Heme Oxygenase Enzymes/Carbon Monoxide in Hepatic Dysfunction from hemorrhage

血红素加氧酶/一氧化碳在出血性肝功能障碍中的作用

• 批准号: 8308578
• 负责人: Brian Scott Zuckerbraun
• 金额: $ 29.25万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8308578
• 关键词: Accounting; Acute; Address; Anti-Inflammatory Agents; Anti-inflammatory; Apoptotic; Area; Bioenergetics; Biogenesis; Brain Hypoxia-Ischemia; Breathing; Carbon Monoxide; Cell Hypoxia; Cell Respiration; Cells; Cessation of life; Chronic; Data; Development; Disease; Endotoxemia; Enzymes; Failure; Functional disorder; Gene Transfer; Genes; HMGB1 Protein; Health; Health Care Costs; Heme; Hemorrhage; Hemorrhagic Shock; Hepatic; Hepatocyte; Homeostasis; Human; Hypoxia; Immune response; Immunity; In Vitro; Infection; Inflammation; Inflammatory Response; Injury; Institutes; Investigation; Ischemia; Laboratories; Lead; Life; Liver; Maintenance; Metabolic; Metabolism; Military Personnel; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Nitric Oxide Synthase; Organ; Organelles; Oxidative Phosphorylation; Oxygen; Oxygenases; Patient Care; Patients; Physiological; Pre-Clinical Model; Predisposition; Process; Property; Proteins; Publishing; Reactive Oxygen Species; Regulation; Reperfusion Therapy; Resources; Resuscitation; Rodent; Role; Secondary to; Sepsis; Shock; Signal Pathway; Signal Transduction; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Tissues; Trauma; Tumor Necrosis Factor-alpha; United States; Work; base; cell growth regulation; design; hepatic necrosis; improved; in vivo; injured; mortality; novel therapeutics; pre-clinical; preclinical study; prevent; public health relevance; research study; respiration regulation; response; response to injury; therapeutic development; treatment strategy

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.

描述（由申请人提供）：在美国，与任何其他疾病相比，创伤性损伤造成的生产寿命年损失更大，并且每年的医疗费用估计为 4000 亿美元。对于受伤的患者来说，大出血造成的死亡人数最多，而无论是平民还是军事创伤，这些死亡都是可以避免的。在最初的损伤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，并开发可以在这些患者护理早期现场使用的治疗辅助剂，具有显着改善发病率和死亡率的巨大潜力。 我们的研究重点是了解一氧化碳 (CO) 在生理和病理生理条件下的作用，以及 CO 作为治疗剂的开发。 CO 是血红素加氧酶分解血红素时内源性产生的，并已被证明具有显着的抗炎特性。可以利用外源 CO 的细胞保护特性，自 1999 年以来，我们一直在研究使用吸入 CO 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 CO 可以防止休克、炎症、器官损伤和出血死亡的发生。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，以适应缺氧和其他表征休克状态的重要细胞资源的情况。直到最近，我们才认识到 H2O 酶和 CO 在控制细胞代谢和生物能学中的作用。我们的实验旨在研究 HO 信号传导机制，以及在急性严重出血和复苏模型中作为治疗剂外源递送 CO 时的保护机制。我们的研究集中在肝脏和肝细胞内 H2O 酶和 CO 的影响，因为肝损伤一直是我们实验室研究的主要领域。根据我们发表的工作和有希望的初步数据，我们假设：血红素加氧酶/一氧化碳可以防止因出血或缺氧而发生休克/生物能衰竭。我们将通过实现以下目标来检验这些假设： 具体目标 I：确定 H2O2/CO2 在呼吸调节中的作用和机制，以防止失血性休克引起的器官功能障碍。具体目标二。确定线粒体作为信号细胞器在出血/复苏中的保护作用以及 H2O/CO 的调节机制。 公共卫生相关性：在美国，与所有其他疾病相比，外伤导致的生产力寿命损失最大。这些死亡中很大一部分是由出血引起的休克和多器官功能障碍所致；然而，制定有效逆转这一过程的治疗策略极其困难。在拟议的研究中，我们将研究吸入一氧化碳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传导以限制出血引起的肝脏和器官损伤中的作用。