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-受体激动剂作为哮喘的支气管扩张剂治疗有效靶向呼吸道 然而，平滑肌细胞可以逆转支气管收缩和缓解呼吸困难 使用这些药物进行慢性大剂量治疗的意想不到和未被发现的副作用 药物可能是肺泡巨噬细胞代谢紊乱的不利影响 宿主防御或组织健康。我们在肺泡中发现了一个独特的基因表达特征 巨噬细胞显示通用细胞激活剂环磷酸腺苷(CAMP)的抑制 严重哮喘患者使用大剂量和长效β-受体激动剂治疗。 细胞机制研究显示，急性治疗人巨噬细胞或 β激动剂异丙肾上腺素诱导单核细胞快速合成cAMP 腺苷环化酶(AC)。然而，这些细胞对异丙肾上腺素不敏感 一夜暴晒。脱敏是由于AC酶丰度下调所致 和AC负性调节因子β-arrestin的诱导，这些单核细胞不能 对常规刺激产生cAMP，但相应地不能激活蛋白质 激酶A长时间暴露于β激动剂会导致错乱的转录 巨噬细胞的表型与PKA激活基因的抑制 CREB/CREM网络，包括几种有益的上皮生长因子和模拟物 在哮喘患者队列中发现的基因特征。如果没有有效的营地- PKA信号转导，这些巨噬细胞代谢紊乱 基础糖酵解和氧化磷酸化。此外，经典巨噬细胞 TLR与内毒素联合激活可迅速诱导糖酵解并增加细胞内游离 葡萄糖来施加宿主防御反应。细胞长期暴露于β受体激动剂 消除对内毒素的糖酵解反应，降低细胞对病原体的能力 回应。这些观察表明，肺泡巨噬细胞的功能和宿主 长期使用大剂量β受体激动剂的患者的防御反应可能是有限的， 这是最常用的肺部疾病处方药之一。这 应用程序寻求探索密集测试版的机制和后果 对巨噬细胞功能的刺激，这可能会影响处方实践或导致 新替代疗法的最终发展。