Vol. 302, Issue 3, 1151-1157, September 2002

Fluticasone Propionate Inhibits Lipopolysaccharide-Induced Proinflammatory Response in Human Cystic Fibrosis Airway Grafts

Sandie Escotte, Claire Danel, Dominique Gaillard , Sylvie Benoit, Jacky Jacquot, Daniel Dusser, Jean-Michel Triglia, Caroline Majer-Teboul and Edith Puchelle

Institut National de la Santé et de la Recherche Médicale Unité 514, IFR 53, CHU Maison Blanche, Reims, France (S.E., D.G., S.B., J.J., E.P.); Service d'Anatomie et de Cytologie Pathologique, Hôpital Européen Georges Pompidou, Paris, France (C.D.); Service de Pneumologie, Hôpital Cochin, Paris, France (D.D.); Laboratoire Pol Bouin, Centre Hospitalier Universitaire Maison Blanche, Reims, France (D.G.); Service d'ORL pédiatrique, Hôpital d'enfants de la Timone, Marseille, France (J.-M.T.); and Département de Pharmacologie Clinique, GlaxoSmithKline, Marly-le-roi, France (C.M.-T.)

Airway inflammation, one of the major factors leading to lung damage in cystic fibrosis (CF) patients, is associated with an abnormal increase in proinflammatory cytokines. In this work, we demonstrate the increased release of the proinflammatory cytokines after lipopolysaccharide (LPS) stimulation: human interleukin (hIL)-8 in CF and non-CF airway xenografts, and hIL-6 and human growth-related oncogene- (hGRO-), which could be only analyzed in non-CF xenografts. Under basal conditions, we observed that hIL-8 was higher in CF xenografts compared with non-CF. We also report the anti-inflammatory effect of a glucocorticoid, fluticasone propionate (FP), on CF airway epithelium using a humanized model of airway inflammation developed in nude mice. In CF and non-CF tracheal xenografts, airway inflammation was induced by inoculating Pseudomonas aeruginosa LPS (4 h; 1 µg/ml) in the lumen of the xenografts. FP pretreatment (2 h; 10⁸ M) followed by P. aeruginosa LPS stimulation induced a significant reduction of LPS-induced hIL-8 release in airway liquid collected from CF and non-CF tracheal xenografts (85 and 80%, respectively). In non-CF tracheal xenografts, FP treatment before LPS stimulation induced a significant decrease in hIL-6 and hGRO-. From these data, we suggest that FP exerts anti-inflammatory properties that may be appropriate to CF therapy, at an early stage of the disease. In addition, these results demonstrate that the humanized airway model of inflammation provides a relevant tool for analyzing the effects of anti-inflammatory drugs in different diseases in which airway inflammation is implicated.