Impact of Opiate abuse on HIV-mediated Pulmonary Vascular Remodeling

项目摘要 随着人类免疫缺陷病毒（HIV-1）的出现， 抗逆转录病毒疗法显然导致非传染性并发症的发病率大幅上升。在 在这方面，最具破坏性的后遗症之一是肺动脉高压的发展， HIV感染者（HPAH）。静脉注射毒品占所有艾滋病新病例的三分之一 在美国，已被确定为被诊断患有 HPAH。我们最近的研究结果显示，在HIV感染的肺组织中， 从静脉注射海洛因和/或可卡因滥用者和感染猕猴暴露于 吗啡表明非法药物和HIV-1可能共同作用导致肺动脉病。 此外，SIV感染的吗啡治疗的猕猴被发现有增加的凋亡细胞数量。 内皮细胞在早期病变，而完全闭塞的积极增殖内皮细胞 猴免疫缺陷 在晚期丛状病变中观察到细胞。 这一观点得到了我们的进一步支持- 体外研究结果显示，人肺细胞凋亡增强，随后增殖显著增加， 内皮细胞与艾滋病毒同时治疗- 转录反式激活因子 (Tat)蛋白质和吗啡 与单独治疗相比。根据我们最近的发现，我们研究的假设是， 肺内皮细胞联合暴露于HIV-蛋白和吗啡导致 自噬导致内皮细胞增殖增强和严重的肺血管重塑。 这一假设将通过追求三个具体目标来检验。在第一个目标中，我们将评估艾滋病毒的影响- 达特和吗啡对氧化应激介导的内皮细胞自噬调控的影响。在 第二个目的，我们提出描绘自噬/线粒体自噬在达特和吗啡介导的增强的细胞凋亡中的作用。 增殖第三个目标将集中在HIV-1 Tg大鼠中PAH和自噬的体内研究， 没有吗啡接触。这些研究是创新的，因为据我们所知， 第一次尝试了解吗啡中自噬/线粒体自噬的作用与 HIV蛋白介导的抗凋亡增强的增殖。建议的研究将提高我们的 了解HPAH发病机制的基本机制，因此直接 对RFA-HL-14-024（HIV相关心脏、肺和血液发病机制的基础研究）有反应 (HLB)成人和儿童疾病）。

Project Summary 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 -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 findings, the hypothesis of our 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 regulation of bulk autophagy in endothelial cells. In the second aim, we propose to delineate the role of autophagy/mitophagy 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. 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/mitophagy 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).