Role of aberrant metalloproteinase activity in the pro-inflammatory phenotype of bronchial epithelium in COPD

Respir Res. 2011 Aug 23;12(1):110. doi: 10.1186/1465-9921-12-110.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / antagonists & inhibitors
  • ADAM Proteins / metabolism
  • ADAM17 Protein
  • Adult
  • Aged
  • Cells, Cultured
  • Female
  • Humans
  • Inflammation Mediators / antagonists & inhibitors
  • Inflammation Mediators / metabolism*
  • Male
  • Middle Aged
  • Phenotype*
  • Pulmonary Disease, Chronic Obstructive / enzymology*
  • Pulmonary Disease, Chronic Obstructive / pathology*
  • Respiratory Mucosa / drug effects
  • Respiratory Mucosa / enzymology*
  • Respiratory Mucosa / metabolism
  • Smoke / adverse effects
  • Tissue Inhibitor of Metalloproteinase-2 / antagonists & inhibitors
  • Tissue Inhibitor of Metalloproteinase-2 / metabolism
  • Tobacco


  • Inflammation Mediators
  • Smoke
  • Tissue Inhibitor of Metalloproteinase-2
  • ADAM Proteins
  • ADAM17 Protein
  • ADAM17 protein, human