Impact of Opiate abuse on HIV-mediated Pulmonary Vascular Remodeling

阿片类药物滥用对 HIV 介导的肺血管重塑的影响

• 批准号: 9115350
• 负责人: Navneet Kaur Dhillon
• 金额: $ 48.86万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9115350
• 关键词: Accounting; Acquired Immunodeficiency Syndrome; Adult; Antioxidants; Apoptosis; Apoptotic; Arterial Disorder; Autophagocytosis; Basic Science; Biological Models; Blood Vessels; Cardiopulmonary; Cells; Child; Cocaine; Complex; Data; Development; Diagnosis; Disease; Drug abuse; Endothelial Cells; Excision; Exposure to; Generations; Genes; Genetic Transcription; Goals; HIV; HIV Infections; HIV-1; Health; Heart; Hematological Disease; Heroin; Human; Hypertrophy; Illicit Drugs; Immunologic Deficiency Syndromes; In Vitro; Incidence; Individual; Intervention; Investigation; Lesion; Lesion by Stage; Link; Lung; Macaca; Medial; Mediating; Mitochondria; Morbidity - disease rate; Morphine; Opioid; Organelles; Oxidative Stress; Pathogenesis; Patients; Pilot Projects; Prevalence; Proliferating; Proteins; Publishing; Pulmonary vessels; Rattus; Reactive Oxygen Species; Research; Resistance; Risk Factors; Role; SIV; Signal Pathway; Source; Specimen; Staging; Structure of parenchyma of lung; Testing; Therapeutic Intervention; Trans-Activators; Transgenic Organisms; United States; Vascular Diseases; Vascular Endothelial Cell; Vascular remodeling; Viral; Viral Proteins; Virus; Work; abstracting; antiretroviral therapy; arteriole; base; cytotoxic; drug of abuse; endothelial dysfunction; improved; in vivo; inhibitor/antagonist; innovation; intravenous drug use; intravenous drug user; mortality; non-drug; novel; novel therapeutics; opioid abuse; prevent; pulmonary arterial hypertension; research study; vascular bed

 DESCRIPTION (provided by applicant): Improved survival among human immuno-deficiency virus (HIV-1) infected individuals with the advent of antiretroviral therapy has clearly led to serious increase in the prevalence of noninfectious complications. In this regard, one of the most devastating sequelae is the development of pulmonary arterial hypertension in HIV-infected individuals (HPAH). Intravenous drug use (IVDU) accounts for one-third of all new cases of AIDS in the United States and has been identified as the most common risk factor in the individuals diagnosed with HPAH. Our recent findings showing enhanced pulmonary vascular remodeling in HIV-infected lung tissues from IV heroin and/or cocaine abusers and in simian immunodeficiency (SIV) -infected macaques exposed to morphine indicate that illicit drugs and HIV-1 potentially act in concert to cause pulmonary arteriopathy. Furthermore, SIV-infected morphine treated macaques were found to have increased number of apoptotic endothelial cells in the early stage lesions, whereas complete occlusion by actively proliferating endothelial simian immunodeficiency (SIV) cells was observed in the advanced stage plexiform lesions. This observation was further supported by our in- vitro findings showing enhanced apoptosis followed by significantly increased proliferation of human pulmonary endothelial cells on simultaneous treatment with HIV- transactivator of transcription (Tat) protein and morphine compared to either treatment alone. Based on our recent preliminary findings, the hypothesis of our pilot study is that the combined exposure of pulmonary endothelial cells to HIV-protein(s) and morphine results in the induction of autophagy that leads to enhanced proliferation of endothelial cells and severe pulmonary vascular remodeling. This hypothesis will be tested by pursuing three specific aims. In the first aim we will evaluate the effect of HIV-Tat and morphine on the oxidative stress mediated bulk autophagy in endothelial cells. In the second aim, we propose to delineate the role of selective autophagy in Tat and morphine mediated enhanced proliferation. Third aim will be focused on in-vivo investigation of PAH and autophagy in HIV-1 Tg rats with or without morphine exposure. In addition, ex-vivo investigation of autophagy using lung specimens from HIV- infected IVDUs and SIV-infected morphine exposed macaques will be tested. These studies are innovative because to the best of our knowledge it will be the first attempt to understand the potential link between the role of autophagy in the morphine and HIV-proteins mediated apoptosis resistant enhanced proliferation. The proposed research will enhance our understanding of the fundamental mechanisms involved in the pathogenesis of HPAH and therefore is directly responsive to RFA-HL-14-024 (Basic Research in the Pathogenesis of HIV-Related Heart, Lung, and Blood (HLB) Diseases in Adults and Children).

 描述（由申请人提供）： 随着抗逆转录病毒疗法的出现，人类免疫缺陷病毒（HIV-1）感染者的生存率得到改善，这显然导致非感染性并发症发生率的严重增加。在这方面，最具破坏性的后遗症之一是肺动脉的发展。在美国，艾滋病毒感染者中的高血压 (HPAH) 占所有新发艾滋病病例的三分之一，并已被确定为确诊艾滋病患者中最常见的危险因素。我们最近的研究结果表明，静脉注射海洛因和/或可卡因滥用者感染的 HIV 肺组织以及接触吗啡的猿猴免疫缺陷 (SIV) 感染的猕猴的肺血管重塑增强，这表明非法药物和 HIV-1 可能协同作用。此外，感染 SIV 的吗啡处理的猕猴被发现在早期病变中凋亡的内皮细胞数量增加，而完全死亡。在晚期丛状病变中观察到活跃增殖的内皮猿免疫缺陷（SIV）细胞引起的闭塞，我们的体外研究结果进一步支持了这一观察结果，显示在同时使用HIV反式激活剂治疗时，人肺内皮细胞的细胞凋亡增强，随后增殖显着增加。与单独治疗相比，转录 (Tat) 蛋白和吗啡的变化根据我们最近的初步研究结果，我们初步研究的假设是肺内皮细胞联合暴露于其中。 HIV 蛋白和吗啡会诱导自噬，从而增强内皮细胞增殖和严重的肺血管重塑。在第一个目标中，我们将评估 HIV 的影响。 -Tat 和吗啡对内皮细胞氧化应激介导的大量自噬的影响在第二个目标中，我们建议描述选择性自噬在 Tat 和吗啡介导的增强增殖中的作用。将重点关注暴露或未暴露吗啡的 HIV-1 Tg 大鼠的 PAH 和自噬的体内研究。此外，还将使用感染 HIV 的 IVDU 和感染 SIV 的暴露吗啡的猕猴的肺标本进行离体自噬研究。这些研究具有创新性，因为据我们所知，这将是首次尝试了解自噬在吗啡和 HIV 蛋白介导的细胞凋亡抵抗增强中的作用之间的潜在联系。拟议的研究将增强我们对 HPAH 发病机制的理解，因此直接响应 RFA-HL-14-024（HIV 相关心脏、肺和血液发病机制的基础研究 (HLB)）。 ）成人和儿童疾病）。