Modulation of Steroid Immunosuppression by Alveolar Efferocytosis
Condition: Pulmonary Disease, Chronic Obstructive; Pneumonia, Bacterial
MeSH terms: Pneumonia; Pneumonia, Bacterial; Pulmonary Disease, Chronic Obstructive
Study type: Interventional

Summary: 
      The long-term goals of this study are (a) to understand the biological underpinnings for the
      increased incidence of community-acquired pneumonia in patients with chronic obstructive
      pulmonary disease (COPD) who are treated with inhaled corticosteroids; and (b) to develop
      novel therapies to treated this problem using over-expression of micro-RNAs (miRNAs).
    

Detailed description: 
      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.
      These defects include reductions in killing of Streptococcus pneumoniae by human AM and
      murine AM in vitro, and in clearance of viable pneumococci from lungs of mice. 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 both ex vivo
      investigation of AM from human volunteers (never-smokers; smokers with normal spirometry; and
      COPD subjects who are current or former smokers), 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 AM defects functionally
      and by whole-transcriptome analysis, identifying genes and miRNAs 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
    

Intervention name(s): Bronchoscopy with bilateral bronchoalveolar lavages
Intervention type(s): Procedure
Intervention description(s): Bronchoscopy with bilateral bronchoalveolar lavages
Intervention MeSH terms: Dimercaprol
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Intervention model description: This study will analyze both healthy subjects (never-smokers and current- or ex-smokers) in one arm, and also subjects with COPD (current- or ex-smokers).
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Apoptosis; Bronchoscopy; Human; Mice, inbred strains; Macrophages, Alveolar; MicroRNAs; Streptococcus pneumoniae; Fluticasone