Macrophage Immunometabolism alteration by intense beta agonist therapy.

强β激动剂治疗改变巨噬细胞免疫代谢。

基本信息

批准号：
9973300
负责人：
Anuradha Ray
金额：
$ 47.57万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9973300
关键词：
Acute Adenylate Cyclase Adrenal Cortex Hormones Adrenergic Receptor Agonist Albuterol Alveolar Macrophages Anabolism Animals Area Asthma Bacteria Bronchoalveolar Lavage Bronchoconstriction Bronchodilator Agents Budesonide CREB1 gene Cell Line Cells Cellular Metabolic Process Chronic Clinical Clustered Regularly Interspaced Short Palindromic Repeats Coculture Techniques Containment Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Dose Drug Prescriptions Dyspnea Endotoxins Enzymes Event Exhibits Exposure to FRAP1 gene Failure Gene Expression Gene Expression Profile Genes Glucose Glycolysis Glycolysis Induction Health Host Defense Human Hypoxia Inducible Factor Immune Immune response Immunity Impairment Infection Inflammation Inhalation Isoproterenol Leukocytes Ligands Link Lung Lung diseases Macrophage Activation Mediating Metabolic Metabolism Microbe Modeling Molecular Molecular Target Mus Nature Oxidative Phosphorylation Pathway interactions Patients Pattern Performance Persons Phagocytosis Pharmaceutical Preparations Pharmacology Phenotype Production Proteins Recovery of Function Research Respiratory Burst Respiratory physiology Risk Role Salmeterol Signal Transduction Signaling Molecule Smooth Muscle Myocytes Steroid therapy Steroids Tissues airway inflammation asthma model asthmatic asthmatic airway asthmatic patient cell type clinical effect clinical risk cohort cytokine defense response desensitization fighting genetic signature insight lipid metabolism lung injury macrophage monocyte mouse model novel overexpression particle pathogen prevent programs respiratory colonization respiratory smooth muscle response side effect transcription factor transcriptomics

项目摘要

ABSTRACT 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 identified 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 revealed that acute treatment of human macrophages or monocytic cells with the beta agonists albuterol or isoproterenol induced rapid cAMP synthesis by adenylyl cyclase (AC). However, these cells became desensitized to repeat administration after prolonged exposure. Desensitization of these monocytes caused them to fail to generate cAMP with corresponding failure of activation of its downstream molecular target Protein Kinase A. Prolonged beta agonist exposure caused a deranged transcriptomic phenotype of macrophages with suppression of genes in the PKA-activated CREB/CREM network and mimicked the gene signature discovered in the asthmatic patient cohort. Other gene expression changes included pathways involved in cell metabolism like glycolysis and lipid metabolism. Beta agonist suppression of cAMP-PKA signaling caused these macrophages to become metabolically quiescent with decreased glycolysis and oxidative phosphorylation. Co-administration of the corticosteroid budesonide partially restored glycolytic capacity but not cAMP activation in the setting of prolonged beta agonist exposure. Activation of the mTOR protein was suppressed by prolonged beta agonist exposure, limiting the glycolytic response to LPS, which is important for pathogen responses. Likewise, beta- agonist induced metabolic quiescence in macrophages impaired their ability to effectively engulf bacterial particles or clear live bacteria from a co-culture model, with partial functional recovery when budesonide was added. Mice with or without induced asthmatic airway inflammation that were treated with the beta agonist salmeterol for 7 days showed sluggish macrophage responses to bacteria or LPS induction of glycolysis, while concurrent budesonide treatment partially restored those functions. 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 intense beta agonist exposure on macrophage performance and the impact of corticosteroids in modulating these drug effects. These studies may give mechanistic and practical insights into the observed clinical risks and effects of these commonly used agents.

抽象的使用β受体激动剂作为支气管扩张剂治疗哮喘可有效靶向气道平滑肌细胞逆转支气管收缩并缓解呼吸困难，但是意想不到的和未被识别的副作用长期使用这些药物进行大剂量治疗可能会导致肺泡巨噬细胞代谢紊乱对宿主防御或组织健康产生不利影响。我们在肺泡中发现了独特的基因表达特征巨噬细胞表明重症患者通用细胞激活剂环磷酸腺苷 (cAMP) 受到抑制用高剂量和长效β受体激动剂治疗哮喘。细胞机制研究表明，急性用β激动剂沙丁胺醇或异丙肾上腺素诱导的人巨噬细胞或单核细胞的治疗通过腺苷酸环化酶 (AC) 快速合成 cAMP。然而，这些细胞对重复操作变得不敏感。长期暴露后给药。这些单核细胞的脱敏导致它们无法生成 cAMP 与其下游分子靶蛋白激酶 A 的激活相应失败。延长 β激动剂暴露导致巨噬细胞转录组表型紊乱并抑制基因在 PKA 激活的 CREB/CREM 网络中，并模仿在哮喘患者中发现的基因特征队列。其他基因表达变化包括参与细胞代谢的途径，如糖酵解和脂质代谢。 β 激动剂抑制 cAMP-PKA 信号传导导致这些巨噬细胞变得代谢静止，糖酵解和氧化磷酸化减少。共同管理皮质类固醇布地奈德部分恢复糖酵解能力，但不恢复 cAMP 激活长期暴露于β受体激动剂。 mTOR 蛋白的激活被延长的 β 激动剂抑制暴露，限制对 LPS 的糖酵解反应，这对于病原体反应很重要。同样，β- 激动剂诱导巨噬细胞代谢静止，损害其有效吞噬细菌的能力共培养模型中的颗粒或透明活细菌，当布地奈德加入时部分功能恢复额外。用β激动剂治疗的患有或不患有哮喘气道炎症的小鼠沙美特罗 7 天显示巨噬细胞对细菌或 LPS 糖酵解诱导反应迟缓，而同时布地奈德治疗部分恢复了这些功能。这些观察结果表明肺泡长期使用高剂量β的患者的巨噬细胞性能和宿主防御反应可能受到限制激动剂，这是治疗肺部疾病最常用的药物之一。该应用程序旨在探索强烈的β激动剂暴露对巨噬细胞性能的机制和后果皮质类固醇在调节这些药物作用中的影响。这些研究可能会提供机制和实践深入了解这些常用药物观察到的临床风险和影响。