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


CONCLUSIONS
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.
Vliagoftis
H
H
Pulmonary Research Group, the Departments Medicine University of Calgary, Calgary, Alberta, Canada.
Schwingshackl
A
A
Milne
C D
CD
Duszyk
M
M
Hollenberg
M D
MD
Wallace
J L
JL
Befus
A D
AD
Moqbel
R
R
D000305:Adrenal Cortex Hormones / Q000494:pharmacology; D004847:Epithelial Cells / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D044464:Receptor, PAR-2; D018179:Receptors, Thrombin / Q000502:physiology*; D012137:Respiratory System / Q000166:cytology*; D015398:Signal Transduction / Q000502:physiology; D014357:Trypsin / Q000494:pharmacology
D000305:Adrenal Cortex Hormones; D012333:RNA, Messenger; D044464:Receptor, PAR-2; D018179:Receptors, Thrombin; D014357:Trypsin; D020780:Matrix Metalloproteinase 9