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

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

展开

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.

抽象的将β激动剂用作哮喘的支气管扩张剂疗法有效地靶向气道平滑肌细胞反向支气管收缩和缓解呼吸困难，但是用这些药物慢性高剂量治疗可能是肺泡巨噬细胞代谢的危险不利影响宿主防御或组织健康。我们确定了牙槽中独特的基因表达特征巨噬细胞表明抑制了严重患者的通用细胞活化剂环状AMP（CAMP）哮喘用高剂量和长时间表演β激动剂治疗。细胞机械研究表明急性用β激动剂或异丙肾上腺素诱导的人类巨噬细胞或单核细胞的治疗腺苷环酶（AC）的快速cAMP合成。但是，这些细胞变得脱敏以重复长时间暴露后的管理。这些单核细胞的脱敏导致它们无法产生其下游分子靶蛋白激酶的相应激活失败的cAMP A延长 β激动剂的暴露引起巨噬细胞的转录型表型，并抑制了基因在PKA激活的CREB/CREM网络中，并模仿哮喘患者中发现的基因签名队列。其他基因表达变化包括参与细胞代谢等糖酵解和脂质的途径代谢。 Beta激动剂抑制营地信号传导导致这些巨噬细胞成为随着糖酵解和氧化磷酸化的降低而代谢静止。共同管理皮质类固醇布地奈德部分恢复了糖酵解能力，而不是在cAMP激活中长时间的β激动剂暴露。长时间的β激动剂抑制MTOR蛋白的激活暴露，限制了对LPS的糖酵解反应，这对于病原体反应很重要。同样，beta- 激动剂诱导巨噬细胞中的代谢静止，损害了它们有效吞噬细菌的能力颗粒或从共培养模型中清除活细菌，当布德索尼德为额外。患有或没有诱发哮喘气道炎症的小鼠用β激动剂治疗沙美醇7天表现出对细菌或LPS诱导糖酵解的巨噬细胞的缓慢反应，而并发的布德索尼治疗部分恢复了这些功能。这些观察结果表明肺泡使用慢性高剂量β的患者，巨噬细胞性能和宿主防御反应可能受到限制激动剂是最常见的肺部疾病药物。本申请寻求探索激烈β激动剂暴露于巨噬细胞性能和的后果皮质类固醇对调节这些药物作用的影响。这些研究可能会提供机械和实用对观察到的这些常用药物的临床风险和影响的见解。