Carbon Monoxide to Prevent Circulatory Collapse

描述（由申请人提供）： 在美国，由于创伤性损伤导致的严重出血是死亡的主要原因。由于严重失血导致的死亡通常发生在“现场”或受伤后4小时内，因此需要阐明可以延迟或预防不可逆出血性休克进展的早期干预和治疗方法。严重出血的损伤是一种多因素的全身损伤，涉及缺血/再灌注伴炎症和自主神经功能障碍，可导致微血管功能障碍和循环衰竭。对这种损伤的细胞和分子反应涉及抗氧化酶和应激反应基因的表达增加，包括 应激诱导基因血红素氧合酶-1（HO-1）。HO-1催化血红素催化还原的第一步和限速步骤，产生等摩尔量的胆绿素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提供细胞保护，以对抗多种损伤模式，包括内毒素血症、缺血/再灌注和出血。最近的研究表明，CO的产生可以介导HO-1诱导的细胞保护作用。除了需要增加HO-1的表达外，外源性CO的递送也可以是细胞保护性的。我们在失血性休克小鼠模型中的初步数据表明，低剂量吸入CO可保护免于器官损伤的发展，降低血清炎性细胞因子水平并增加血清抗炎因子水平。 细胞因子IL-10。此外，我们证明吸入CO可以减少出血时的组织缺氧。 进一步的初步数据表明，这些作用可能是次要的微循环的维持和调节，以及通过防止多种模式的细胞死亡。CO，无论是通过吸入或控制药物释放，代表了一种新的和可行的治疗，可以迅速和容易地作为严重失血和创伤的院外辅助。我们假设一氧化碳可以防止低血容量性循环衰竭的发生和不可逆性失血性休克的发展。 此外，这种保护是CO通过防止内皮细胞活化和细胞死亡来调节和保持微循环血流和组织灌注的能力的结果。我们将通过解决以下目标来检验这些假设： 具体目标#1：证明CO可防止休克和循环衰竭的发生。 具体目标#2：探讨CO对休克和组织缺氧的保护作用是否与维持和/或调节血管内皮和微循环有关。

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.