Effects of marijuana use on inflammation and vascular injury in adults with HIV infection

吸食大麻对成人艾滋病毒感染者炎症和血管损伤的影响

• 批准号: 9548431
• 负责人: Dana H. Gabuzda
• 金额: $ 61.65万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9548431
• 关键词: Acquired Immunodeficiency Syndrome; Acrolein; Address; Adult; Age; Aldehydes; Antiinflammatory Effect; Antioxidants; Aromatic Polycyclic Hydrocarbons; Attenuated; Automobile Driving; Bioinformatics; Biological Assay; Biological Markers; Blood Vessels; Cannabinoids; Cardiovascular Diseases; Cardiovascular system; Cell Adhesion; Cell Culture Techniques; Chronic; Clinical; Clinical Data; Coagulation Process; Comorbidity; Computer Simulation; Data; Data Set; Disease Marker; Disease Progression; Drug Metabolic Detoxication; Enzyme-Linked Immunosorbent Assay; Event; Experimental Models; Exposure to; Expression Profiling; Gene Expression; Gene Expression Profile; Goals; HIV; HIV Infections; Health; Immunologic Markers; In Vitro; Individual; Inflammasome; Inflammation; Inflammatory; Injury; Innate Immune Response; Lipid Peroxidation; Machine Learning; Marijuana; Marijuana Smoking; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Modeling; Nicotine; Outcome; Oxidative Stress; Pathway interactions; Pattern; Peripheral Blood Mononuclear Cell; Plasma; Population; Process; Prospective cohort; Proteomics; Risk Factors; Role; Safety; Sampling; Smoke; Smoker; Smoking; Testing; The Multicenter AIDS Cohort Study; Therapeutic Intervention; Time; Tobacco; Tobacco smoke; Tobacco smoking behavior; Toxic effect; Urine; cardiovascular risk factor; cohort; combustion product; immune activation; liquid chromatography mass spectrometry; marijuana smoke; marijuana use; men; metabolomics; middle age; monocyte; network models; neutrophil; predictive modeling; predictive test; response; therapeutic development; therapeutic target; tobacco exposure; transcriptome; vascular inflammation; volatile organic compound

Project Summary The goal of this proposal is to characterize biomarkers of marijuana smoke exposure in ART-treated HIV+ adults over age 40, and their relationship to inflammation and vascular injury in heavy users. Marijuana and tobacco smoking are both prevalent among HIV+ populations, but their individual and combined impacts on inflammation and cardiovascular risk are unknown. Preliminary studies using longitudinal data from a prospective cohort showed that chronic heavy marijuana smoking has no significant effect on HIV disease markers, but is associated with increased rates of incident cardiovascular events in ART-treated HIV+ men age 40-60 independently of tobacco smoking and traditional risk factors. Furthermore, we showed that heavy marijuana and/or tobacco smoking was associated with elevated WBC and neutrophil counts, immune activation, inflammation, and vascular injury in ART-treated HIV+ smokers. We hypothesize that specific combustion products in marijuana and tobacco smoke, including acrolein, other reactive aldehydes, and VOCs, can induce proinflammatory responses mediated through activated neutrophils and monocytes that promote chronic inflammation in ART-treated adults, contributing to cardiovascular risk by promoting lipid peroxidation, coagulation, vascular inflammation, and endothelial injury, while attenuating protective responses. We further hypothesize that these effects are additive upon dual exposure to both marijuana and tobacco smoke and augmented by HIV infection. To address these questions, we will use clinical samples and data from well- characterized longitudinal HIV+ cohorts to characterize marijuana smoke exposure biomarkers in plasma and urine samples and their relationship to inflammation, oxidative stress, and vascular injury. Bioinformatics, computational modeling, and cell culture models will be used to build and test models to explain the effects of specific constituents of marijuana smoke on inflammatory pathways, and how these pathways are modified in the setting of HIV infection. These studies will provide information that helps to explain chronic inflammation and elevated cardiovascular risk in ART-treated HIV+ adults, safety profiles of smoked cannabinoids, and potential strategies for therapeutic intervention.

项目摘要 该提案的目标是描述ART治疗的HIV+患者大麻烟雾暴露的生物标志物。 40岁以上的成年人，以及它们与重度使用者的炎症和血管损伤的关系。大麻和 吸烟在艾滋病毒阳性人群中都很普遍，但它们对艾滋病毒感染者的个体和综合影响 炎症和心血管风险是未知的。初步研究使用的纵向数据， 前瞻性队列研究表明，长期大量吸食大麻对艾滋病没有显著影响 标记物，但与ART治疗的HIV+男性中心血管事件发生率增加相关。 40-60独立于吸烟和传统的危险因素。此外，我们还发现， 吸食大麻和/或烟草与WBC和中性粒细胞计数升高、免疫球蛋白 ART治疗的HIV+吸烟者的活化、炎症和血管损伤。我们假设 大麻和烟草烟雾中的燃烧产物，包括丙烯醛、其他活性醛和VOC， 可以诱导通过激活的中性粒细胞和单核细胞介导的促炎反应， ART治疗成人的慢性炎症，通过促进脂质过氧化而导致心血管风险， 凝血、血管炎症和内皮损伤，同时减弱保护性反应。我们进一步 假设这些效应是在同时暴露于大麻和烟草烟雾时叠加， 艾滋病毒感染加剧了这种情况。为了解决这些问题，我们将使用来自良好的临床样本和数据- 表征纵向HIV+队列，以表征血浆中大麻烟雾暴露生物标志物， 尿液样本及其与炎症、氧化应激和血管损伤的关系。生物信息学， 计算模型和细胞培养模型将用于建立和测试模型，以解释 大麻烟的特定成分对炎症通路的影响，以及这些通路在炎症过程中是如何被修饰的。 艾滋病毒感染的背景。这些研究将提供有助于解释慢性炎症的信息 ART治疗的HIV+成人中心血管风险升高，吸烟大麻素的安全性特征，以及 治疗干预的潜在策略。