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)： 随着联合抗逆转录病毒疗法(CART)死亡率的降低，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药物会导致胰岛素抵抗和血脂异常，动脉粥样硬化性疾病的风险增加主要归因于这些药物。然而，越来越多的证据表明，未经治疗的艾滋病毒感染极大地增加了未来心血管事件的风险。在普通人群中，炎症和内皮细胞功能障碍是动脉粥样硬化的关键促进剂。HIV感染患者的血管病变表现为白细胞与内皮细胞的黏附增加，单核细胞趋化蛋白-1(MCP-1)和血管细胞黏附分子-1(VCAM-1)水平升高。在幼稚的患者中，这些黏附分子的水平升高，内皮功能障碍是常见的。CART仅部分降低了这些分子的水平，仅部分恢复了内皮功能。我们新的初步数据表明，抗炎药物己酮可可碱(PTX)可能通过抑制白细胞的募集和黏附，显著改善HIV感染者的血流介导的肱动脉扩张，这是体内衡量内皮功能的指标。使用细胞模型，我们发现HIV感染的T细胞上调内皮细胞MCP-1，而PTX抑制内皮细胞MCP-1的产生。我们将直接针对RFA-HL-08-003的一个具体目标，即在拟议的合作研究中“检查艾滋病毒本身对内皮的直接影响，并确定任何缓解因素”。在这项应用中，我们将解决中心假设，即艾滋病毒相关的炎症导致内皮细胞功能障碍，而己酮可可碱可以逆转这一假设。我们的具体目标是(1)确定己酮可可碱对HIV感染者内皮功能的影响；(2)分析HIV和PTX在体外调节内皮细胞激活和损伤的机制。我们将在治疗试验中研究PTX改善HIV相关内皮功能障碍的效用。我们还将利用我们的体外模型研究HIV诱导的内皮功能障碍的机制以及PTX逆转这一过程的能力。这项研究既及时又有意义，因为它将超越观察性临床研究，包括治疗试验和机制研究，以确定炎症和内皮功能之间的新的因果关系和病理机制。如果在拟议的研究中发现己酮可可碱在改善内皮功能方面有效，那么这种廉价、安全、可广泛获得的药物可以在更大规模的试验中进行研究，以减少艾滋病毒感染患者的心血管终点。这项拟议的研究将确定艾滋病毒感染是否通过增加炎症来损害血管内皮细胞，以及抗炎药物己酮可可碱是否可以逆转这种损害。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艾滋病毒感染患者内皮功能障碍知识的一个重要空白，并最终可能导致更好的预防和治疗干预措施，以减少这一人群的心血管疾病。(摘要结束)