Bibliographic Details
| Title: |
Role of aberrant metalloproteinase activity in the pro-inflammatory phenotype of bronchial epithelium in COPD |
| Authors: |
Postma Dirkje S, Slebos Dirk-Jan, Noordhoek Jacobien A, Brandenburg Simone M, Heijink Irene H, van Oosterhout Antoon J |
| Source: |
Respiratory Research, Vol 12, Iss 1, p 110 (2011) |
| Publisher Information: |
BMC, 2011. |
| Publication Year: |
2011 |
| Collection: |
LCC:Diseases of the respiratory system |
| Subject Terms: |
Cigarette smoke, ADAM17, IL-8, TGF-α, TIMP-2, Diseases of the respiratory system, RC705-779 |
| More Details: |
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. |
| Document Type: |
article |
| File Description: |
electronic resource |
| Language: |
English |
| ISSN: |
1465-9921 |
| Relation: |
http://respiratory-research.com/content/12/1/110; https://doaj.org/toc/1465-9921 |
| DOI: |
10.1186/1465-9921-12-110 |
| Access URL: |
https://doaj.org/article/0fb411236409478597433ec335c10484 |
| Accession Number: |
edsdoj.0fb411236409478597433ec335c10484 |
| Database: |
Directory of Open Access Journals |
