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 逆转支气管收缩和缓解呼吸困难，但这是一种意想不到的和未被认识到的副作用 这些药物慢性大剂量治疗可能是肺泡巨噬细胞代谢紊乱 对宿主防御或组织健康造成不利影响。我们在肺泡中发现了一种独特的基因表达特征。 巨噬细胞提示重症患者通用细胞激活剂环磷酸腺苷(CAMP)的抑制 使用大剂量和长效β受体激动剂治疗哮喘。细胞力学研究表明，急性 β激动剂沙丁胺醇或异丙肾上腺素对人巨噬细胞或单核细胞的作用 腺酰环化酶(AC)快速合成cAMP。然而，这些细胞变得对重复不敏感 在长时间暴露后给药。这些单核细胞的脱敏导致它们不能产生 CAMP下游分子靶蛋白Kinase A相应激活失败延长 β-激动剂暴露引起巨噬细胞基因错乱转录抑制表型 在PKA激活的CREB/CREM网络中，并模仿在哮喘患者中发现的基因签名 一群人。其他基因表达的变化包括参与细胞代谢的途径，如糖酵解和脂肪 新陈代谢。β激动剂抑制cAMP-PKA信号导致这些巨噬细胞 代谢静止，糖酵解和氧化磷酸化减少。共同管理 糖皮质激素布地奈德部分恢复糖酵解能力，但不能恢复cAMP激活 长期接触β-受体激动剂。延长的β激动剂抑制mTOR蛋白的激活 暴露，限制了对内毒素的糖酵解反应，这对病原体反应很重要。同样，测试版- 激动剂诱导的巨噬细胞代谢停滞削弱其有效吞噬细菌的能力 共培养模型中的颗粒或清除活细菌，当布地奈德被 添加了。用β-激动剂治疗的有或没有诱发哮喘气道炎症的小鼠 沙美特罗治疗7天后，巨噬细胞对细菌或脂多糖诱导的糖酵解反应迟缓，而 同时接受布地奈德治疗的患者部分恢复了这些功能。这些观察结果表明，肺泡 慢性大剂量β-受体阻滞剂患者的巨噬细胞功能和宿主防御反应可能有限 激动剂，这是最常用的肺部疾病处方药之一。此应用程序旨在 探讨高强度β受体激动剂暴露对巨噬细胞功能及后果的影响 皮质类固醇在调节这些药物效应中的作用。这些研究可能会给出机械性和实用性 对观察到的这些常用药物的临床风险和效果的洞察。

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.