title: A short-term mouse model that reproduces the immunopathological features of rhinovirus-induced exacerbation of COPD.
abstract: Viral exacerbations of chronic obstructive pulmonary disease (COPD), commonly caused by rhinovirus (RV) infections, are poorly controlled by current therapies. This is due to a lack of understanding of the underlying immunopathological mechanisms. Human studies have identified a number of key immune responses that are associated with RV-induced exacerbations including neutrophilic inflammation, expression of inflammatory cytokines and deficiencies in innate anti-viral interferon. Animal models of COPD exacerbation are required to determine the contribution of these responses to disease pathogenesis. We aimed to develop a short-term mouse model that reproduced the hallmark features of RV-induced exacerbation of COPD. Evaluation of complex protocols involving multiple dose elastase and lipopolysaccharide (LPS) administration combined with RV1B infection showed suppression rather than enhancement of inflammatory parameters compared with control mice infected with RV1B alone. Therefore, these approaches did not accurately model the enhanced inflammation associated with RV infection in patients with COPD compared with healthy subjects. In contrast, a single elastase treatment followed by RV infection led to heightened airway neutrophilic and lymphocytic inflammation, increased expression of tumour necrosis factor (TNF)-α, C-X-C motif chemokine 10 (CXCL10)/IP-10 (interferon γ-induced protein 10) and CCL5 [chemokine (C-C motif) ligand 5]/RANTES (regulated on activation, normal T-cell expressed and secreted), mucus hypersecretion and preliminary evidence for increased airway hyper-responsiveness compared with mice treated with elastase or RV infection alone. In summary, we have developed a new mouse model of RV-induced COPD exacerbation that mimics many of the inflammatory features of human disease. This model, in conjunction with human models of disease, will provide an essential tool for studying disease mechanisms and allow testing of novel therapies with potential to be translated into clinical practice.
authors.affiliation: *Airway Disease Infection Section, National Heart and Lung Institute, Imperial College London, London W2 1PG, U.K.
authors.forename: Aran
authors.initials: A
authors.lastname: Singanayagam
authors.affiliation: *Airway Disease Infection Section, National Heart and Lung Institute, Imperial College London, London W2 1PG, U.K.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Glanville
authors.affiliation: *Airway Disease Infection Section, National Heart and Lung Institute, Imperial College London, London W2 1PG, U.K.
authors.forename: Ross P
authors.initials: RP
authors.lastname: Walton
authors.affiliation: *Airway Disease Infection Section, National Heart and Lung Institute, Imperial College London, London W2 1PG, U.K.
authors.forename: Julia
authors.initials: J
authors.lastname: Aniscenko
authors.affiliation: *Airway Disease Infection Section, National Heart and Lung Institute, Imperial College London, London W2 1PG, U.K.
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Pearson
authors.affiliation: †Priority Research Centre for Asthma and Respiratory Disease, Hunter Medical Research Institute and University of Newcastle, Newcastle, NSW 2305, Australia.
authors.forename: James W
authors.initials: JW
authors.lastname: Pinkerton
authors.affiliation: †Priority Research Centre for Asthma and Respiratory Disease, Hunter Medical Research Institute and University of Newcastle, Newcastle, NSW 2305, Australia.
authors.forename: Jay C
authors.initials: JC
authors.lastname: Horvat
authors.affiliation: †Priority Research Centre for Asthma and Respiratory Disease, Hunter Medical Research Institute and University of Newcastle, Newcastle, NSW 2305, Australia.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Hansbro
authors.affiliation: *Airway Disease Infection Section, National Heart and Lung Institute, Imperial College London, London W2 1PG, U.K.
authors.forename: Nathan W
authors.initials: NW
authors.lastname: Bartlett
authors.affiliation: *Airway Disease Infection Section, National Heart and Lung Institute, Imperial College London, London W2 1PG, U.K.
authors.forename: Sebastian L
authors.initials: SL
authors.lastname: Johnston
mesh_terms: D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000821:virology; D018925:Chemokines / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D008070:Lipopolysaccharides / Q000276:immunology; D008810:Mice, Inbred C57BL; D010850:Picornaviridae Infections / Q000276:immunology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology / Q000821:virology*; D012229:Rhinovirus / Q000276:immunology*; D013997:Time Factors
chemical_list: D018925:Chemokines; D008070:Lipopolysaccharides