Recombinant E-NTPDase for shock

摘要 失血性休克继发的缺血再灌注损伤后炎症反应 美国的重大死亡率和发病率。事发时可使用的静脉输液 现场救治低血容量性休克并不能完全预防缺血再灌注损伤。重新启动 血流引起几种炎症介质的激活，如细胞因子、选择素和其他分子。 迅速动员炎症反应，导致随后的多器官衰竭。建议的目标是 该项目旨在预防或减少复苏后缺血损伤的有害影响 可溶性重组人三磷酸胞外核苷二磷酸水解酶 失血性休克患者的静脉输液。这种方法是基于有充分记录的 E-NTPDase在脑缺血再灌注损伤中的生理学保护作用我们的预赛 数据证实，内源性E-NTPDase CD39和外源性E-NTPDase模拟 Apyrase在公认的固定血压休克小鼠模型中均可预防器官损伤。我们有 合成了一种新的、高效的E-NTPDase，hENTPD3-ECD，我们将测试它在预防 创伤和失血性休克后的器官损伤。这项建议的具体目的是评估 HENTPD3-ECD对失血性休克器官损伤的影响HENTPD3将进行剂量-递增研究- 小鼠在剖腹手术(创伤)和失血性休克的联合损伤下的ECD。这些研究将 HENTPD3-ECD对创伤和出血时器官损伤保护作用的有效剂量 令人震惊。报告的结果将是肺、肠道、肾脏、肝脏和肌肉损伤，以及红细胞损伤和免疫。 功能。这一建议促进了控制和/或减轻缺血/再灌注的新的治疗应用。 休克复苏期间和之后的损伤。

SUMMARY Inflammation after ischemia and reperfusion injury secondary to hemorrhagic shock is responsible for significant mortality and morbidity in the United States. Available intravenous fluids administered at the incident scene to treat hypovolemic shock do not completely prevent ischemia and reperfusion injury. Re-initiation of blood flow causes activation of several inflammatory mediators, such as cytokines, selectins and other molecules that rapidly mobilize the inflammatory response with subsequent multiple organ failure. The goal of the proposed project is to prevent or reduce the deleterious effects of ischemic damage following resuscitation by using a soluble recombinant human ectonucleoside triphosphate diphosphohydrolase (E-NTPDase) in conjunction with intravenous fluids in patients with hemorrhagic shock. The approach is based on the well-documented physiological protective role of E-NTPDases in protecting against ischemia-reperfusion injury. Our preliminary data confirm that the endogenous E-NTPDase CD39 and the exogenously administered E-NTPDase mimic apyrase both prevent organ injury in a well-accepted mouse model of fixed blood pressure shock. We have synthesized a novel, highly potent E-NTPDase, hENTPD3-ECD, which we will test for efficacy in preventing organ injury following trauma and hemorrhagic shock. The specific aim of this proposal is to assess the effect of hENTPD3-ECD on organ injury in hemorrhagic shock. A dose-escalation study will be conducted with hENTPD3- ECD in mice subjected to a combined insult of laparotomy (trauma) and hemorrhagic shock. These studies will establish the effective dose of hENTPD3-ECD in protecting against organ injury in trauma and hemorrhagic shock. Outcomes reported will be lung, gut, kidney, liver, and muscle injury, and red blood cell injury and immune function. This proposal advances new therapeutic applications to control and/or alleviate ischemia/reperfusion injury during and following resuscitation from shock.