Carbon Monoxide to Prevent Circulatory Collapse

一氧化碳防止循环衰竭

• 批准号: 6872969
• 负责人: LEO E OTTERBEIN
• 金额: $ 42.5万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6872969
• 关键词: blood circulation; carbon monoxide; cardiovascular disorder prevention; cytokine; free radical oxygen; hemorrhagic shock; high performance liquid chromatography; hypovolemia; hypoxia; laboratory mouse; laboratory rat; nitric oxide; oximetry; oxygen transport; ultrasound blood flow measurement; vascular endothelium; vasodilation

DESCRIPTION (provided by applicant): Severe hemorrhage as a result of traumatic injury is major cause of death in the United Stated. Because death from severe blood loss often occurs 'in the field' or within 4 hours of injury, early intervention and therapeutics that can delay or prevent the progression to irreversible hemorrhagic shock need to be elucidated. The insult from severe hemorrhage is a multifactorial global injury involving ischemia/reperfusion with inflammatory and autonomic dysfunction, which can result in microvascular dysfunction and circulatory collapse. The cellular and molecular responses to such an insult involve increased expression of antioxidant enzymes and stress response genes, including the stress-inducible gene heme oxygenase-1 (HO-1). HO-1 catalyzes the first and rate-limiting step in the catabolism of heme to yield equimolar quantities of biliverdin IXa, carbon monoxide (CO), and iron. Our laboratories and others have demonstrated that the induction of HO-1 provides cytoprotection both in vivo and in vitro against multiple modes of injury including endotoxemia, ischemia/reperfusion, and hemorrhage. Recent studies have illustrated that production of CO can mediate the cytoprotection seen with induction of HO-1. Bypassing the need to increase expression of HO-1, delivery of exogenous CO can also be cytoprotective. Our preliminary data in a murine model of hemorrhagic shock demonstrates that delivery of low dose inhaled CO can protect against the development of endorgan injury, decreases serum levels of inflammatory cytokines and increases serum levels of the anti-inflammatory cytokine IL-10. Additionally, we demonstrate that inhaled CO can decrease tissue hypoxia during hemorrhage. Further preliminary data suggests that these effects may be secondary to maintenance and regulation of the microcirculation as well as by protecting against multiple modes of cell death. CO, either by inhalation or controlled pharmacological release, represents a novel and feasible therapy that could be instituted rapidly and with ease as an out-of-hospital adjunct for severe blood loss and trauma. We hypothesize that carbon monoxide can protect against the onset of hypovolemic circulatory collapse and the development of irreversible hemorrhagic shock. Furthermore, that this protection is the result of the ability of CO to regulate and preserve microcirculatory blood flow and tissue perfusion by preventing endothelial cell activation and cell death. We shall test these hypotheses by addressing the following aims: Specific Aim #l: To demonstrate that CO confers protection against the development of shock and circulatory collapse. Specific Aim #2: To test whether the protective effects of CO on shock and tissue hypoxia involve maintenance and/or regulation of the endothelium and microcirculation.

描述（由申请人提供）：造成创伤的严重出血是曼联所说的主要死亡原因。由于严重失血导致的死亡经常发生“野外”或受伤后4小时内发生，因此需要阐明可能延迟或防止不可逆性出血性休克的早期干预和治疗剂。严重出血的侮辱是一种多因素的全球损伤，涉及炎症和自主功能障碍的缺血/再灌注，这可能导致微血管功能障碍和循环崩溃。细胞和分子对这种侮辱的反应涉及抗氧化酶的表达增加，应激反应基因，包括 应力诱导基因血红素氧酶-1（HO-1）。 HO-1催化血红素分解代谢中的第一个和限速步骤，以产生等摩尔量的biliverdin IXA，一氧化碳（CO）和铁。我们的实验室和其他实验室已经证明，HO-1的诱导在体内和体外都可以针对多种损伤模式提供细胞保护作用，包括内毒素血症，缺血/再灌注和出血。最近的研究表明，CO的产生可以通过诱导HO-1介导细胞保护作用。绕过增加HO-1表达的需求，外源性CO的递送也可以具有细胞保护作用。我们在出血性休克的鼠模型中我们的初步数据表明，低剂量吸入CO的递送可以预防内龙损伤的发展，降低炎症细胞因子的血清水平，并增加抗炎的血清水平 细胞因子IL-10。此外，我们证明吸入CO可以减少出血期间组织缺氧。 进一步的初步数据表明，这些影响可能是微循环的维持和调节以及通过保护多种细胞死亡模式的继发。 CO是通过吸入或受控的药理学释放，代表了一种新颖且可行的疗法，可以快速起来，并轻松作为院外辅助，以实现严重失血和创伤。我们假设一氧化碳可以预防低血容量的循环崩溃和不可逆的出血性休克的发展。 此外，这种保护是CO通过防止内皮细胞激活和细胞死亡来调节和保留微循环血流和组织灌注能力的结果。我们将通过解决以下目的来检验这些假设： 特定目的#L：证明CO赋予防震和循环崩溃发展的保护。 具体目的＃2：测试CO对冲击和组织缺氧的保护作用是否涉及维持和/或调节内皮和微循环。