Carbon Monoxide Therapy to Prevent Circulatory Collapse and Shock From Hemorrhage

摘要 背景创伤性损伤造成了极低的发病率和死亡率，其中大部分是继发于出血。对于受伤的病人来说，大出血是军事和平民创伤中可能预防的最大死亡人数。因此，在这些平民和现役士兵的早期护理中，可以在现场制定的标准护理和复苏的发展有可能显着改善结果。 我们的调查集中在了解一氧化碳（CO）在生理和病理生理条件下的作用，以及CO作为治疗药物的发展。一氧化碳是血红素加氧酶分解血红素时内源性产生的，具有显著的抗炎作用。外源性一氧化碳可以利用其细胞保护特性，我们一直在研究使用吸入性一氧化碳作为临床前模型的治疗， 1999.为了开发一种用于治疗创伤受害者的救生复苏辅助剂/生物制剂，我们提出了以下假设： 一氧化碳可防止休克、循环衰竭和出血/创伤导致的死亡。 本申请的目的是研究在临床前模型中使用CO作为治疗剂和复苏辅助剂治疗失血性休克。我们强有力的临床前初步数据表明，吸入CO可以防止休克、炎症、器官损伤和出血死亡的发展，并且已经进行了初步研究，说明吸入CO的可行性。 人类的管理。 具体目标确定CO的最佳给药方案/制备，以防止小鼠模型中因出血和创伤而发生休克和循环衰竭。 二、具体目标探讨血红素氧合酶/一氧化碳对失血性休克和循环衰竭的保护作用及其机制。 研究设计：为了研究一氧化碳对失血性休克和死亡的影响，我们将利用一个完善的小鼠出血模型。该模型将允许彻底研究用于治疗出血的CO的剂量和动力学。吸入CO（25-500 ppm）或药理学CO释放分子将在与战伤患者护理相关的时间点开始作为治疗。所有适当的对照组（包括假手术动物）将纳入所有研究。终点将 检查，包括循环衰竭和死亡的发展时间，以及休克的临床测量，如pH值，碱缺乏，乳酸和凝血研究。此外，将采集组织和血清，用于确定器官损伤和炎症。此外，将研究CO和血红素加氧酶对内皮损伤的影响。这些研究将利用小鼠体内 失血性休克模型以及体外内皮细胞缺氧和炎症刺激模型。研究将集中于内皮激活。将进行CO作用机制的研究，重点是促分裂原活化蛋白激酶。 总之，这些研究将进一步加深我们对失血性休克的理解，并在开发可能的治疗辅助手段以改善退伍军人、现役士兵和所有平民的生活结果方面具有巨大潜力。

Abstract Background. Traumatic injury accounts for an abysmal amount morbidity and mortality, much of which is secondary to hemorrhage. For patients that are injured, major bleeding accounts for the largest number of deaths that are potentially preventable both in military and civilian trauma. Thus, the development of adjuncts to standard care and resuscitation that can be instituted in the field early in the care of these civilians and active duty soldiers has the potential to significantly improve outcomes. Our investigations have focused on the understanding of the role of carbon monoxide (CO) in physiological and pathophysiological conditions, as well as the development of CO as a therapeutic. CO is produced endogenously in the breakdown of heme by heme oxygenase enzymes and has been shown to possess significant anti-inflammatory properties. Exogenous CO can be harnessed for its cytoprotectiveproperties and we have been studying the use of inhaled CO as a therapeutic in pre-clinical models since 1999. In an effort to develop a life-saving resuscitation adjunct/biologic for the treatment of trauma victims we have developed the following hypothesis: Carbon Monoxide protects against the development of shock, circulatory failure and death from hemorrhage/trauma. The goal of this application is to study the use of CO as a therapeutic agent and resuscitative adjunct in the treatment of hemorrhagic shock in pre-clinical models. Our strong preclinical preliminary data demonstrates that inhaled CO can protect against the development of shock, inflammation, organ injury, and death from hemorrhage and preliminary studies have been performed illustrating the feasibility of inhaled CO administration in humans. SPECIFIC OBJECTIVE I. To determine the optimum dosing regimen/preparation of CO to protect against the development of shock and circulatory collapse from hemorrhage and trauma in a mouse model. SPECIFIC OBJECTIVE II. To determine the role and mechanism(s) of heme oxygenase/carbon monoxide in protecting against endothelial injury and the development shock and circulatory collapse from hemorrhage. Study Design: In order to study the influence of CO on hemorrhage-induced shock, and death, we will utilize a well-established murine model of hemorrhage. This model will allow thorough investigation of dosing and kinetics of CO for the treatment of hemorrhage. Inhaled CO (25-500 ppm) or pharmacological COreleasing molecules will be initiated as a therapy at time points relevant to the care of patients with combat injuries. All appropriate controls including sham animals will be included in all investigations. Endpoints will be examined, including time to the development of circulatory collapse and death, as well as clinical measurements of shock such as pH, base deficit, lactate, and coagulation studies. Furthermore, tissues and serum will be collected for determination of organ injury and inflammation. Additionally, the influence of CO and heme oxygenase enzymes on endothelial injury will be investigated. These studies will utilize the murine in vivo model of hemorrhagic shock as well as an in vitro model of hypoxia and inflammatory stimulation in endothelialcells. Investigations will focus on endothelial activation. Studies investigating the mechanisms of action of CO will be executed, focusing on mitogen activated protein kinases. Together, these studies will further our understanding of hemorrhagic shock and have great potential in the development of a possible therapeutic adjunct to improve outcomes of the lives of veterans, active duty soldiers and all civilians.