title: Increased CD8 T-cell granzyme B in COPD is suppressed by treatment with low-dose azithromycin.
abstract: OBJECTIVE
  Corticosteroid resistance in chronic obstructive pulmonary disease (COPD) is a major challenge. We have reported increased bronchial epithelial cell apoptosis and increased airway CD8 T-cell numbers in COPD. Apoptosis can be induced via the serine protease, granzyme B. However, glucocorticosteroids fail to adequately suppress granzyme B production by CD8 T cells. We previously showed that low-dose azithromycin reduced airways inflammation in COPD subjects and we hypothesized that it would also reduce granzyme B production by CD8 T cells.
  
  
  METHODS
  We administered 250 mg azithromycin daily for 5 days then twice weekly (total 12 weeks) to 11 COPD subjects (five current smokers; six ex-smokers) and assessed granzyme B in the airway (bronchoalveolar lavage), intra-epithelial compartment and peripheral blood, collected before and following administration of azithromycin. To then dissect the effects of on CD4 and CD8 T-cell subsets, we applied an in vitro assay and physiologically relevant concentrations of azithromycin (and, for comparison, n-acetyl cysteine) and stimulation of peripheral blood mononuclear cells from five healthy subjects with CD3/CD28 T-cell expander.
  
  
  RESULTS
  T-cell granzyme B production in both airway and intra-epithelial compartments was reduced in COPD patients following 12 weeks of azithromycin treatment, with no significant effect in blood. Both azithromycin and n-acetyl cysteine suppressed CD4 T-cell granzyme B production, but only azithromycin was effective at reducing CD8+ T-cell granzyme B production in vitro.
  
  
  CONCLUSIONS
  We provide further evidence for the application of low-dose azithromycin as an attractive adjunct treatment option for controlling epithelial cell apoptosis, abnormal airway repair and chronic inflammation in COPD.
authors.affiliation: Lung Research Laboratory, Hanson Institute, Adelaide, South Australia, Australia; Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, South Australia, Australia.
authors.forename: Sandra
authors.initials: S
authors.lastname: Hodge
authors.forename: Greg
authors.initials: G
authors.lastname: Hodge
authors.forename: Mark
authors.initials: M
authors.lastname: Holmes
authors.forename: Hubertus
authors.initials: H
authors.lastname: Jersmann
authors.forename: Paul N
authors.initials: PN
authors.lastname: Reynolds
mesh_terms: D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D017963:Azithromycin / Q000008:administration & dosage / Q000493:pharmacokinetics; D001682:Biological Availability; D018893:Bronchoalveolar Lavage / Q000379:methods; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D053804:Granzymes / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D012137:Respiratory System / Q000187:drug effects / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D017963:Azithromycin; D053804:Granzymes
keywords: CD8 T-cell; azithromycin; chronic obstructive pulmonary disease; corticosteroid; granzyme B