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: 10471332
• 负责人: ELLEN L BURNHAM
• 金额: $ 18.6万
• 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 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10471332
• 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; 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; Persons; Pneumonia; Population; Public Health; Reporting; Research; Research Personnel; Resources; Respiratory Tract Infections; Risk; Substance Use Disorder; Therapeutic; Time; Tissues; Toll-like receptors; Western Blotting; 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; translational potential

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.

项目概要/摘要 在美国，因饮酒导致的死亡率持续攀升，而吸食大麻及相关的死亡率则持续上升。 疾病也变得越来越普遍。据估计 11% 的人同时吸食大麻 经常饮酒的消费者中，大麻的使用与饮酒频率和数量的增加有关 饮酒量。有害饮酒会增加呼吸道感染的风险，尤其是 社区获得性肺炎（CAP）。然而，双重饮酒和大麻消费如何影响 CAP 风险尚不清楚，并且它们对肺免疫细胞功能的综合影响尚未确定。通过 科罗拉多肺酒精研究合作组织 (CoPARC) 协助开展了一项调查，该合作组织是 NIAAA- 在 R24 研究资源的支持下，我们试图揭示双重酒精和大麻的使用如何加剧 发生肺部感染（包括 CAP）的风险。我们的初步研究表明，有害的酒精 大麻暴露改变了对呼吸道病原体识别至关重要的基因表达 上皮细胞（AEC）和肺泡巨噬细胞（AM）。该提案的重点是获得详细的见解 研究有害酒精和大麻的结合如何改变基本免疫细胞功能 病原体识别和清除。具体目标 1 将建立双醇的分子特征 人类 AEC 和 AM 中的大麻滥用。将使用支气管镜获得的细胞进行研究 （AEC 和 AM）以及 CoPARC 生物样本库中四种参与者类型的液体，包括那些患有 酒精使用障碍 (AUD)，无论是否使用大麻；大麻使用者；并控制参与者。 RNA- 将进行 seq，以详细了解与物质使用相关的免疫调节变化。 此外，物质使用与粘液分泌标记物和炎症介质的关系将是 在 BAL 液中进行评估。在具体目标 2 中，我们将建立酒精和大麻素 (CB) 之间的协同作用 受体激动剂对人 BEAS-2B 细胞系中病原体和病原体成分​​的细胞反应的影响 （支气管上皮）和 THP1 单核细胞衍生的巨噬细胞 (Macs)。细胞将用±酒精处理± 特定的 CB 受体激动剂，结果测量将包括中和和杀死细菌的效率， 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。将在 BEAS-2B 细胞系和 Mac 中研究进一步的功能结果 接受来自四种参与者类型的人体 BAL 液体（对于目标 1）。通过这些相互联系的 目标，我们将获得关于酒精和大麻对病原体的双重改变的宝贵见解 认出。

项目成果

Association between Substance Misuse and Outcomes in Critically III Patients with Pneumonia.

药物滥用与 III 级危重肺炎患者预后之间的关联。

• DOI: 10.1513/annalsats.202206-532oc
• 发表时间: 2023
• 期刊: Annals of the American Thoracic Society
• 影响因子: 8.3
• 作者: Reynolds,PaulM;Afshar,Majid;Wright,GarthC;Ho,PMichael;Kiser,TyreeH;Sottile,PeterD;Althoff,MeghanD;Moss,Marc;Jolley,SarahE;Vandivier,RWilliam;Burnham,EllenL
• 通讯作者: Burnham,EllenL