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)

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)