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

项目摘要 这项提议的目标是确定接受抗逆转录病毒药物治疗的HIV+患者暴露于大麻的生物标志物的特征。 40岁以上的成年人，以及他们与重度使用者的炎症和血管损伤的关系。大麻和 吸烟在HIV+人群中很普遍，但它们的单独和联合影响 炎症和心血管风险尚不清楚。使用纵向数据进行的初步研究 前瞻性队列研究表明，长期大量吸食大麻对HIV疾病没有显著影响 标记物，但与接受抗逆转录病毒治疗的HIV+男性年龄的心血管事件发生率增加有关 40-60岁，不受吸烟和传统风险因素的影响。此外，我们还展示了沉重的 吸食大麻和/或吸烟与WBC和中性粒细胞计数升高有关，免疫 接受抗逆转录病毒药物治疗的吸烟者的活化、炎症和血管损伤。我们假设具体的 大麻和烟草烟雾中的燃烧产物，包括丙烯醛、其他活性醛和挥发性有机化合物， 可通过激活的中性粒细胞和单核细胞介导的促炎反应 接受抗逆转录病毒治疗的成年人的慢性炎症，通过促进脂质过氧化而增加心血管风险。 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 假设这些影响在双重暴露于大麻和烟草烟雾中是相加的 因感染艾滋病毒而加重。为了解决这些问题，我们将使用来自油井的临床样本和数据。 表征纵向HIV+队列以表征血浆和血浆中大麻烟雾暴露的生物标志物 尿样及其与炎症、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 大麻烟雾的特定成分对炎症途径的影响，以及这些途径是如何在 HIV感染的背景。这些研究将提供有助于解释慢性炎症的信息 以及接受抗逆转录病毒药物治疗的成年人心血管风险增加，吸烟大麻类药物的安全概况，以及 潜在的治疗干预策略。

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.