Glucocorticoids augment fibroblast-mediated contraction of collagen gels by inhibition of endogenous PGE production

Glucocorticoids are currently regarded as the drug of choice in the treatme nt of inflammatory airway and lung diseases, however, they are not routinel y effective in fibrotic phases of inflammation. In the current study, gluco corticoids were investigated for their ability to affect fibroblast mediate d contraction of a three dimensional collagen gel, a measure of one aspect of tissue remodeling. Dexamethasone, budesonide, hydrocortisone and flutica sone propionate were all able to significantly augment fibroblast contracti lity in a concentration dependent manner. Glucocorticoids also had an augme ntative effect on collagen gel contraction mediated by fibroblasts from bro nchi, skin and bone marrow. The increased contractility was not due to cell proliferation or to collagen degradation, since the glucocorticoids did no t alter the amounts of DNA and hydroxyproline in the gels. The concentratio n of prostaglandin E-2 (PGE(2)) in supernatant media was lower from glucoco rticoid-treated gels compared to control gels. Consistent with this, additi on of exogenous PGE(2) to the culture system restored the contractile prope rties and indomethacin augmented contraction similar to the glucocorticoids suggesting that inhibition of prostaglandins or related eicosanoids may be the mechanism by which the increased contractility occurs. DBcAMP, forskol in and the long lasting beta(2)-agonist formoterol were able to reverse the effect of the glucocorticoids on fibroblast mediated collagen gel contract ion suggesting that enhancers of cAMP can counteract the effect of glucocor ticoids. Thus, we provide evidence that glucocorticoids have the ability to directly augment fibroblast contractility by inhibiting fibroblast endogen ous PGE synthesis. The findings could be one possible mechanism to explain the poor therapeutic response to glucocorticoids on the later stages of fib rotic diseases.