Improved effects of novel glucocorticosteroids on immune-induced epithelial pathophysiology

Glucocorticosteroids are a mainstay therapy in inflammatory bowel disease and other chronic inflammatory conditions. However, severe systemic side effects are associated with their long-term use. The new generation of glucocorticosteroids have a high degree of topical activity with reduced systemic effects due to rapid metabolism. We previously described an in vitro model of inflammation in which monolayers of the human T84 colonic epithelial cell line displayed altered ion secretion and increased permeability after coculture with endotoxin-activated monocytes/macrophages (MPhi). Here, we tested the effects of budesonide and two novel analogs, D5519 and S1316, on MPhi-induced epithelial changes. Filter-grown T84 monolayers were cocultured with activated MPhi and single daily doses of drug were added to the luminal (physiological) side of the monolayer. Basal and stimulated epithelial ion transport [baseline short-circuit current (Isc) and DeltaIsc to forskolin, respectively] and barrier (transepithelial resistance) parameters were measured 48 h later in Ussing chambers. D5519, S1316, and budesonide (10(-7) to 10(-9) M) dose dependently inhibited the MPhi-induced epithelial abnormalities, restoring normal resistance, decreasing the elevated baseline Isc, and improving the reduced Isc response to forskolin. Of the drugs tested, D5519 was consistently the most potent and effective in inhibiting the MPhi-induced epithelial irregularities. Coupled with a further improvement in their rate of hepatic inactivation, our findings indicate that the novel steroids, particularly D5519, will be a valuable addition to current treatment strategies for inflammatory bowel disease and other chronic inflammatory conditions.