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.

项目总结/摘要 在美国，酒精消费导致的死亡率继续攀升，而大麻的使用和相关的 疾病也变得越来越普遍。据报告，估计有11%的人同时使用大麻 经常饮酒的人中，大麻的使用与饮酒频率和数量的增加有关。 酒精消费。有害的酒精使用会增加呼吸道感染的风险， 社区获得性肺炎（CAP）然而，双重酒精和大麻消费如何影响CAP 风险是未知的，它们对肺免疫细胞功能的联合影响尚未确定。通过 由科罗拉多肺酒精研究协作组织（CoPARC），一个NIAAA- 支持R24研究资源，我们试图解开如何双重酒精和大麻使用加剧 发生肺部感染的风险，包括CAP。我们的初步研究表明， 暴露于大麻会改变对两个气道中的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）。这份提案的重点是获得详细的见解 有害的酒精和大麻使用的结合如何改变免疫细胞的基本功能， 病原体识别和清除。具体目标1将建立二元醇的分子特征， 在人类AEC和AM中滥用大麻。将使用支气管镜下获得的细胞进行研究 (AECs和AM）和来自CoPARC生物储存库中四种参与者类型的流体，包括那些具有 酒精使用障碍（AUD），使用和不使用大麻;大麻使用者;和对照参与者。核糖核酸 将进行seq以获得与物质使用相关的免疫调节变化的详细见解。 此外，将研究物质使用与粘液分泌标志物和炎症介质的关系。 在BAL液中评估。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组分的细胞应答的影响 （支气管上皮）和THP 1单核细胞衍生的巨噬细胞（Macs）。细胞将用±酒精± 特异性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MUC 5AC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局 对来自四种参与者类型的人BAL液进行处理（与目标1相同）。通过这些相互关联的 目的，我们将获得有价值的见解双重酒精和大麻强加的病原体的改变， 识别.