HIV, Inflammation, and Endothelial Dysfunction

HIV、炎症和内皮功能障碍

• 批准号: 8112433
• 负责人: Matthias Clauss
• 金额: $ 77.2万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-25 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8112433
• 关键词: Address; Adhesions; Anti-Inflammatory Agents; Anti-inflammatory; Atherosclerosis; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell Adhesion Molecules; Cell model; Cells; Clinical Research; Clinical Trials; Control Groups; Data; Disease; Dyslipidemias; Endothelial Cells; Endothelium; Enrollment; Event; Functional disorder; Future; General Population; Goals; HIV; HIV Infections; Immunologics; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Injury; Insulin Resistance; Interruption; Investigation; Knowledge; Laboratories; Lead; Lesion; Leukocytes; Matched Group; Measures; Mediating; Metabolic; Monocyte Chemoattractant Protein-1; Mononuclear; Pathologic; Pathway interactions; Patients; Pentoxifylline; Pharmaceutical Preparations; Population; Process; Production; Research; Resources; Risk; Structure; T-Lymphocyte; Therapeutic; Therapeutic Intervention; Therapy Clinical Trials; Toxic effect; Vascular Cell Adhesion Molecule-1; Vascular Endothelium; Viral Proteins; abstracting; antiretroviral therapy; brachial artery; cardiovascular risk factor; clinical effect; cytokine; improved; in vitro Model; in vivo; mortality; novel; promoter; randomized placebo controlled trial

DESCRIPTION (provided by applicant): With the reduction in mortality due to combination antiretroviral therapy (cART), cardiovascular disease has emerged as a leading cause of death in HIV-infected patients. Because several antiretrovirals cause insulin resistance and dyslipidemia, the increased risk for atherosclerotic disease has been attributed primarily to these drugs. However, evidence is emerging that suggest untreated HIV infection contributes significantly to the risk for future cardiovascular events. Inflammation and endothelial cell dysfunction are key promoters of atherosclerosis in the general population. Vascular lesions in HIV-infected patients demonstrate increased leukocyte adhesion to the endothelium with elevated levels of monocyte chemoattractant protein-1 (MCP-1) and vascular cell adhesion molecule-1 (VCAM-1). In cART-naIve patients, levels of these adhesion molecules are increased and endothelial dysfunction is common. cART only partly reduces levels of these molecules and only partly restores endothelial function. Our novel preliminary data suggest that the anti-inflammatory drug pentoxifylline (PTX) may significantly improve flow-mediated dilation of the brachial artery, an in vivo measure of endothelial function, in HIV-infected subjects by inhibiting leukocyte recruitment and adhesion. Using a cellular model, we found that HIV-infected T cells upregulate endothelial MCP-1 and that PTX inhibits endothelial production of MCP-1. We will directly address a specific objective of RFA-HL-08-003, which is to "examine the direct effects of HIV itself on the endothelium and identify any mitigating factors" in the proposed collaborative studies. In this application, we will address the central hypothesis that HIV-related inflammation induces endothelial cell dysfunction that is reversed with pentoxifylline. Our Specific Aims are (1) To determine the effects of pentoxifylline on endothelial function in HIV-infected subjects and (2) To analyze in vitro mechanisms by which HIV and PTX modulate endothelial cell activation and injury. We will investigate the utility of PTX to improve HIV-related endothelial dysfunction in therapeutic trials. We will also study the mechanism of HIV-induced endothelial dysfunction and the ability of PTX to reverse this process using our in vitro models. This research is both timely and significant because it will move beyond observational clinical research by involving both therapeutic trials and mechanistic investigations to identify novel causal relationships and pathologic mechanisms between inflammation and endothelial function. If pentoxifylline is found to be effective in improving endothelial function in the proposed studies, then this inexpensive, safe, and widely available drug can be studied in larger trials to reduce cardiovascular endpoints in HIV-infected patients. The proposed research will determine if HIV infection damages the vascular endothelium, the inner lining of blood vessels, by increasing inflammation and if this damage can be reversed with the anti-inflammatory drug pentoxifylline. Both clinical trials and laboratory investigations will address these key issues. These studies will fill a critical gap in our knowledge of endothelial dysfunction in HIV-infected patients and may eventually lead to better preventative and therapeutic interventions to reduce cardiovascular disease in this population. (End of Abstract)

描述（由申请人提供）： 由于抗逆转录病毒疗法（CART）导致的死亡率降低，心血管疾病已成为HIV感染患者的主要死亡原因。由于几种抗逆转录病毒会引起胰岛素抵抗和血脂异常，因此动脉粥样硬化疾病的风险增加主要归因于这些药物。但是，有证据表明未经治疗的艾滋病毒感染对未来心血管事件的风险产生了重大贡献。炎症和内皮细胞功能障碍是普通人群动脉粥样硬化的关键启动子。 HIV感染患者的血管病变表明，对内皮的白细胞粘附增加，单核细胞趋化剂蛋白-1（MCP-1）和血管细胞粘附分子1（VCAM-1）的水平升高。在手推车患者中，这些粘附分子的水平增加，内皮功能障碍很常见。卡车仅部分降低了这些分子的水平，只部分恢复内皮功能。我们新的初步数据表明，在HIV感染的受试者中，抗炎药五胞化素（PTX）可以显着改善臂动脉的流动介导的臂动脉的扩张，这是内皮功能的体内测量值。使用细胞模型，我们发现感染HIV的T细胞上调内皮MCP-1，并且PTX抑制了MCP-1的内皮产生。我们将直接解决RFA-HL-08-003的具体目标，该目标是“检查艾滋病毒本身对内皮的直接影响，并在拟议的协作研究中确定任何缓解因素”。在此应用程序中，我们将解决以下中心假设：HIV相关炎症会诱导用五氧化氨基林逆转的内皮细胞功能障碍。我们的具体目的是（1）确定戊昔丁素对HIV感染受试者内皮功能的影响，以及（2）分析HIV和PTX调节内皮细胞激活和损伤的体外机制。我们将研究PTX在治疗试验中改善与HIV相关的内皮功能障碍的效用。我们还将研究HIV诱导的内皮功能障碍的机制以及PTX使用我们的体外模型逆转此过程的能力。这项研究既及时又具有重要意义，因为它将通过涉及治疗试验和机械研究来确定炎症和内皮功能之间的新因果关系和病理机制，从而超越观察性临床研究。如果发现五氧化苯胺可以有效地改善所提出的研究中的内皮功能，那么可以在较大的试验中研究这种廉价，安全且可广泛的药物，以减少感染HIV感染的患者的心血管终点。拟议的研究将通过增加炎症来确定HIV感染是否会损害血管内皮，血管内部的内壁，以及是否可以使用抗炎药五氧化苯胺来逆转这种损害。临床试验和实验室调查都将解决这些关键问题。这些研究将填补我们对HIV感染患者内皮功能障碍的了解，并最终可能导致更好的预防和治疗性干预措施，以减少该人群的心血管疾病。 （抽象的结尾）