Derangement of alveolar macrophage immunuometabolism by prolonged beta agonist therapy: Implications for host defense and tissue health

长期β受体激动剂治疗引起的肺泡巨噬细胞免疫代谢紊乱：对宿主防御和组织健康的影响

• 批准号: 9791199
• 负责人: NATHANIEL M WEATHINGTON
• 金额: $ 7.54万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-23 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9791199
• 关键词: Acute; Address; Adenylate Cyclase; Agonist; Airway Disease; Alveolar Macrophages; Asthma; Bacteria; Biological Assay; Bronchoalveolar Lavage; Bronchoconstriction; Bronchodilator Agents; CREB1 gene; Cell physiology; Cells; Cellular Metabolic Process; Chemicals; Chronic; Chronic Obstructive Airway Disease; Citric Acid Cycle; Clinical; Complex; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Development; Disease; Dose; Down-Regulation; Dyspnea; Enzymes; Epithelial; Event; Exhibits; Exposure to; Failure; Functional disorder; Gene Expression; Gene Expression Profile; Gene Targeting; Genes; Genus Hippocampus; Glucose; Glycolysis; Glycolysis Induction; Growth Factor; Health; Host Defense; Human; Immune; Infection; Inhalation; Isoproterenol; Knowledge; Lead; Ligands; Ligation; Lung; Lung diseases; Macrophage Activation; Maintenance Therapy; Measures; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Molecular; Mus; Mutation; Oxidative Phosphorylation; Participant; Patients; Performance; Persons; Phagocytosis; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Pneumonia; Proteins; RNA; Research; Respiratory Burst; Respiratory Tract Infections; Role; Sampling; Second Messenger Systems; Shortness of Breath; Signal Transduction; Smooth Muscle Myocytes; Stimulus; Tissues; asthmatic; asthmatic patient; beta-arrestin; body system; clinical investigation; cohort; cytokine; defense response; desensitization; drug development; exome; fighting; gene synthesis; genetic signature; in vivo; inhibitor/antagonist; macrophage; metabolomics; monocyte; mouse model; novel therapeutics; pathogen; pathogen exposure; prevent; programs; respiratory smooth muscle; response; side effect; transcription factor; transcriptomics

The use of beta agonists as bronchodilator therapy for asthma effectively targets airway smooth muscle cells to reverse bronchoconstriction and relieve breathlessness, however an unintended and unrecognized side effect of chronic high dose therapy with these drugs may be that derangement of alveolar macrophage metabolism adversely impacts host defense or tissue health. We identify a unique gene expression signature in alveolar macrophages indicating suppression of the universal cell activator cyclic AMP (cAMP) in persons with severe asthma treated with high dose and long acting beta agonists. Cellular mechanistic studies reveal that acute treatment of human macrophages or monocytic cells with the beta agonist Isoproterenol induces rapid cAMP synthesis by adenylyl cyclase (AC). However, these cells become desensitized to isoproterenol after overnight exposure. Desensitization is due to downregulation of AC enzyme abundance and induction of the AC negative regulator β-arrestin, and these monocytes fail to generate cAMP to conventional stimuli with corresponding failure to activate Protein Kinase A. Prolonged beta agonist exposure causes a deranged transcriptomic phenotype of macrophages with suppression of genes in the PKA-activated CREB/CREM network that includes several salutary epithelial growth factors and mimics the gene signature discovered in the asthmatic patient cohort. Without effective cAMP- PKA signaling, these macrophages become metabolically deranged with decreases in basal glycolysis and oxidative phosphorylation. Furthermore, classical macrophage activation by TLR ligation with LPS rapidly induces glycolysis and increases cellular free glucose to exert host defensive responses. Prolonged cellular exposure to beta agonist eliminates the glycolytic response to LPS, reducing cellular capacity for pathogen responses. These observations suggest that alveolar macrophage performance and host defense responses may be limited in patients using chronic high dose beta agonists, which are among the most commonly prescribed agents for lung disease. This application seeks to explore the mechanism and consequences of intensive beta agonism on macrophage performance, which may inform prescribing practice or lead to the eventual development of new alternate therapies.

使用β激动剂作为支气管扩张剂治疗哮喘有效地针对气道 平滑肌细胞以逆转支气管收缩和拯救呼吸困难，但是 慢性高剂量疗法的意外且无法识别的副作用 药物可能是肺泡巨噬细胞代谢的演变对影响不利的影响 宿主防御或组织健康。我们在肺泡中确定独特的基因表达特征 巨噬细胞表明抑制通用细胞活化剂环状AMP（CAMP） 患有严重哮喘的人接受高剂量和长作用β激动剂。 细胞机械研究表明，人类巨噬细胞的急性治疗或 与β激动剂异丙肾上腺素的单核细胞可通过 腺苷酸环化酶（AC）。但是，这些细胞在 隔夜暴露。脱敏是由于AC酶丰度下调 AC负调节剂β-甲蛋白的诱导，这些单核细胞无法 生成cAMP到常规刺激，以相应的失败激活蛋白质 激酶A.长时间的β激动剂暴露会导致乱伦转录组 巨噬细胞的表型，在PKA激活中抑制基因 CREB/CREM网络，其中包括几个有益的上皮生长因子和模仿 在哮喘患者队列中发现的基因信号。没有有效的营地 - PKA信号传导，这些巨噬细胞在代谢中随着下降而危险 碱性糖酵解和氧化磷酸化。此外，经典巨噬细胞 通过TLR连接LPS激活迅速诱导糖酵解并增加无细胞的糖酵解 葡萄糖发挥宿主防御反应。长时间的细胞暴露于β激动剂 消除对LPS的糖酵解反应，从而降低了病原体的细胞能力 回答。这些观察结果表明肺泡巨噬细胞性能和宿主 使用慢性高剂量β激动剂的患者可能会受到防御反应的限制， 这是最常见的肺部疾病药物。这 应用程序旨在探索密集beta的机制和后果 对巨噬细胞性能的激动性，这可能会为处方实践提供信息或导致 新替代疗法的事件开发。