PPARγ ligands, 15‐deoxy‐Δ^12,14‐prostaglandin J₂ and rosiglitazone regulate human cultured airway smooth muscle proliferation through different mechanisms

Abstract

1 The influence of two peroxisome proliferator-activated receptor g (PPARg) ligands, a thiazolidinedione, rosiglitazone (RG) and the prostaglandin D 2 metabolite 15-deoxy-D 12,14 -prostaglandin J 2 (15d-PGJ 2 ) on the proliferation of human cultured airway smooth muscle (HASM) was examined. 2 The increases in HASM cell number in response to basic fibroblast growth factor (bFGF, 300 pM) or thrombin (0.3 U ml À1 ) were significantly inhibited by either RG (1-10 mM) or 15d-PGJ 2 (1-10 mM). The effects of RG, but not 15d-PGJ 2 , were reversed by the selective PPARg antagonist GW9662 (1 mM). 3 Neither RG nor 15d-PGJ 2 (10 mM) decreased cell viability, or induced apoptosis, suggesting that the regulation of cell number was due to inhibition of proliferation, rather than increased cell death. 4 Flow-cytometric analysis of HASM cell cycle distribution 24 h after bFGF addition showed that RG prevented the progression of cells from G1 to S phase. In contrast, 15d-PGJ 2 caused an increase in the proportion of cells in S phase, and a decrease in G2/M, compared to bFGF alone. 5 Neither RG nor 15d-PGJ 2 inhibited ERK phosphorylation measured 6 h post mitogen addition. The bFGF-mediated increase in cyclin D1 protein levels after 8 h was reduced in the presence of 15d-PGJ 2 , but not RG. 6 Although both RG and 15d-PGJ 2 can inhibit proliferation of HASM irrespective of the mitogen used, only the antiproliferative effects of RG appear to be PPARg-dependent. The different antimitogenic mechanisms of 15d-PGJ 2 and synthetic ligands for PPARg may be exploited to optimise the potential for these compounds to inhibit airway remodelling in asthma.

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

“…We confirm previous observations that HASM cells express the PPARa and c isoforms [9][10][11]. In addition, they also express the PPARb.…”

“…The PPARa and c isoforms are reported to be expressed on airway smooth muscle cells [9,10], and their activation by ligands such as the thiazolidinedione rosiglitazone have anti-inflammatory properties that are superior to corticosteroids [11]. PPAR ligands can decrease human vascular smooth muscle migration [12] and matrix production by renal mesangial cells [13].…”

Rosiglitazone induces interleukin‐1 receptor antagonist in interleukin‐1β–stimulated rat synovial fibroblasts via a peroxisome proliferator–activated receptor β/δ–dependent mechanism

“…Such differences between natural and synthetic PPAR␥ ligands is not surprising, since it has been reported in other cell types, including chondrocytes (47)(48)(49). In synoviocytes, rosiglitazone partly restored the imbalance between IL-1␤ and IL-1Ra, whereas 15-deoxy-PGJ 2 triggered the deleterious effects of IL-1␤ because of its ability to decrease the production of IL-1Ra more efficiently than that of IL-1␤.…”

Airway smooth muscle dynamics: a common pathway of airway obstruction in asthma

“…Peroxisome proliferatoractivated receptor (PPAR)-c ligands have also been shown to reduce ASM proliferation in response to thrombin, basic fibroblast growth factor and foetal bovine serum [102,103]. The PPAR-c ligand ciglitazone induces ASM cell apoptosis [102] at concentrations exceeding that required to inhibit proliferation [103]. Future studies are needed in this important area to assess the therapeutic potential of pro-apoptotic agents in reducing or reversing ASM tissue thickening.…”

“…Therapeutic approaches to alter rates of apoptosis might well be useful to diminishing airway remodelling. Peroxisome proliferatoractivated receptor (PPAR)-c ligands have also been shown to reduce ASM proliferation in response to thrombin, basic fibroblast growth factor and foetal bovine serum [102,103]. The PPAR-c ligand ciglitazone induces ASM cell apoptosis [102] at concentrations exceeding that required to inhibit proliferation [103].…”