A Novel Resuscitation for Hemorrhagic Shock: AM/AMBP-1

描述（由申请人提供）： 创伤每年导致大约150，000人死亡，并且是美国1至44岁人群的主要死亡原因。由此造成的生产生命年损失超过任何其他疾病，估计每年的社会成本超过4 500亿美元。大多数创伤死亡是由于失血过多造成的组织灌注不足。创伤受害者的临床管理目前依赖于大量和快速的液体输注，大量的这种受害者往往没有反应。因此，迫切需要制定有效的策略来复苏严重创伤性失血。仅在美国，出血治疗的市场潜力估计为> 100亿美元/年。我们最近发现，大鼠出血后血管对肾上腺髓质素（AM）（一种最近发现的有效血管活性肽）的反应性降低，其新型结合蛋白（即，AMBP-1）。大鼠AM联合AMBP-1治疗可减少出血和大容量复苏后的组织损伤和炎症反应，表明AM/AMBP-1可能是人类创伤的有益治疗方法。阻碍AM/AMBP-1作为出血性休克治疗剂的一个障碍是大鼠蛋白在人体中的潜在免疫原性。然而，人AM加人AMBP-1是否也是有益的，以及如果是有益的，它们与减少的复苏液体积一起施用是否降低出血后的死亡率，仍然是未知的。因此，我们假设，即使在低容量复苏的情况下，给予人AM/AMBP-1也能改善严重失血后的存活率。因此，本项目的主要目的是证明进一步开发人AM/AMBP-1作为一种新型治疗剂的可行性，以减少大鼠出血模型中创伤诱导的器官损伤、炎症和死亡率。这些研究为进一步开发AM/AMBP-1作为治疗失血性休克的有效方法提供了可行性信息。我们的最终目标（阶段IISBIR及以后）是开发人AM/AMBP-1的商业利用，作为严重失血的创伤受害者的安全有效的复苏方法，特别是用于在遥远的战场环境中的战斗伤员护理。

DESCRIPTION (provided by applicant): Trauma causes approximately 150,000 deaths per year, and is the leading cause of death in the population between ages 1 to 44 in the United States. The resulting loss of productive life years exceeds that of any other disease, with estimated societal costs of >$450 billion annually. Most trauma deaths result from insufficient tissue perfusion due to excessive blood loss. Clinical management of trauma victims currently relies on massive and rapid infusion of fluids, to which a large number of such victims often do not respond. The development of effective strategies for resuscitation of severe traumatic blood loss therefore is critically needed. The market potential for hemorrhage treatment is estimated at >$10 billion/year in the US alone. We have recently discovered that vascular responsiveness to adrenomedullin (AM), a recently-discovered potent vasoactive peptide, decreases after hemorrhage in rats, which is markedly improved by its novel binding protein (i.e., AMBP-1). Treatment with rat AM plus AMBP-1 reduces tissue injury and inflammatory responses after hemorrhage and large volume resuscitation, suggesting that AM/AMBP-1 may be a beneficial treatment approach in human trauma. One obstacle hampering development of AM/AMBP-1 as a therapeutic agent for hemorrhagic shock is the potential immunogenicity of rat proteins in humans. It remains unknown, however, whether human AM plus human AMBP-1 is also beneficial and, if so, whether their administration with the reduced resuscitation fluid volume decreases mortality after hemorrhage. We therefore hypothesize that administration of human AM/AMBP-1, even with low volume resuscitation, improves survival after severe blood loss. The primary objective of this project, therefore, is to demonstrate the feasibility of further development of human AM/AMBP-1 as a novel therapeutic agent to reduce hemorrhage-induced organ injury, inflammation, and mortality in a rat model of hemorrhage. The proposed studies should provide useful feasibility information for further developing AM/AMBP-1 as an effective therapy for the treatment of hemorrhagic shock. Our ultimate goal (Phase IISBIR and beyond) is to develop the commercial utilization of human AM/AMBP-1 as a safe and effective resuscitation approach for the trauma victim with severe blood loss, especially for the use in combat casualty care at the far-forward battlefield setting.