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Carbon monoxide mediated inhibition of intimal hyperplasia

一氧化碳介导的内膜增生抑制

基本信息

批准号：
8597356
负责人：
Edith Tzeng
金额：
--
依托单位：
VETERANS HEALTH ADMINISTRATION
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-10-01 至 2015-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8597356
关键词：
Acute Adverse effects Angioplasty Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Antioxidants Apoptotic Arterial Occlusive Diseases Asphyxia Atherosclerosis Balloon Angioplasty Binding Biological Preservation Blood Vessels Breathing Bypass Carbon Monoxide Cardiac Cardiovascular system Caring Carrying Capacities Cell Culture Techniques Cell Proliferation Cells Cessation of life Characteristics Chronic Clinical Clinical Treatment Congestive Heart Failure Coronary Coronary Arteriosclerosis Coronary heart disease Data Development Diabetes Mellitus Diet Modification Disease model Dose Endothelial Cells Environment Etiology Event Exposure to Failure Family suidae Functional disorder General Population Goals Grant Healed Healthcare Healthcare Systems Heart Diseases Hemoglobin Human Hyperplasia In Vitro Incidence Inflammatory Inflammatory Response Injury Intervention Ischemia Kidney Failure Knowledge Lesion Limb structure Link Lipids Mediating Medical Metabolic syndrome Modality Modeling Morbidity - disease rate Myocardial Infarction Myocardial Ischemia Myocardial dysfunction Nature Non-Insulin-Dependent Diabetes Mellitus Obesity Operative Surgical Procedures Oxygen Pathology Patient Care Patients Peripheral Peripheral Vascular Diseases Pharmaceutical Preparations Physiological Population Prevention Procedures Property Regimen Rehabilitation therapy Rodent Role Safety Site Smooth Muscle Myocytes Stents Stimulus Stroke Systemic disease Therapeutic Therapeutic Agents Time Tissues Toxic Environmental Substances Toxic effect Translations Treatment Efficacy Treatment Failure United States Vascular Diseases Vascular Patency Veno-Occlusive Disease Veterans Work base cell type clinically relevant conventional therapy defined contribution functional status healing hemodynamics improved in vivo limb amputation mortality neointima formation operation patient population preclinical study public health relevance research study response response to injury restenosis stem tobacco abuse treatment duration

项目摘要

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.

描述（由申请人提供）：动脉粥样硬化性血管疾病是一个严重的系统性问题，在退伍军人管理局医疗系统照顾的退伍军人中极为普遍。闭塞性血管病变的常规治疗包括血管成形术和支架置入术以及外科搭桥术，但这些疗法受到内膜增生（IH）的限制，内膜增生会导致再狭窄和治疗失败。一氧化碳 (CO) 是一种非常有前景的 IH 治疗方法，最近已成为热门。短期暴露于吸入 CO 可以显着抑制动物球囊血管成形术引起的 IH，且没有任何毒性证据。这些临床前研究有力地支持了吸入 CO 成为 IH 有效临床治疗方法的潜力。该提案的总体目标是进一步开发用于人类的吸入 CO，并研究吸入 CO 通过 CO 对动脉壁的直接作用以及以调节全身炎症反应性为中心的间接作用来抑制 IH 的假设。因此，我们将重点关注以下目标。具体目标 I：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。已知吸入高浓度 CO 会产生毒性，因为它能够与氧气竞争与血红蛋白 (Hb) 的结合，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。在此目标中，将确定吸入 CO 的最佳剂量和治疗持续时间，以显着减少治疗性血管损伤后的 IH。这些研究将在啮齿动物和猪的血管损伤模型中进行。具体目标 II：在已有心功能不全的猪模型中评估 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患有许多合并症，其中最重要的是冠状动脉疾病。应用吸入二氧化碳的一个重要问题是，氧气携带能力的降低可能会导致心脏储备很少的患者出现严重的心脏缺血和生理损害。因此，在本目标中，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 抑制的直接和间接影响的贡献。 CO 具有多种细胞保护特性，已在多种组织和细胞类型中得到证实。这些包括内皮细胞 (EC) 的抗凋亡作用、抗炎作用和抗氧化功能。吸入二氧化碳的好处似乎源于其在血管损伤时或紧接之前的存在，并且支持二氧化碳正在调节涉及血管损伤反应启动的事件。我们的初步研究揭示了 CO 系统递送时的作用与它对直接暴露于 CO 的细胞和组织的影响截然不同。我们的假设是，CO 通过 CO 对动脉壁的局部作用和炎症反应的全身改变来介导血管保护。在此基础上，我们将研究吸入二氧化碳治疗的直接和间接作用对其血管保护作用的贡献。在这些目标下进行的研究将更好地确定吸入 CO 抑制 IH 的功效和可行性，并将提供对 CO 提供的血管保护作用的机制理解。这些研究通过延长血运重建后的血管通畅时间、提高功能状态和肢体保存，对退伍军人的医疗保健具有巨大的潜在益处。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，会导致针对冠状动脉和外周动脉闭塞性疾病进行的血管搭桥、血管成形术和支架置入部位再狭窄，并大大降低这些治疗的疗效。血管损伤动物模型显示，吸入一氧化碳能够以安全且可耐受的方式抑制内膜增生。这笔赠款的目的是确定吸入一氧化碳的最低剂量和最短治疗持续时间，以有效减少内膜增生，检查这种治疗在心脏病情况下的安全性，并了解一氧化碳如何在全身和局部水平介导这些影响。