A short-term mouse model that reproduces the immunopathological features of rhinovirus-induced exacerbation of COPD.

Aran Singanayagam,Nathan W Bartlett,Philip M Hansbro,Nicholas Glanville,James W Pinkerton,Rebecca M Pearson,Jay C Horvat,Ross P Walton,Julia Aniscenko,Sebastian L Johnston

doi:10.1042/cs20140654

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.

Highlights

Chronic obstructive pulmonary disease (COPD) is the most common chronic respiratory condition in adults and its prevalence is expected to increase markedly in the future [1]
Consistent with the previous report of this model, we found that induction of IFN-β and IFN-λ mRNAs in lung tissue in vivo were reduced with 4 weeks of elastase/LPS administration followed by RV infection compared with treatment with PBS and infection with RV (PBS+RV; modelling RV infected healthy subjects) (Figures S1b and S1c)
In contrast with the original report of this model, we found that elastase/LPS treatment followed by RV infection led to reduced rather than increased lung virus loads compared with non-COPD mice infected with RV (Figure S1e), reduced rather than increased expression of tumour necrosis factor (TNF)-α and no difference in MUC5AC mRNA levels in lung tissue compared with PBS + RV-treated mice (Supplementary Figures S1f and S1g)

Summary

Introduction

Chronic obstructive pulmonary disease (COPD) is the most common chronic respiratory condition in adults and its prevalence is expected to increase markedly in the future [1]. A. Singanayagam and others studies, but these studies are limited by variability in factors such as time between virus infection and presentation and treatments initiated prior to sampling. Singanayagam and others studies, but these studies are limited by variability in factors such as time between virus infection and presentation and treatments initiated prior to sampling To address these issues, we have developed a model of experimental RV-induced COPD exacerbation in humans that allows sequential measurement of a range of clinical and inflammatory parameters and has provided a clearer understanding of the relationship between virus infection, inflammatory responses and biological and physiological markers [7]. RV infection in patients with COPD has been shown to be associated with enhanced airway neutrophilia and lymphocytosis and increased neutrophil chemokine CXCL8/IL-8 expression compared with RV infection in healthy smokers [7,15,16]

Objectives

Methods

Results

Conclusion