title: Glucocorticosteroids differentially regulate MMP-9 and neutrophil elastase in COPD.
abstract: BACKGROUND
  Chronic Obstructive Pulmonary Disease (COPD) is currently the fifth leading cause of death worldwide. Neutrophilic inflammation is prominent, worsened during infective exacerbations and is refractory to glucocorticosteroids (GCs). Deregulated neutrophilic inflammation can cause excessive matrix degradation through proteinase release. Gelatinase and azurophilic granules within neutrophils are a major source of matrix metalloproteinase (MMP)-9 and neutrophil elastase (NE), respectively, which are elevated in COPD.
  
  
  METHODS
  Secreted MMP-9 and NE activity in BALF were stratified according to GOLD severity stages. The regulation of secreted NE and MMP-9 in isolated blood neutrophils was investigated using a pharmacological approach. In vivo release of MMP-9 and NE in mice exposed to cigarette smoke (CS) and/or the TLR agonist lipopolysaccharide (LPS) in the presence of dexamethasone (Dex) was investigated.
  
  
  RESULTS
  Neutrophil activation as assessed by NE release was increased in severe COPD (36-fold, GOLD II vs. IV). MMP-9 levels (8-fold) and activity (21-fold) were also elevated in severe COPD, and this activity was strongly associated with BALF neutrophils (r = 0.92, p<0.001), but not macrophages (r = 0.48, p = 0.13). In vitro, release of NE and MMP-9 from fMLP stimulated blood neutrophils was insensitive to Dex and attenuated by the PI3K inhibitor, wortmannin. In vivo, GC resistant neutrophil activation (NE release) was only seen in mice exposed to CS and LPS. In addition, GC refractory MMP-9 expression was only associated with neutrophil activation.
  
  
  CONCLUSIONS
  As neutrophils become activated with increasing COPD severity, they become an important source of NE and MMP-9 activity, which secrete proteinases independently of TIMPs. Furthermore, as NE and MMP-9 release was resistant to GC, targeting of the PI3K pathway may offer an alternative pathway to combating this proteinase imbalance in severe COPD.
authors.affiliation: Department of Pharmacology, The University of Melbourne, Victoria, Australia.
authors.forename: Ross
authors.initials: R
authors.lastname: Vlahos
authors.forename: Peter A B
authors.initials: PA
authors.lastname: Wark
authors.forename: Gary P
authors.initials: GP
authors.lastname: Anderson
authors.forename: Steven
authors.initials: S
authors.lastname: Bozinovski
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D018450:Disease Progression; D004351:Drug Resistance; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D019272:Leukocyte Elastase / Q000378:metabolism*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D018375:Neutrophil Activation / Q000187:drug effects / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000201:enzymology*
chemical_list: D005938:Glucocorticoids; D019272:Leukocyte Elastase; D020780:Matrix Metalloproteinase 9