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European Respiratory Society Annual Congress 2013 Abstract Number: 2862 Publication Number: P3128 Abstract Group: 3.2. Airway Cell Biology and Immunopathology Keyword 1: Inflammation Keyword 2: Pharmacology Keyword 3: Smoking Title: Anti-inflammatory effects of roflumilast N-oxide and dexamethasone in human bronchial epithelial cells stimulated with toll-like receptor agonists Javier 12009 Milara [email protected] 1, Javier 12022 Lluch [email protected] 1, Patricia 12023 Almudever [email protected] 1, Teresa 12024 Peiró [email protected] 1, Adela 12025 Serrano [email protected] 1, Magdalena 12087 Alonso-Galicia [email protected] 2, Jose 12091 Freire [email protected] 2, Xiaozhong 12092 Qian [email protected] 2 and Julio 12093 Cortijo [email protected] 1. 1 Pharmacology, U Valencia, Fundación De Investigación Del Hospital General De Valencia, Valencia, Spain and 2 Pharmacology and Discovery, Forest Research Institute, Jersey City, United States . Body: Objective Bacterial and viral infections in COPD contribute to inflammation and exacerbations, and toll-like receptors (TLR) modulate the innate immune response to these infectious agents. This study explored the anti-inflammatory effects of dexamethasone (DEX) and roflumilast N-oxide (RNO) following TLR stimulation and cigarette smoke exposure, a condition which impairs glucocorticoid function. Methods Human bronchial epithelial cells (BEAS2B) were preincubated with DEX (0.1nM-1µM) or RNO (0.1nM-1µM) for 1h and then stimulated with the TLR2, 3, 4, 5 and 9 agonists peptidoglycan (10µg/ml), poly(I:C) (10µg/ml), LPS (1µg/ml), flagellin (1µg/ml) and ODN-2395 (5µM), in the presence or absence of 1% cigarette smoke extract (CSE) for 24h. IL-8 was measured by ELISA in cell supernatants. Results DEX dose-dependently inhibited TLR2-, 3-, 4-, 5- and 9-induced IL-8 release in cells exposed to air (–logIC50 (M): 7.6, 8.0, 8.2, 8.7 and 7.7). CSE impaired the response of DEX following stimulation with TLR4, 5 and 9 agonists (–logIC50 (M): 6.4, 6.9 and 5.8) but not TLR2 and 3 agonists. In contrast, RNO dose-dependently inhibited TLR2-, 3-, 4-, 5- and 9-induced IL-8 release in the absence (–logIC50 (M): 7.9, 8.0, 9.1, 8.1 and 7.4) and presence (–logIC50 (M): 7.8, 8.0, 9.0, 7.8 and 7.6) of CSE. Conclusions CSE exposure induced glucocorticosteroid resistance in bronchial epithelial cells, as shown by the shift in the –logIC50 values of DEX in inhibiting IL-8 release following TLR4, 5, and 9 stimulations compared to cells exposed to air. In contrast, RNO inhibited IL-8 release induced by all TLR agonists tested in the presence or absence of CSE.