Treating chronic obstructive pulmonary disease (COPD) patients with inhaled glucocorticosteroids has been convincingly shown to increase their risk of pneumonia, but the responsible mechanisms are undefined. Work from this laboratory suggests a possible mechanism, related to the increased numbers of cells dying by apoptosis in the lungs in COPD, especially in emphysema. Uptake of apoptotic cells (efferocytosis) suppresses the ability of alveolar macrophages (AM) to fight infections. By markedly increasing AM efferocytosis, glucocorticoids plus apoptotic cells cause greater immune defects than either stimulus alone. This effect is called glucocorticoid-augmented efferocytosis (GCAE). MicroRNAs (miRNAs) are 19-25 nucleotide-long non-coding RNAs that coordinately target large numbers of genes and reduce their protein products. Preliminary data imply that defective AM function is caused by down-regulation of specific miRNAs by GCAE (but not by apoptotic cells alone or glucocorticosteroids alone). The long-term goal of this project is to develop novel, inhalational treatments, based on transient over-expression of these specifically decreased miRNAs, to reverse defective AM immune function when COPD patients taking inhaled glucocorticoids present with community-acquired pneumonia. This project will use ex vivo investigation of AM from both smoke-exposed mice and human volunteers (including active smokers and patients with COPD), and an established murine model of pneumococcal pneumonia. Its immediate goals are to: (a) confirm that GCAE increases pneumococcal pneumonia risk and severity, and in the process, validate a murine model for testing strategies to reverse those defects; (b) define GCAE-induced defects in human AM functionally and by whole- transcriptome analysis, identifying genes uniquely regulated by the GCAE x pneumococcus interaction; (c) validate and optimize miRNA-over-expression to reverse the adverse effects of GCAE on AM defensive functions. Successful completion of this project could lead to more precisely personalized therapies and better outcomes in COPD, currently the third leading cause of death in the USA, and the most expensive-to-treat chronic disease on a per-case basis among Veterans.

Public Health Relevance

Inhaled corticosteroids are commonly used to treat chronic obstructive pulmonary disease (COPD) but cause more frequent pneumonias. The lungs are normally protected from pneumonia by white blood cells called alveolar macrophages. In the lungs of COPD patients, especially those with emphysema, cells die in larger numbers than in healthy lungs. Eating those dead cells ('efferocytosis') lessens the ability of alveolar macro- phages to fight infection. This laboratory found that the combination of dead cells plus corticosteroids greatly reduces the ability of alveolar macrophages to kill the most common cause of community-acquired pneumonia. Reduced alveolar macrophage function appears to be caused by decreases in specific molecules, called microRNAs. This project uses mice and alveolar macrophages from human volunteers to develop a new treatment that would reverse this particular harmful effects of inhaled corticosteroids, by replacing those specific microRNAs when COPD patients taking inhaled corticosteroids develop pneumonia.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01CX000911-04
Application #
9604735
Study Section
Respiration (PULM)
Project Start
2015-10-01
Project End
2019-09-30
Budget Start
2018-10-01
Budget End
2019-09-30
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Veterans Health Administration
Department
Type
DUNS #
096318480
City
Ann Arbor
State
MI
Country
United States
Zip Code
48105
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