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

Singanayagam A, Glanville N, Walton RP, Aniscenko J, Pearson RM, Pinkerton JW, Horvat JC, Hansbro PM, Bartlett NW, Johnston SL - Clin. Sci. (2015)

Bottom Line: 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.Therefore, these approaches did not accurately model the enhanced inflammation associated with RV infection in patients with COPD compared with healthy subjects.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.

View Article: PubMed Central - PubMed

Affiliation: *Airway Disease Infection Section, National Heart and Lung Institute, Imperial College London, London W2 1PG, U.K.

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.

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Deficient IFN-λ production in RV-infected mice with elastase-induced COPDMice were challenged intranasally with single-dose elastase or PBS as control. On day 10 after elastase or PBS challenge, mice were additionally challenged intranasally with RV1B or UV-inactivated RV1B (UV). (a) IFN-λ mRNA, (b) IFN-β mRNA and (c) RV RNA in lung tissue was measured by Taqman quantitative PCR. n=5 mice/group. Data were analysed by two-way ANOVA and Bonferroni post-hoc test. ***P<0.001.
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Figure 7: Deficient IFN-λ production in RV-infected mice with elastase-induced COPDMice were challenged intranasally with single-dose elastase or PBS as control. On day 10 after elastase or PBS challenge, mice were additionally challenged intranasally with RV1B or UV-inactivated RV1B (UV). (a) IFN-λ mRNA, (b) IFN-β mRNA and (c) RV RNA in lung tissue was measured by Taqman quantitative PCR. n=5 mice/group. Data were analysed by two-way ANOVA and Bonferroni post-hoc test. ***P<0.001.

Mentions: In our human model of RV-induced COPD exacerbation, there was evidence of a deficiency in type I interferon responses to RV [7]. We therefore assessed innate anti-viral immune responses and virus loads in the single-dose elastase-induced COPD model. Lung tissue IFN-λ levels were reduced in elastase + RV- compared with PBS + RV-treated mice on day 1 post-infection (Figure 7a). There was no significant difference in lung IFN-β mRNA levels (Figure 7b) and no significant effect of elastase treatment on lung tissue RV RNA levels on either day 1 or day 4 post-infection (Figure 7c).


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

Singanayagam A, Glanville N, Walton RP, Aniscenko J, Pearson RM, Pinkerton JW, Horvat JC, Hansbro PM, Bartlett NW, Johnston SL - Clin. Sci. (2015)

Deficient IFN-λ production in RV-infected mice with elastase-induced COPDMice were challenged intranasally with single-dose elastase or PBS as control. On day 10 after elastase or PBS challenge, mice were additionally challenged intranasally with RV1B or UV-inactivated RV1B (UV). (a) IFN-λ mRNA, (b) IFN-β mRNA and (c) RV RNA in lung tissue was measured by Taqman quantitative PCR. n=5 mice/group. Data were analysed by two-way ANOVA and Bonferroni post-hoc test. ***P<0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4557402&req=5

Figure 7: Deficient IFN-λ production in RV-infected mice with elastase-induced COPDMice were challenged intranasally with single-dose elastase or PBS as control. On day 10 after elastase or PBS challenge, mice were additionally challenged intranasally with RV1B or UV-inactivated RV1B (UV). (a) IFN-λ mRNA, (b) IFN-β mRNA and (c) RV RNA in lung tissue was measured by Taqman quantitative PCR. n=5 mice/group. Data were analysed by two-way ANOVA and Bonferroni post-hoc test. ***P<0.001.
Mentions: In our human model of RV-induced COPD exacerbation, there was evidence of a deficiency in type I interferon responses to RV [7]. We therefore assessed innate anti-viral immune responses and virus loads in the single-dose elastase-induced COPD model. Lung tissue IFN-λ levels were reduced in elastase + RV- compared with PBS + RV-treated mice on day 1 post-infection (Figure 7a). There was no significant difference in lung IFN-β mRNA levels (Figure 7b) and no significant effect of elastase treatment on lung tissue RV RNA levels on either day 1 or day 4 post-infection (Figure 7c).

Bottom Line: 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.Therefore, these approaches did not accurately model the enhanced inflammation associated with RV infection in patients with COPD compared with healthy subjects.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.

View Article: PubMed Central - PubMed

Affiliation: *Airway Disease Infection Section, National Heart and Lung Institute, Imperial College London, London W2 1PG, U.K.

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.

Show MeSH
Related in: MedlinePlus