fluticasone and Metaplasia

Bronchial epithelial goblet cell metaplasia (GCM) with hyperplasia is a prominent feature of asthma, but the effects of treatment with corticosteroids alone or in combination with a long-acting β. To determine whether corticosteroid alone or in combination with a LABA alters protein and gene expression pathways associated with IL-13-induced goblet cell metaplasia.. We evaluated the effects of fluticasone propionate (FP) and of salmeterol (SM), on the response of well-differentiated cultured bronchial epithelial cells to interleukin-13 (IL-13). Outcome measures included gene expression of SPDEF/FOXa2, gene expression and protein production of MUC5AC/MUC5B and morphologic appearance of cultured epithelial cell sheets. We additionally analysed expression of these genes in bronchial epithelial brushings from healthy, steroid-naïve asthmatic and steroid-treated asthmatic subjects. In cultured airway epithelial cells, FP treatment inhibited IL-13-induced suppression of FOXa2 gene expression and up-regulation of SPDEF, alterations in gene and protein measures of MUC5AC and MUC5B and induction of GCM. The addition of SM synergistically modified the effects of FP modestly-only for gel-forming mucin MUC5AC. In bronchial epithelial cells recovered from asthmatic vs healthy human subjects, we found FOXa2 and MUC5B gene expression to be reduced and SPDEF and MUC5AC gene expression to be increased; these alterations were not observed in bronchial epithelial cells recovered after treatment with inhaled corticosteroids.. Corticosteroid treatment inhibits IL-13-induced GCM of the airways in asthma, possibly through its effects on SPDEF and FOXa2 regulation of mucin gene expression. These effects are modestly augmented by the addition of a long-acting ß-agonist. As we found evidence for drug treatment counteracting the effects of IL-13 on the epithelium, we conclude that further exploration into the mechanisms by which corticosteroids and long-acting β

Topics: Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Asthma; Biomarkers; Cells, Cultured; Enzyme-Linked Immunosorbent Assay; Fluticasone; Gene Expression Regulation; Goblet Cells; Hepatocyte Nuclear Factor 3-beta; Humans; Interleukin-13; Metaplasia; Mucins; Proto-Oncogene Proteins c-ets; Respiratory Mucosa; Salmeterol Xinafoate

Ozone (O3) is the principal oxidant pollutant in photochemical smog. Repeated exposures to O3 induces inflammation and mucous cell metaplasia in the nasal airways of laboratory animals. Our study was designed to determine the efficacy of a topical anti-inflammatory corticosteroid in preventing O3-induced rhinitis and mucous cell metaplasia in rat nasal epithelium. Male F344 rats were exposed to filtered air (0 ppm O3; air-controls) or 0.5 ppm O3, 8 h/day, for 3 or 5 days. Immediately before and after each exposure, rats received an intranasal instillation (50 microl/nasal passage) of a topical corticosteroid, fluticasone propionate (FP; 25 microg/nasal passage) or its vehicle only (0.01% ethanol in saline). Rats were killed 2 h after the third exposure (3-day exposure) or 3 days after the fifth exposure (5-day exposure) and nasal tissues were processed for light microscopy. Numeric densities of epithelial cells and neutrophils, and the amount of intraepithelial mucosubstances (IM) in the epithelium lining the maxilloturbinates were morphometrically determined. There were no significant differences in any measured parameter in air-exposed rats instilled with FP compared with air-exposed rats instilled with vehicle. Vehicle-treated rats exposed to ozone had neutrophilic rhinitis with 3.3- and 1.6-fold more intraepithelial neutrophils (3-day and 5-day exposure, respectively) and marked mucous cell metaplasia (5-day exposure only) with numerous mucous cells and approximately 60 times more IM in the nasal transitional epithelium compared with vehicle-treated air-controls. FP-treated rats exposed to ozone had minimal nasal inflammation (1.3-fold more intraepithelial neutrophils only after 3-day exposure) and minimal mucous cell metaplasia (5-fold more IM only after 5-day exposure) compared with vehicle-instilled, air-exposed rats. Results of this study indicate that FP-treatment is effective in attenuating not only O3-induced rhinitis (30-60% reduction) but also O3-induced mucous cell metaplasia (85% reduction) in rat nasal transitional epithelium. The cellular and molecular mechanisms involved in FP-induced attenuation of O3-induced nasal lesions remain to be determined.

Topics: Administration, Topical; Androstadienes; Animals; Anti-Inflammatory Agents; Cell Count; DNA; Epithelial Cells; Fluticasone; Glucocorticoids; Male; Metaplasia; Nasal Mucosa; Neutrophils; Ozone; Rats; Rats, Inbred F344; Rhinitis