Proteinase-activated receptor-2-mediated matrix metalloproteinase-9 release from airway epithelial cells
H Vliagoftis1, A Schwingshackl, C D Milne
1Pulmonary Research Group, the Departments Medicine University of Calgary, Calgary, Alberta, Canada.
Background:
Matrix metalloproteinases (MMPs) digest extracellular matrix components and might be important mediators of tissue remodeling. Proteinase activated receptor-2 (PAR-2) is expressed in a variety of cell types including epithelial cells. PAR-2 receptors are activated by serine proteases such as trypsin and mast cell tryptase and have been implicated in inflammation.
Objective:
To study the effects of PAR-2-mediated airway epithelial cell activation on the production of MMP-9.
Methods:
A specific PAR-2-activating peptide and trypsin were used to activate the human airway epithelial cell line A549 as well as primary cultures of small airway epithelial cells (SAEC). MMP-2 and MMP-9 messenger RNA and enzymatic activity were evaluated by RT-PCR and gelatin zymography, respectively.
Results:
PAR-2-activating peptides upregulated MMP-9 mRNA expression and release of MMP-9 enzymatic activity from airway epithelial cells but had no effect on MMP-2 production. Dexamethasone and budesonide (10(-6) to 10(-10) mmol) inhibited PAR-2-mediated MMP-9 release. Pretreatment with indomethacin indicated that MMP-9 release was not prostaglandin dependent. Inhibitors of the MAP kinase MEK- 1, and NFkappaB showed that both pathways are important for PAR-2-mediated MMP-9 release. Trypsin, a physiologic PAR-2 activator, upregulated MMP-9 but also MMP-2 release from airway epithelial cells.
Conclusion:
PAR-2 receptors appear to play an important role in the regulation of MMP-9 release from airway epithelial cells. As such, these receptors may be critical elements in tissue remodeling in asthma and other inflammatory conditions in the airways.
Insights
Proteinase-activated receptor-2 (PAR-2) activation in airway epithelial cells upregulates matrix metalloproteinase-9 (MMP-9) production, a key factor in airway remodeling. Corticosteroids inhibit this process, suggesting PAR-2
Area of Science:
- Cellular biology
- Molecular biology
- Respiratory medicine
Background:
- Matrix metalloproteinases (MMPs) are enzymes involved in tissue remodeling.
- Proteinase-activated receptor-2 (PAR-2) is expressed in epithelial cells and activated by proteases, implicated in inflammation.
- PAR-2 activation may influence airway inflammation and remodeling.
Purpose of the Study:
- To investigate the impact of PAR-2 activation on matrix metalloproteinase-9 (MMP-9) production in airway epithelial cells.
- To explore the signaling pathways involved in PAR-2-mediated MMP-9 release.
- To assess the effect of anti-inflammatory agents on this process.
Main Methods:
- Human airway epithelial cell lines (A549) and primary cells (SAEC) were stimulated with PAR-2 activating peptides and trypsin.
- Messenger RNA (mRNA) expression of MMP-2 and MMP-9 was analyzed using RT-PCR.
- MMP-2 and MMP-9 enzymatic activity was measured by gelatin zymography.
- Involvement of MAP kinase and NF-kappaB pathways was assessed using specific inhibitors.
- Effects of dexamethasone, budesonide, and indomethacin were evaluated.
Main Results:
- PAR-2 activation significantly upregulated MMP-9 mRNA and enzymatic activity, but not MMP-2.
- Dexamethasone and budesonide inhibited PAR-2-mediated MMP-9 release.
- MMP-9 release was independent of prostaglandin synthesis.
- MAP kinase (MEK-1) and NF-kappaB signaling pathways were crucial for PAR-2-mediated MMP-9 release.
- Trypsin induced MMP-9 and MMP-2 release.
Conclusions:
- PAR-2 plays a significant role in regulating MMP-9 release from airway epithelial cells.
- PAR-2 mediated MMP-9 production is a potential target for therapeutic intervention in airway inflammatory diseases.
- These findings highlight the importance of PAR-2 in airway tissue remodeling associated with conditions like asthma.
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