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.

Public Health Relevance

Beta agonists and inhaled corticosteroids are the most commonly prescribed drugs for lung diseases, and while safe, they are known to cause desensitization of nontarget cell types like leukocytes. In this application, we describe a possible side effect to beta agonist therapy that might prevent important immune cells in the lung (alveolar macrophages) from changing their metabolism to appropriately respond to pathogens like bacteria, and how corticosteroids might correct these metabolic changes. We are studying the molecular events that cause thes drug effects on the cells as well as the consequences of impaired macrophage metabolism on cells? ability to eliminate bacteria.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL148604-01A1
Application #
9973300
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Lu, Jining
Project Start
2020-09-01
Project End
2024-08-31
Budget Start
2020-09-01
Budget End
2021-08-31
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15260