Soluble E-NTPDase for sepsis

摘要 脓毒症是一种由感染引起的压倒性全身炎症反应引起的内科疾病。 尽管潜在的感染现在可以用抗生素有效地治疗，但还没有有效的治疗方法。 控制宿主炎症反应引起的器官损伤。因此，败血症是 它是重症监护病房死亡的主要原因，也是美国第十大主要死亡原因。这个 胞外核苷三磷酸二磷酸水解酶(E-NTPDase)CD39是一种细胞表面相关的抗磷脂酶 炎性酶。它有多种抗炎作用，包括降解内源性 促炎症分子三磷酸腺苷与抗炎物质的产生 腺苷剂。我们发现，内源性CD39可以保护小鼠免受多菌败血症的侵袭。 导致死亡、器官损伤和炎症。同样，注射可溶性E-NTPDase/CD39模拟 (Apyrase)具有保护性。基于这些结果，我们建议外源给予可溶性E-NTPDase作为 一种新的有效的脓毒症治疗方法。然而，apyrase，一种模拟植物起源的E-NTPDase/CD39，很可能 在人体内引发危险的抗体反应，阻止其用作败血症的治疗剂 病人。为了克服这个问题，在目前的提案中，我们将评估优化的人类的效果 重组可溶性E-NTPDase(APT102)与脓毒症的关系我们的假设是APT102会降低死亡率， 败血症时的器官损伤和炎症。为了解决这一假设，我们提出了两个具体目标。具体而言 目的1、检测APT102预防盲肠多菌败血症死亡率的效果。 小鼠结扎和穿刺法。在具体目标2中，我们将描述APT102对器官损伤和 脓毒症中的炎症。我们预计APT102将减少脓毒症的死亡率、器官损伤和炎症。 老鼠。这项研究的长期目标是开发APT102作为一种安全有效的治疗方案 脓毒症患者的处理。

SUMMARY Sepsis is a medical condition caused by an overwhelming systemic inflammatory response to infection. Although the underlying infection can now be efficiently treated with antibiotics, there are no effective therapies to control the organ damage caused by the inflammatory response of the host. As a result, sepsis is the leading cause of mortality in intensive care units and is the tenth leading cause of death overall in the US. The ectonucleoside triphosphate diphosphohydrolase (E-NTPDase) CD39 is a cell surface-associated anti- inflammatory enzyme. It has multiple anti-inflammatory actions, which include degradation of the endogenous proinflammatory molecule adenosine triphosphate and triggering of the production of the anti-inflammatory agent adenosine. We have discovered that endogenous CD39 protects mice against polymicrobial sepsis- induced mortality, organ damage, and inflammation. Similarly, injecting a soluble E-NTPDase/CD39 mimic (apyrase) is protective. Based on these results, we propose exogenously administered soluble E-NTPDase as a novel and effective therapy for sepsis. However, apyrase, an E-NTPDase/CD39 mimic of plant origin, is likely to provoke a hazardous antibody response in humans preventing its use as a therapeutic agent for septic patients. To overcome this problem, in the current proposal we will evaluate the effect of an optimized human recombinant soluble E-NTPDase (APT102) in sepsis. Our hypothesis is that APT102 would reduce mortality, organ injury, and inflammation in sepsis. To address this hypothesis, we propose two Specific Aims. In Specific Aim 1, we will test the efficacy of APT102 in preventing mortality in polymicrobial sepsis induced by cecal ligation and puncture in mice. In Specific Aim 2, we will delineate the effect of APT102 on organ injury and inflammation in sepsis. We expect that APT102 will reduce mortality, organ injury, and inflammation in septic mice. The long-term goal of this study is to develop APT102 as a safe and effective treatment option for the management of patients with sepsis.