No 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.

No abstract

Subepithelial fibrosis is one of the characteristic features of asthmatic airways. The fibrotic response includes an increase in volume occupied by extracellular matrix (ECM) tissue, and a change in the ECM composition favouring wound type collagens, fibronectin and a number of glycoproteins and proteoglycans normally associated with development. The altered ECM is likely to be deposited by the mesenchymal cells (including (myo) fibroblasts and smooth muscle) that are increased in number in asthmatic airways. In turn, the altered asthmatic ECM is likely to influence the function of the resident airway cells, and may be directly responsible for increasing proliferation, migration, ECM synthesis, inflammatory mediator release, and survival of resident mesenchymal cells. Therefore, the deposited ECM may perpetuate the disease phenotype. The different components of the ECM bi-directionally communicate with cells through a family of transmembrane receptors called integrins. Current research has begun to characterize: 1) the particular ECM components altered in airways disease; 2) the breadth of activity of different ECM components on airway cell function; and 3) the particular integrins responsible for mediating these effects. Further understanding of the role of integrins in transmitting responses of ECM in healthy or diseased airways may lead to novel targets for anti-asthma therapy.

Glucocorticoids (GCS) inhibit mitogenesis of airway smooth muscle (ASM) cells grown on plastic. We have now evaluated the effects of GCS on proliferation of ASM grown on extracellular matrix proteins (ECM) abundant in noninflamed airways (laminin) and in fibrotic asthmatic airways (collagen type I). Dexamethasone inhibited basic fibroblast growth factor (bFGF)-induced proliferation in cells maintained on laminin, but not collagen. Cells grown on collagen were resistant to the anti-mitogenic actions of fluticasone propionate. In addition, dexamethasone did not inhibit thrombin-induced proliferation. Thus, resistance induced by collagen is not dependent on the mitogen and appears to be a class effect on GCS. The inhibition of bFGF-induced granulocyte -macrophage colony-stimulating factor production was unaffected by the ECM type on which cells were grown. The impaired anti-mitogenic activity of GCS in cells maintained on collagen may be due to a lack of efficacy against the collagen-amplified mitogenesis, rather than any defect in responsiveness that is specific to glucocorticoid receptor mechanisms.