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.

Airway mesenchymal cells, such as myofibroblasts and airway smooth muscle cells, contribute to inflammation, airway remodelling and hyperresponsiveness in asthma by excessive proliferation and inflammatory mediator production.Using endobronchial biopsies obtained from both nonasthmatic and asthmatic subjects, in situ proliferation was assessed by immunostaining for cyclin D1. The number of immunoreactive cells increased with asthma severity and was restricted to the epithelium and subepithelial connective tissue. Despite increases in smooth muscle area, cyclin D1 was not detected in cells in intact muscle bundles.Biopsy-derived cell cultures were characterised as predominantly myofibroblasts, and were assessed to determine whether proliferation and cytokine production varied with asthma status. Cell enumeration showed that basal proliferation was similar in cells from nonasthmatics and asthmatics, and mitogenic responses to fibroblast growth factor-2, thrombin or serum were either reduced or unchanged in cells from asthmatics. Interleukin (IL)-1-dependent granulocytemacrophage colony-stimulating factor and IL-8 release was increased in cell supernatants from asthmatics.Thus, increased rates of cellular proliferation identified in situ in the asthmatic airway occurred outside the expanded smooth muscle compartment. Although reduced proliferative responses were observed in cultured myofibroblasts from asthmatics, the increased cytokine production by these cells suggests that this contributes to and may perpetuate ongoing inflammation in asthma.

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Inflammation is a major component in the pathology of chronic lung diseases, including asthma. Anti-inflammatory treatment with corticosteroids is not effective in all patients. Thus, new therapeutic options are required to control diverse cellular functions that are currently not optimally targeted by these drugs in order to inhibit inflammation and its sequelae in lung disease. Peroxisome proliferator activated receptors (PPARs), originally characterised as regulators of lipid and glucose metabolism, offer marked potential in this respect. PPARs are expressed in both lung infiltrating and resident immune and inflammatory cells, as well as in resident and structural cells in the lungs, and play critical roles in the regulation of airway inflammation. In vitro, endogenous and synthetic ligands for PPARs regulate expression and release of proinflammatory cytokines and chemoattractants, and cell proliferation and survival. In murine models of allergen-induced inflammation, PPARα and PPARγ ligands reduce the influx of inflammatory cells, cytokine and mucus production, collagen deposition, and airways hyperresponsiveness. The activity profiles of PPAR ligands differ to corticosteroids, supporting the hypothesis that PPARs comprise additional therapeutic targets to mimimise the contribution of inflammation to airway remodelling and dysfunction.

We have monitored oscillations in arterial pH (of respiratory frequency) in normal man at rest and during exercise. The pH oscillations are known to reflect respiratory oscillations in arterial carbon dioxide tension generated at the lungs. We have found that the pH oscillations increase in their upslope and downslope during exercise. This means that oscillations in arterial carbon dioxide tension can be considered as a control signal.