PPAR ligands decrease human airway smooth muscle cell migration and extracellular matrix synthesis.
Airway smooth muscle cells produce extracellular matrix proteins, which in turn can promote smooth muscle survival, proliferation and migration. Currently available therapies have little effect on airway smooth muscle matrix production and migration. Peroxisome proliferator-activated receptor (PPAR) ligands are reported to decrease migration and matrix production in various cell lines. In this study, we examined the effect of PPAR ligands on human airway smooth muscle (HASM) matrix production and migration. PPAR expression was examined by RT-PCR and Western blotting. Endogenous PPAR activity was examined by transfecting cells with a PPAR response element-luciferase reporter plasmid. We observed that HASM cells express PPARα, β and γ. A six-fold induction of luciferase activity was observed by stimulating cells with a pan-agonist, indicating endogenous PPAR activity. The PPAR ligands ciglitazone, 15-deoxy-Δ12,14-prostaglandin J(2) and WY-14643 decreased migration towards platelet-derived growth factor receptor. This was not mediated by inhibiting Akt phosphorylation or promoting PTEN activity, but partly through cyclooxygenase-2 induction and prostaglandin E(2) production that increased cyclic AMP levels in the cells. All three ligands also caused an inhibition of collagen and fibronectin secretion by cultured smooth muscle cells. We conclude that PPAR ligands decrease HASM migration and matrix production and are, therefore, potentially useful for modulating airway remodelling.
Firestone Institure for Respiratory Health, St Joseph's Healthcare, Dept of Medicine, McMaster University, Hamilton, Ontario, Canada.
Jancy
J
Stephen
Chris
C
Delvecchio
Naomi
N
Spitale
Amanda
A
Giesler
Katherine
K
Radford
Pat
P
Bilan
P Gerard
PG
Cox
John P
JP
Capone
Parameswaran
P
Nair
D000328:Adult; D000368:Aged; D002465:Cell Movement; D002478:Cells, Cultured; D015232:Dinoprostone / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008024:Ligands; D008297:Male; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000187:drug effects; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D005353:Fibronectins; D008024:Ligands; D047492:Peroxisome Proliferator-Activated Receptors; D010744:Phosphoric Monoester Hydrolases; D015232:Dinoprostone