RT Journal Article SR Electronic T1 Improved Effects of Novel Glucocorticosteroids on Immune-Induced Epithelial Pathophysiology JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 1245 OP 1249 VO 289 IS 3 A1 Mehri Zareie A1 Ralph Brattsand A1 Philip M. Sherman A1 Derek M. McKay A1 Mary H. Perdue YR 1999 UL http://jpet.aspetjournals.org/content/289/3/1245.abstract AB 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 (MΦ). Here, we tested the effects of budesonide and two novel analogs, D5519 and S1316, on MΦ-induced epithelial changes. Filter-grown T84 monolayers were cocultured with activated MΦ 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 ΔIsc to forskolin, respectively] and barrier (transepithelial resistance) parameters were measured 48 h later in Ussing chambers. D5519, S1316, and budesonide (10−7 to 10−9m) dose dependently inhibited the MΦ-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 MΦ-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. The American Society for Pharmacology and Experimental Therapeutics