PPAR ligands decrease human airway smooth muscle cell migration and extracellular matrix synthesis

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 proliferatoractivated 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 PPARa, b and c. 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-D12,14-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.

Regulation of IL-17A responses in human airway smooth muscle cells by Oncostatin M

“…Cultures of human airway smooth muscle cells (HASMC) were generated from airways obtained from lung cancer patients (ex–smokers, five diagnosed with COPD and 2 with no other conditions) undergoing thoracic surgery at St Joseph’s Healthcare Hamilton after obtaining their informed consent and with the approval of the local Research Ethics Board (approval RP#00-1839). Smooth muscle cells were isolated from disease-free areas of the airways and expanded in RPMI supplemented with 10% fetal bovine serum (FBS) and 1% L-Glutamine for up to 8 passages as previously described [ 45 ]. For analysis of cytokine synthesis, HASMC were plated at a cell density of 10,000- 20,000 cells per well in 24-well or 96-well tissue culture plates and incubated overnight.…”

Airway smooth muscle in airway reactivity and remodeling: what have we learned?

“…Certainly, therapeutic agents such as corticosteroids and even ␤ 2 -agonists can reduce proliferation (19,86). Furthermore, peroxisome proliferatoractivated receptor (PPAR)-␥ ligands can blunt ASM proliferation, migration, and ECM formation (63,72,73,250,293), and this mechanism may be of interest, given its emerging role in lung development and injury (180,220,247,260). Finally, there is increasing interest in atypical anti-inflammatory stimuli such as vitamin D (44,50).…”

Regulation of human airway smooth muscle cell migration and relevance to asthma

“…The precise mechanism of how LXR inhibits ASMC migration has yet to be established, but it has been speculated that it is not the Src Kinase, Akt or P38 MAPK pathways [ 107 ]. With respect to PPAR receptors, Stephen et al, reported that activation of PPAR receptors expressed on human ASMCs, resulted in decreased migration towards PGDF, an effect independent both of the promotion of PTEN activity, and inhibition of Akt phosphorylation [ 110 ]. They determined that the PPAR-mediated inhibition of ASMC migration was through an increase in intracellular cAMP, partly mediated by the induction of COX-2 and production of PGE 2 [ 110 ].…”