Glucocorticoids Augment Fibroblast‐Mediated Contraction of Collagen Gels by Inhibition of Endogenous PGE Production

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Abstract
Glucocorticoids are currently regarded as the drug of choice in the treatment of inflammatory airway and lung diseases, however, they are not routinely effective in fibrotic phases of inflammation. In the current study, glucocorticoids were investigated for their ability to affect fibroblast mediated contraction of a three dimensional collagen gel, a measure of one aspect of tissue remodeling. Dexamethasone, budesonide, hydrocortisone and fluticasone propionate were all able to significantly augment fibroblast contractility in a concentration dependent manner. Glucocorticoids also had an augmentative effect on collagen gel contraction mediated by fibroblasts from bronchi, skin and bone marrow. The increased contractility was not due to cell proliferation or to collagen degradation, since the glucocorticoids did not alter the amounts of DNA and hydroxyproline in the gels. The concentration of prostaglandin E2 (PGE2) in supernatant media was lower from glucocorticoid-treated gels compared to control gels. Consistent with this, addition of exogenous PGE2 to the culture system restored the contractile properties 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, forskolin and the long lasting beta2-agonist formoterol were able to reverse the effect of the glucocorticoids on fibroblast mediated collagen gel contraction suggesting that enhancers of cAMP can counteract the effect of glucocorticoids. Thus, we provide evidence that glucocorticoids have the ability to directly augment fibroblast contractility by inhibiting fibroblast endogenous PGE synthesis. The findings could be one possible mechanism to explain the poor therapeutic response to glucocorticoids on the later stages of fibrotic diseases.

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