@article {XiaOA4751, author = {Yuxiu Connie Xia and Shenna Langenbach and Asmaa Radwan and Meina Li and Christine Keenan and Zixin Wong and Rosa Gualano and Alastair Stewart}, title = {Respiratory syncytial virus induces glucocorticoid insensitivity}, volume = {46}, number = {suppl 59}, elocation-id = {OA4751}, year = {2015}, doi = {10.1183/13993003.congress-2015.OA4751}, publisher = {European Respiratory Society}, abstract = {Introduction: Respiratory syncytial virus (RSV) and rhinovirus (RV) infection associates with asthma/COPD exacerbation, which responds inadequately to glucocorticoids (GC). Viral infection induces transforming growth factor-β (TGF-β). TGF-β is a mediator of GC insensitivity in epithelial cell types (Salem, S. et al. Br J Pharmacol2012;166:2036-2048; Keenan, C.R. et al. Respir Res 2014; 15:55)Aim: To explore the contribution of TGF-β to RSV-induced GC insensitivity.Methods: Bronchial epithelial cell line BEAS-2B cells were inoculated with strain A2 RSV or strain 16 RV at a multiplicity of infection of 0.1 for 1 hour, and incubated for 48 hour. BALB/c mice inoculated intranasally with 2{\texttimes}106 RSV for 5 days. GC transactivation was measured by GC Response Element (GRE)-dependent promoter activity and GC-responsive gene expression.Results: Viral infection ablated GC-induced GRE activation, and impaired GC-induced mRNA expression of GILZ (glucocorticoid-induced leucine zipper protein) and ENaCα (α subunit of epithelial sodium channel) in the cells. The impairment was attenuated by the selective ALK5 (TGFβRI) inhibitor, SB431542 and prevented by tranilast, which reduces TGF-β activity. RSV infection increased the number of cells and protein levels in bronchoalveolar lavage fluid of mice. RSV infection impairment of the GC-induced mRNA expression of GILZ in the lung was attenuated by tranilast.Conclusion: Both in vitro and in vivo data suggest that virus infection-induced GC insensitivity is partially mediated by TGF-β. Establishing the effectiveness of tranilast in viral infection supports the use of TGF-β modifying drugs in prevention/treatment of RSV infection-induced bronchiolitis and asthma/ COPD exacerbations.}, issn = {0903-1936}, URL = {https://erj.ersjournals.com/content/46/suppl_59/OA4751}, eprint = {https://erj.ersjournals.com/content}, journal = {European Respiratory Journal} }