Impact of Dual Alcohol and Cannabis Use on Lung

双重酒精和大麻使用对肺的影响

• 批准号: 10302164
• 负责人: ELLEN L BURNHAM
• 金额: $ 23.8万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-20 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10302164
• 关键词: Adult; Affect; Agonist; Alcohol consumption; Alcohols; Alveolar Macrophages; B-Lymphocytes; Bacteria; Bronchoalveolar Lavage Fluid; Cannabinoids; Cannabis; Cause of Death; Cell Line; Cell physiology; Cells; Colorado; Complement; Complex; Consumption; Development; Disease; Dose; Epithelial; Epithelial Cells; Exposure to; Frequencies; Functional disorder; Future; Gene Expression; Genes; Habits; Health; Homeostasis; Human; Immune; Immune system; Immunity; Immunoblotting; Impairment; In Vitro; Individual; Inflammation Mediators; Inflammatory; Investigation; Knowledge; Laboratories; Link; Liquid substance; Lung; Lung infections; MUC5AC gene; Mediating; Molecular; Molecular Profiling; Monoclonal Antibody R24; Mucous body substance; National Institute on Alcohol Abuse and Alcoholism; Natural Immunity; Outcome Measure; Participant; Pattern; Pneumonia; Population; Public Health; Reporting; Research; Research Personnel; Resources; Respiratory Tract Infections; Risk; Substance Use Disorder; Therapeutic; Time; Tissues; Toll-like receptors; absorption; airway epithelium; alcohol exposure; alcohol research; alcohol use disorder; antimicrobial; attributable mortality; base; biobank; bronchial epithelium; cannabinoid receptor; chemokine; combat; community acquired pneumonia; cytokine; experimental study; functional outcomes; immunoregulation; insight; interest; macrophage; marijuana use; marijuana use disorder; marijuana user; microbial; monocyte; pathogen; respiratory health; response; substance use; transcriptome sequencing

Project Summary/Abstract In the US, mortality attributable to alcohol consumption continues to climb, while cannabis use and associated disorders are also becoming increasingly prevalent. Concurrent cannabis use is reported by an estimated 11% of regular alcohol consumers, and cannabis use has been linked to increased frequency and quantity of alcohol consumption. Harmful alcohol use can heighten the risk of respiratory infections, particularly community-acquired pneumonia (CAP). However, how dual alcohol and cannabis consumption influences CAP risk is unknown, and their combined impact on pulmonary immune cell function is not established. Through investigations facilitated by the Colorado Pulmonary-Alcohol Research Collaborative (CoPARC), a NIAAA- supported R24 Research Resource, we seek to unravel how dual alcohol and cannabis use exacerbate the risk of developing pulmonary infections, including CAP. Our preliminary studies indicate that harmful alcohol and cannabis exposures alter expression of genes that are critical for pathogen recognition in both airway epithelial cells (AECs) and alveolar macrophages (AMs). The focus of this proposal is to gain detailed insights into how the combination of harmful alcohol and cannabis use alter fundamental immune cell functions in pathogen recognition and clearance. Specific Aim 1 will establish the molecular signature of dual alcohol and cannabis misuse in human AECs and AMs. Studies will be performed with bronchoscopically obtained cells (AECs and AMs) and fluid from four participant types in the CoPARC biorepository, including those with alcohol use disorders (AUDs), with and without cannabis use; cannabis users; and control participants. RNA- seq will be performed to gain detailed insights into immunomodulatory changes associated with substance use. Additionally, the relationship of substance use on mucus secretion markers and inflammatory mediators will be assessed in BAL fluid. In Specific Aim 2, we will establish cooperativity between alcohol and cannabinoid (CB) receptor agonists on cellular responses to pathogens and pathogen components in human BEAS-2B cell lines (bronchial epithelium) and THP1 monocyte-derived macrophages (Macs). Cells will be treated with ± alcohol ± specific CB receptor agonists, and outcome measures will include efficiency in neutralizing and killing bacteria, modulation of TLR responsiveness, expression of immunomodulatory cytokines, and expression of MUC5AC and epithelial barrier disruption. Further functional outcomes will be studied in BEAS-2B cell lines and Macs subjected to human BAL fluid from the four participant types (as for Aim 1). Through these mutually linked aims, we will gain valuable insights into dual alcohol- and cannabis-imposed alterations in pathogen recognition.

项目摘要/摘要 在美国，归因于饮酒的死亡率继续攀升，而大麻的使用和相关 疾病也变得越来越普遍。同时使用大麻的使用估计有11％ 常规酒精消费者和大麻的使用已与增加的频率和数量有关 饮酒。有害饮酒会增加呼吸道感染的风险，特别是 社区获得的肺炎（上限）。但是，双重酒精和大麻消耗如何影响上限 风险是未知的，并且尚未确定它们对肺免疫功能的综合影响。通过 科罗拉多州肺泡研究合作（COPARC）进行的调查，NIAAA- 支持R24的研究资源，我们试图揭示双重酒精和大麻的使用如何加剧 患有肺部感染的风险，包括CAP。我们的初步研究表明有害酒精 大麻暴露会改变基因表达，这对于两种气道中的病原体识别至关重要 上皮细胞（AEC）和肺泡巨噬细胞（AMS）。该建议的重点是获得详细的见解 有害酒精和大麻的组合如何改变基本的免疫细胞功能 病原体识别和清除。具体目标1将建立双重酒精的分子特征和 大麻在人类的AEC和​​AMS中被遗忘。研究将使用支气管镜获得的细胞进行 （AEC和AMS）和来自四种参与类型的液体，包括 饮酒障碍（AUDS），有和不使用大麻；大麻使用者；和控制参与者。 RNA- 将进行SEQ，以获取对与药物使用相关的免疫调节变化的详细见解。 此外，将药物使用在粘液分泌标记和炎症介质上的关系将是 在BAL液中进行评估。在特定的目标2中，我们将在酒精和大麻素（CB）之间建立协调 受体激动剂对人Beas-2b细胞系中病原体和病原体成分​​的细胞反应 （支气管上皮）和THP1单核细胞衍生的巨噬细胞（MAC）。细胞将用±酒精± 特定的CB受体激动剂，结果指标将包括中和细菌的效率， TLR反应性的调节，免疫调节细胞因子的表达和MUC5AC的表达 和上皮屏障破坏。进一步的功能结果将在BEAS-2B细胞系和MAC中研究 受到四种参与类型的人类BAL液（AIM 1）。通过这些相互联系 目的，我们将获得对病原体中双重酒精和大麻变化的宝贵见解 认出。