent lipid peroxidation resulting from the action of oxygen derived free radicals. Appropriate blocking agents including human superoxide dismutase (h-SOD) against superoxide ions (e.g., N-2-mercaptoproprionyl glycine), against hydroxyl ions, Transforming Growth Factor (TGF-beta) against cytokines especially TNFalpha and against the expression of integrins, the monoclonal antibody (RI5.7) directed against the common subunit (CD/18) of the LFA-1 heterodimer family of adhesive proteins, acting against neutrophil and endothelial adhesive proteins. Additionally, we will study the interaction of neutrophils with the endothelium by studying perfused hearts and isolated coronary and mesenteric artery rings in the presence and absence of neutrophils and by measuring myeloperoxidase, a specific neutrophil marker in intact animals subjected to ischemia and reperfusion. These findings should provide valuable basic information on the pathophysiology of myocardial ischemia, bowel ischemia, and traumatic shock, and should open up new therapeutic approaches to these potentially lethal circulatory disorders.