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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：
10160953
负责人：
Anuradha Ray
金额：
$ 47.72万
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/10160953
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 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 pulmonary function 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.

摘要