The effect of glucocorticoids on proliferation of human cultured airway smooth muscle.

1. Airway smooth muscle proliferation is a significant component of the airway wall remodelling that occurs in asthma. In this study, the effects of glucocorticoids on mitogenic responses of human airway smooth muscle have been examined. 2. Pretreatment of smooth muscle cells with dexamethasone (100 nM, 60 min) inhibited thrombin-induced increases in [3H]-thymidine incorporation (DNA synthesis) and cell number. 3. Inhibition of thrombin-induced [3H]-thymidine incorporation was also observed with hydrocortisone (0.01-1 microM) and methylprednisolone (0.001-0.1 microM) pretreatment. In contrast, pretreatment with either testosterone (0.001-1 microM) progesterone (0.001-1 microM), 17 beta-oestradiol (0.001-1 microM), or aldosterone (0.001-1 microM) had no effect on the response to thrombin. 4. Responses to a range of mitogens including thrombin (0.01-. 10 u ml-1), epidermal growth factor (EGF, 3-3000 pM), basic fibroblast growth factor (bFGF, 0.3-300 pM) and foetal calf serum (FCS, 0.1-10% v/v) were inhibited by dexamethasone (100 nM) pretreatment. However, the magnitude of the inhibitory effect was dependent on the mitogen, with EGF being the least, and thrombin being the most sensitive to the inhibitory effect. 5. The potency of hydrocortisone as an inhibitor of [3H]-thymidine incorporation was reduced when FCS (10% v/v, which caused a 40 fold increase in [3H]-thymidine incorporation) was used as the mitogen in place of thrombin (0.3 u ml-1, which caused a 10 fold increase in [3H]-thymidine incorporation). 6. The effect of post-treatment with dexamethasone (100 nM) indicated that addition of the glucocorticoid up to 17-19 h after thrombin (0.3 u ml-1) produced similar degrees of inhibition to those obtained when it was added as a pretreatment. Dexamethasone no longer produced an inhibitory effect if added 21 h or more after the addition of thrombin. 7. These results suggest that glucocorticoids regulate airway smooth muscle proliferation initiated by a range of stimuli. This effect may be of importance in the therapeutic actions of these compounds in asthma, particularly when they are used for prolonged periods of time.