Proteinase-activated receptor-2-mediated matrix metalloproteinase-9 release from airway epithelial cells

Background: Matrix metalloproteinases (MMPs) digest extracellular matrix co mponents and might be important mediators of tissue remodeling. Proteinase activated receptor-2 (PAR-2) is expressed in a variety of cell types includ ing epithelial cells. PAR-2 receptors are activated by serine proteases suc h as trypsin and mast cell tryptase and have been implicated in inflammatio n. Objective: To study the effects of PAR-2-mediated airway epithelial cell ac tivation on the production of MMP-9. Methods: A specific PAR-2-activating peptide and trypsin were used to activ ate 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; respect ively. Results: PAR-2-activating peptides upregulated MMP-9 mRNA expression and re lease of MMP-9 enzymatic activity from airway epithelial cells but had no e ffect on MMP-2 production. Dexamethasone and budesonide (10(-6) to 10(-10) mmol) inhibited PAR-2-mediated MMP-9 release. Pretreatment with indomethaci n indicated that MMP-9 release was not prostaglandin dependent. Inhibitors of the MAP kinase MEK-1, and NF kappa B showed that both pathways are impor tant for PAR-2-mediated MMP-9 release. Trypsin, a physiologic PAR-2 activat or, upregulated MMP-9 but also MMP-2 release from airway epithelial cells. Conclusion: PAR-2 receptors appear to play an important role in the regulat ion of MMP-9 release from airway epithelial cells. As such, these receptors may be critical elements in tissue remodeling in asthma and other inflamma tory conditions in the airways.