Abstract
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 J2 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 E2 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.
- Airway smooth muscle migration
- asthma
- extracellular matrix
- peroxisome proliferator-activated receptor
- prostaglandin E2
Footnotes
Support Statement
This study was supported by a Firestone Institute–GlaxoSmithKline Research Award and an Ontario Thoracic Society Block-Term Grant. P. Nair holds a Canada Research Chair in Airway Inflammometry.
Statement of Interest
A statement of interest for the study itself can be found at www.erj.ersjournals.com/site/misc/statements.xhtml
- Received September 12, 2009.
- Accepted April 17, 2012.
- ©ERS 2013