Macrophage Immunometabolism alteration by intense beta agonist therapy.

摘要 使用β激动剂作为哮喘的支气管扩张剂治疗有效地靶向气道平滑肌细胞， 逆转支气管收缩并缓解呼吸困难，然而， 慢性高剂量用药可能导致肺泡巨噬细胞代谢紊乱 不利地影响宿主防御或组织健康。我们发现了一个独特的基因表达签名， 巨噬细胞，表明在严重的人中抑制通用细胞激活剂环腺苷酸（cAMP） 用大剂量长效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 腺苷酸环化酶（AC）快速合成cAMP。然而，这些细胞变得不敏感， 长期暴露后给药。这些单核细胞的脱敏导致它们不能产生 cAMP与其下游分子靶蛋白激酶A的相应活化失败。延长 β激动剂暴露导致巨噬细胞转录组学表型紊乱， 在PKA激活的CREB/CREM网络中， 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。 新陈代谢.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。共同施用 皮质类固醇布地奈德部分恢复了糖酵解能力，但不能恢复cAMP激活。 长期暴露于β受体激动剂mTOR蛋白的激活被长期的β激动剂抑制， 暴露，限制对LPS的糖酵解反应，这对于病原体反应是重要的。同样，贝塔- 激动剂诱导的巨噬细胞代谢静止损害了它们有效吞噬细菌的能力， 颗粒或明确的活菌从共培养模型，与部分功能恢复时，布地奈德是 补充说用β受体激动剂治疗的有或没有诱导哮喘气道炎症的小鼠 沙美特罗给药7天后，巨噬细胞对细菌或LPS诱导的糖酵解反应迟缓， 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 巨噬细胞的性能和宿主防御反应可能在使用慢性高剂量β 激动剂，这是最常见的肺部疾病的处方药。本申请旨在 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作用。这些研究可能会给机械和实用 观察到的这些常用药物的临床风险和影响的见解。

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.