title: Role of aberrant metalloproteinase activity in the pro-inflammatory phenotype of bronchial epithelium in COPD.
abstract: BACKGROUND
  Cigarette smoke, the major risk factor for COPD, is known to activate matrix metalloproteinases in airway epithelium. We investigated whether metalloproteinases, particularly A Disintegrin and Metalloproteinase (ADAM)17, contribute to increased pro-inflammatory epithelial responses with respect to the release of IL-8 and TGF-α, cytokines implicated in COPD pathogenesis.
  
  
  METHODS
  We studied the effects of cigarette smoke extract (CSE) and metalloproteinase inhibitors on TGF-α and IL-8 release in primary bronchial epithelial cells (PBECs) from COPD patients, healthy smokers and non-smokers.
  
  
  RESULTS
  We observed that TGF-α was mainly shed by ADAM17 in PBECs from all groups. Interestingly, IL-8 production occurred independently from ADAM17 and TGF-α shedding, but was significantly inhibited by broad-spectrum metalloproteinase inhibitor TAPI-2. CSE did not induce ADAM17-dependent TGF-α shedding, while it slightly augmented the production of IL-8. This was accompanied by reduced endogenous inhibitor of metalloproteinase (TIMP)-3 levels, suggesting that CSE does not directly but rather indirectly alter activity of ADAM17 through the regulation of its endogenous inhibitor. Furthermore, whereas baseline TGF-α shedding was lower in COPD PBECs, the early release of IL-8 (likely due to its shedding) was higher in PBECs from COPD than healthy smokers. Importantly, this was accompanied by lower TIMP-2 levels in COPD PBECs, while baseline TIMP-3 levels were similar between groups.
  
  
  CONCLUSIONS
  Our data indicate that IL-8 secretion is regulated independently from ADAM17 activity and TGF-α shedding and that particularly its early release is differentially regulated in PBECs from COPD and healthy smokers. Since TIMP-2-sensitive metalloproteinases could potentially contribute to IL-8 release, these may be interesting targets to further investigate novel therapeutic strategies in COPD.
authors.affiliation: Laboratory of Allergology & Pulmonary Diseases, Department of Pathology & Medical Biology, University Medical Center Groningen, University of Groningen, The Netherlands. h.i.heijink@int.umcg.nl
authors.forename: Irene H
authors.initials: IH
authors.lastname: Heijink
authors.forename: Simone M
authors.initials: SM
authors.lastname: Brandenburg
authors.forename: Jacobien A
authors.initials: JA
authors.lastname: Noordhoek
authors.forename: Dirk-Jan
authors.initials: DJ
authors.lastname: Slebos
authors.forename: Dirkje S
authors.initials: DS
authors.lastname: Postma
authors.forename: Antoon J
authors.initials: AJ
authors.lastname: van Oosterhout
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D000072198:ADAM17 Protein; D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D029424:Pulmonary Disease, Chronic Obstructive / Q000201:enzymology* / Q000473:pathology*; D020545:Respiratory Mucosa / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D012906:Smoke / Q000009:adverse effects; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D014026:Nicotiana
chemical_list: D018836:Inflammation Mediators; D012906:Smoke; D019716:Tissue Inhibitor of Metalloproteinase-2; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human