Carbon monoxide mediated inhibition of intimal hyperplasia

描述（由申请人提供）： 动脉粥样硬化性血管疾病是一个重大的系统性问题，是非常普遍的退伍军人在退伍军人保健系统照顾。闭塞性血管病变的常规治疗包括血管成形术和支架植入术以及外科搭桥术，但这些治疗受到内膜增生（IH）的限制，内膜增生导致再狭窄和治疗失败。一氧化碳（CO）是最近出现的一种非常有希望的IH治疗方法。短时间暴露于吸入性CO显著抑制球囊血管成形术诱导的动物IH，而没有任何毒性证据。这些临床前研究强烈支持吸入CO作为IH的有效临床治疗的潜力。该提案的总体目标是进一步开发用于人类应用的吸入性CO，并研究吸入性CO通过CO对动脉壁的直接作用以及通过以调节全身炎症反应为中心的间接作用抑制IH的假设。因此，我们将重点关注以下目标。具体目标一：确定治疗性血管损伤后抑制和消退IH所需的吸入CO的最低有效剂量和持续时间。已知的毒性与高浓度的吸入CO相关，因为其能够与氧气竞争结合血红蛋白（Hb）并降低携氧能力。因此，需要确定CO的最低有效剂量和最短治疗持续时间。在此目的中，将确定吸入CO的最佳剂量和治疗持续时间，其将介导治疗性血管损伤后IH的显著降低。这些研究将在啮齿动物和猪血管损伤模型中进行。特定目的II：在既存心功能不全的猪模型中评价CO对心功能和血流动力学参数的耐受性。接受血运重建手术的患者具有许多共病状况，最重要的是冠状动脉疾病。一个重要的问题是，吸入CO的应用，在氧气携带能力的降低可能会导致严重的心脏缺血和生理损害的患者几乎没有心脏储备。因此，在该目的中，将在急性心肌缺血和慢性心肌功能障碍的猪模型中检查吸入CO的耐受性和安全性。具体目标III：定义CO对IH抑制的直接和间接作用的贡献。CO具有许多细胞保护特性，已在多种组织和细胞类型中鉴定。这些包括内皮细胞（EC）中的抗凋亡作用、抗炎作用和抗氧化功能。吸入CO的益处似乎源于其在血管损伤时或即将发生血管损伤之前的存在，并支持CO调节血管损伤反应启动所涉及的事件。我们的初步研究揭示了非常独特的行动时，提供系统与其对细胞和组织的影响，直接暴露于CO。我们的假设是，CO介导的血管保护作用，通过局部CO对动脉壁的影响，并通过全身炎症反应的改变。在此基础上，我们将研究吸入CO治疗的直接和间接作用对其血管保护作用的贡献。根据这些目标进行的研究将更好地确定吸入CO抑制IH的有效性和可行性，并将提供CO提供的血管保护机制的理解。这些研究对退伍军人的医疗保健的潜在益处是巨大的，通过延长血管重建后的血管通畅性，增加功能状态和肢体保护。 公共卫生相关性： 项目叙述：内膜增生或再狭窄是一种愈合反应，可导致血管旁路、血管成形术和支架置入部位的再狭窄，这些部位用于冠状动脉和外周动脉闭塞性疾病，并大大降低这些治疗的疗效。在血管损伤的动物模型中，吸入一氧化碳可以安全和耐受的方式抑制内膜增生。这项资助的目的是确定吸入一氧化碳的最低剂量和最短治疗时间，这将有效地减少内膜增生，检查这种治疗在心脏病背景下的安全性，并了解一氧化碳如何在全身和局部水平上介导这些影响。

DESCRIPTION (provided by applicant): Atherosclerotic vascular disease is a significant systemic problem and is extremely prevalent in veterans cared for in the VA Healthcare System. The conventional treatments for occlusive vascular lesions include angioplasty and stenting as well as surgical bypass but these therapies are limited by intimal hyperplasia (IH) which leads to restenosis and treatment failure. One very promising treatment for IH that has come to the forefront recently is carbon monoxide (CO). A short exposure to inhaled CO dramatically inhibits balloon angioplasty induced IH in animals without any evidence of toxicity. These preclinical studies strongly support the potential for inhaled CO to be an effective clinical treatment for IH. The overall goal of this proposal is to further develop inhaled CO for human application and to investigate the hypothesis that inhaled CO inhibits IH through both direct effects of CO on the arterial wall as well as through indirect effects that center around modulation of systemic inflammatory responsiveness. Therefore, we will focus on the following Aims. Specific Aim I: Determine the lowest effective dose and duration of inhaled CO required for the inhibition and regression of IH following therapeutic vascular injury. There are known toxicities associated with high concentrations of inhaled CO through its ability to compete with oxygen for binding to hemoglobin (Hb) and reduces oxygen carrying capacity. Therefore, the lowest effective dose of CO and the shortest treatment duration need to be identified. In this Aim, the optimal dose and treatment duration of inhaled CO that will mediate a significant reduction in IH following therapeutic vascular injury will be identified. These studies will be performed in both rodent and pig models of vascular injury. Specific Aim II: Evaluate the tolerability of CO on cardiac function and hemodynamic parameters in porcine models of preexisting cardiac dysfunction. Patients undergoing revascularization procedures possess many co-morbid conditions, the most significant being coronary artery disease. An important concern about the application of inhaled CO is that a reduction in O2 carrying capacity may induce significant cardiac ischemia and physiologic compromise in patients with little cardiac reserve. Therefore, in this Aim, the tolerability and safety of inhaled CO will be examined in pig models of acute myocardial ischemia as well as chronic myocardial dysfunction. Specific Aim III: Define the contributions of the direct and indirect effects of CO on the inhibition of IH. CO has many cytoprotective properties that have been identified in a variety of tissues and cell types. These include anti-apoptotic actions in endothelial cells (EC), anti-inflammatory actions, and antioxidant functions. The benefit of inhaled CO appears to stem from its presence at the time of or immediately prior to vascular injury and would support that CO is modulating events involved in the initiation of the vascular injury response. Our preliminary studies reveal very distinct actions of CO when delivered systemically vs. its effects on cells and tissues that are directly exposed to CO. Our hypothesis is that CO mediates vasoprotection through both local effects of CO on the arterial wall and through systemic alterations of inflammatory responsiveness. Based on this, we will examine the contribution of direct and indirect actions of inhaled CO treatment to its role in vasoprotection. The studies performed under these Aims will better definite the efficacy and feasibility of inhaled CO for the inhibition of IH and will provide a mechanistic understanding of the vasoprotection offered by CO. The potential benefit of these studies to the health care of veterans is great by prolonging vascular patency after revascularization and increase functional status and limb preservation. PUBLIC HEALTH RELEVANCE: Project Narrative: Intimal hyperplasia or restenosis is a healing response that results in restenosis at sites of vascular bypass, angioplasty, and stent placement that are performed for coronary and peripheral arterial occlusive disease and greatly reduces the efficacy of these treatments. Inhaled carbon monoxide has been shown in animal models of vascular injury to inhibit intimal hyperplasia in a safe and tolerable fashion. The goal of this grant is to identify the lowest dose and shortest treatment duration for inhaled carbon monoxide that will effectively reduce intimal hyperplasia, examine the safety of this treatment in the setting of heart disease, and to understand how carbon monoxide is mediating these effects at a systemic and local level.