MUC5AC drives COPD exacerbation severity through amplification of virus-induced airway inflammation

Aran Singanayagam; Joseph Footitt; Benjamin T Kasdorf; Matthias Marczynski; Michael T Cross; Lydia J Finney; Maria-Belen Trujillo Torralbo; Maria Calderazzo; Jie Zhu; Julia Aniscenko; Thomas B Clarke; Philip L Molyneaux; Nathan W Bartlett; Miriam F Moffatt; William O Cookson; Jadwiga Wedzicha; Christopher M Evans; Oliver Lieleg; Patrick Mallia; Sebastian L Johnston

Administration of the EGFR inhibitor AG1478 prior to RV infection in elastase treated mice ( Fig.6a) suppressed RV-induction of lung Muc5ac mRNA, BAL MUC5AC protein (Fig.6b) and suppressed airway epithelial cell mucus staining in lung sections (Fig. 6c , control groups are shown in Supplementary Fig. 7) . AG1478 had no effect on BAL MUC5B protein concentrations (Supplementary Fig.8a&b ). AG1478 administration in elastase-treated mice also suppressed RV-induction of BAL cellular airway inflammation (Fig.6d) , as well as chemokines CXCL1/KC, CXCL2/MIP-2 and CCL5/RANTES (Fig.6e) , pro-inflammatory cytokines IL-1b, IL-6, TNF and GM-CSF ( Fig.6f ) and neutrophil elastase (Fig.6g ). AG1478 treatment in elastase-treated RV-infected mice also enhanced BAL SLPI levels and reduced pulmonary bacterial loads (Fig.6h ). Finally, elastase and AG1478-treated RV-infected mice had reduced AHR to methacholine challenge compared to elastase and vehicle treated, RV infected controls (Fig.6i) These anti-inflammatory effects of AG1478 were not mediated via interference with antiviral immune responses or virus control, as we also observed no effect of AG1478 on RVinduction of IFN-α, IFN-l2/3 (Supplementary Fig.8c&d ) or lung virus loads.