Recombinant E-NTPDase for shock

SUMMARYInflammation 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.