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

Abstract

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.

• Authors: H Vliagoftis, A Schwingshackl, C D Milne, M Duszyk, M D Hollenberg, J L Wallace, A D Befus, R Moqbel
• Journal: The Journal of allergy and clinical immunology (J Allergy Clin Immunol) Vol. 106 Issue 3 Pg. 537-45 (Sep 2000) ISSN: 0091-6749 [Print] United States
• PMID: 10984375 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adrenal Cortex Hormones
• RNA, Messenger
• Receptor, PAR-2
• Receptors, Thrombin
• Trypsin
• Matrix Metalloproteinase 9

Topics

• Adrenal Cortex Hormones (pharmacology)
• Epithelial Cells (enzymology, metabolism)
• Humans
• Matrix Metalloproteinase 9 (drug effects, genetics, metabolism)
• RNA, Messenger (metabolism)
• Receptor, PAR-2
• Receptors, Thrombin (physiology)
• Respiratory System (cytology)
• Signal Transduction (physiology)
• Trypsin (pharmacology)