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 该提案的目的是表征经艺术治疗的艾滋病毒+大麻烟雾暴露的生物标志物 40岁以上的成年人及其与重型使用者的炎症和血管损伤的关系。大麻和 在艾滋病毒+种群中吸烟既普遍烟草，但是他们的个人和综合影响 炎症和心血管风险尚不清楚。初步研究使用来自A的纵向数据 前瞻性队列表明，慢性大麻吸烟对艾滋病毒疾病没有显着影响 标记，但与艺术治疗的艾滋病毒+男性年龄增加的心血管事件发生率增加有关 40-60独立于吸烟和传统危险因素。此外，我们表明了很重 大麻和/或烟草吸烟与升高的WBC和中性粒细胞计数有关，免疫 ART治疗的HIV+吸烟者的激活，炎症和血管损伤。我们假设该具体 大麻和烟草烟雾中的燃烧产品，包括丙烯醛，其他反应性醛和VOC， 可以通过激活的中性粒细胞和单核细胞介导的促炎反应，从而促进 经过艺术治疗的成年人的慢性炎症，通过促进脂质过氧化，导致心血管风险 凝结，血管炎症和内皮损伤，同时减弱保护性反应。我们进一步 假设这些影响是在双重暴露于大麻和烟草烟以及 受艾滋病毒感染增强。为了解决这些问题，我们将使用临床样本和数据 表征了纵向艾滋病毒+队列，以表征血浆中的大麻烟雾曝光生物标志物 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， 计算建模和细胞培养模型将用于构建和测试模型，以解释 炎症途径上大麻烟的特定成分，以及这些途径如何在 艾滋病毒感染的情况。这些研究将提供有助于解释慢性炎症的信息 在经过艺术治疗的艾滋病毒+成年人，熏制大麻素的安全概况和 治疗干预的潜在策略。