Heme Oxygenase Enzymes/Carbon Monoxide in Hepatic Dysfunction from hemorrhage

描述(申请人提供)：在美国，创伤造成的生产寿命年损失比任何其他疾病都大，估计每年的医疗保健费用为4000亿美元。对于受伤的患者，大出血是平民和军事创伤中潜在可预防的死亡人数最多的原因。在最初的侮辱中幸存下来的患者的死亡通常是由于器官功能障碍和/或脓毒症的发展。因此，了解导致组织损伤的细胞机制以及可在现场早期对这些患者进行护理的治疗辅助设备的开发，具有显著提高发病率和死亡率的巨大潜力。我们的研究集中在了解一氧化碳(CO)在生理和病理生理条件下的作用，以及一氧化碳作为一种治疗手段的发展。一氧化碳是在血红素加氧酶分解血红素的过程中内源性产生的，已被证明具有显著的抗炎特性。外源性一氧化碳可以利用其细胞保护特性，自1999年以来，我们一直在研究吸入一氧化碳作为临床前模型的治疗方法。我们强有力的临床前数据表明，吸入一氧化碳可以预防休克、炎症、器官损伤和出血死亡。重要的是，细胞和组织必须能够调整新陈代谢和细胞内过程，以适应缺乏氧气和其他以休克状态为特征的重要细胞资源。直到最近，我们才认识到HO酶和CO在控制细胞代谢和生物能量学中的作用。我们的实验旨在研究HO信号转导机制(S)以及CO外源性给药对急性大出血和复苏模型的保护机制(S)。我们的研究集中在HO酶和CO在肝脏和肝细胞中的影响，因为肝损伤一直是我们实验室的一个主要研究领域。基于我们已发表的工作和有希望的初步数据，我们假设：血红素加氧酶/一氧化碳可以预防因出血或缺氧而导致的休克/生物能量衰竭。我们将通过以下目标来验证这些假说：具体目标1：确定HO/CO在呼吸调节中的作用和机制(S)，以保护失血性休克所致的器官功能障碍。具体目的II.确定线粒体作为信号细胞器在失血/复苏过程中的保护作用及HO/CO的调节机制。 公共卫生相关性：与美国所有其他疾病相比，创伤导致的生产寿命年损失最大。继发于出血的休克和多器官功能障碍是这些死亡的重要原因；然而，开发有效逆转这一过程的治疗策略是极其困难的。在拟议的研究中，我们将研究一氧化碳吸入的治疗效果以及血红素加氧酶在调节细胞代谢和适应性生物能量信号以限制出血所致肝脏和器官损伤中的作用(S)。

DESCRIPTION (provided by applicant): In the United States, traumatic injury accounts for a greater loss of productive life years than that of any other disease and has an estimated annual healthcare cost of 400 billion dollars per year. For patients that are injured, major bleeding accounts for the largest number of deaths that are potentially preventable both in civilian and military trauma. Mortality in patients that survive the initial insult is often due to the development of organ dysfunction and/or sepsis. Thus, understanding the cellular mechanisms that lead to tissue injury and the development of therapeutic adjuncts that can be instituted in the field early in the care of these patients has tremendous potential to significantly improve morbidity and mortality. 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 produces 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 cytoprotective properties and we have been studying the use of inhaled CO as a therapeutic in pre-clinical models since 1999. Our strong preclinical data demonstrates that inhaled CO can protect against the development of shock, inflammation, organ injury, and death from hemorrhage. Importantly, cells and tissues must be able to adjust metabolism and intracellular processes to accommodate for the lack of oxygen and other vital cellular resources that characterize shock states. Only recently we have recognized a role for HO enzymes and CO in the control of cellular metabolism and bioenergetics. Our experiments are designed to study the mechanism(s) of HO signaling, as well as the protective mechanism(s) of CO when delivered exogenously as a therapeutic in models of acute severe hemorrhage and resuscitation. Our studies concentrate on the influence of HO enzymes and CO within the liver and hepatocytes, as hepatic injury has been a major area of investigation within our laboratory. Based on our published work and promising preliminary data we hypothesize that: Heme Oxygenase Enzymes/Carbon Monoxide protect against the development of shock/bioenergetic failure from hemorrhage or hypoxia. We shall test these hypotheses by addressing the following aims: Specific Aim I: To determine the role and mechanism(s) of HO/CO in the regulation of respiration to protect against organ dysfunction from hemorrhagic shock. Specific Aim II. To determine the protective role of mitochondria as signaling organelles in hemorrhage/resuscitation and the mechanisms of regulation by HO/CO. PUBLIC HEALTH RELEVANCE: Traumatic injury results in the greatest loss of productive life years compared to all other diseases in the United States. The development of shock and multiple organ dysfunction secondary to hemorrhage accounts for a significant portion of these deaths; however, it has been exceedingly difficult to develop treatment strategies that effectively reverse the processes. In the proposed study, we will investigate the therapeutic effect of inhaled carbon monoxide as well as the role(s) of heme oxygenase enzymes in the regulation of cellular metabolism and adaptive bioenergetic signaling to limit hepatic and organ injury from hemorrhage.