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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: 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.

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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Single-dose elastase treatment induces lung function changesMice were challenged intranasally with a single dose of elastase or PBS as control. Ten days later, mice were infected intranasally with RV1B or UV-inactivated RV1B (UV). At day 1 after RV challenge, forced manoeuvre techniques and Flexivent were used to assess lung function parameters including (a) FRC, (b) TLC, (c) dynamic compliance, (d) tissue damping and (e) lung hysteresis. (f) AHR was measured by whole-body plethysmography at day 1 post-infection. (a–e) n=10 mice/group, two independent experiments combined. Data analysis by one-way ANOVA and Bonferroni post-hoc test (f) n=8 mice/group, two independent experiments combined. Data analysis by two-way ANOVA and Bonferroni post-hoc test. *P<0.05; **/ψψP<0.01; ***P<0.001. In (f), * indicates statistical comparison between elastase + RV and PBS + RV groups and ψ indicates comparison between elastase + RV and elastase + UV groups.
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Figure 6: Single-dose elastase treatment induces lung function changesMice were challenged intranasally with a single dose of elastase or PBS as control. Ten days later, mice were infected intranasally with RV1B or UV-inactivated RV1B (UV). At day 1 after RV challenge, forced manoeuvre techniques and Flexivent were used to assess lung function parameters including (a) FRC, (b) TLC, (c) dynamic compliance, (d) tissue damping and (e) lung hysteresis. (f) AHR was measured by whole-body plethysmography at day 1 post-infection. (a–e) n=10 mice/group, two independent experiments combined. Data analysis by one-way ANOVA and Bonferroni post-hoc test (f) n=8 mice/group, two independent experiments combined. Data analysis by two-way ANOVA and Bonferroni post-hoc test. *P<0.05; **/ψψP<0.01; ***P<0.001. In (f), * indicates statistical comparison between elastase + RV and PBS + RV groups and ψ indicates comparison between elastase + RV and elastase + UV groups.

Mentions: Assessment of lung function parameters in the single-dose elastase model showed abnormalities consistent with human COPD including increased FRC, TLC and increased dynamic lung compliance associated with elastase administration (elastase + UV compared with PBS + UV-treated mice; Figures 6a–6c). We did not observe any additional effect of RV infection on these abnormal parameters at day 1 post-challenge with no increases in FRC, TLC or dynamic compliance observed in elastase + RV- compared with elastase + UV-treated mice (Figures 6a–6c). There were no significant effects of elastase treatment and/or RV infection on tissue damping or lung hysteresis (Figures 6d and 6e). We also assessed AHR measured as PenH using whole-body plesmythography at 24 h post-RV challenge. Neither RV infection nor elastase treatment alone caused increased AHR compared with PBS + UV-treated controls. However, mice exposed to single-dose elastase followed by RV infection had significantly increased PenH at the highest dose of methacholine compared with PBS + RV- or elastase + UV-treated mice (Figure 6f).


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)

Single-dose elastase treatment induces lung function changesMice were challenged intranasally with a single dose of elastase or PBS as control. Ten days later, mice were infected intranasally with RV1B or UV-inactivated RV1B (UV). At day 1 after RV challenge, forced manoeuvre techniques and Flexivent were used to assess lung function parameters including (a) FRC, (b) TLC, (c) dynamic compliance, (d) tissue damping and (e) lung hysteresis. (f) AHR was measured by whole-body plethysmography at day 1 post-infection. (a–e) n=10 mice/group, two independent experiments combined. Data analysis by one-way ANOVA and Bonferroni post-hoc test (f) n=8 mice/group, two independent experiments combined. Data analysis by two-way ANOVA and Bonferroni post-hoc test. *P<0.05; **/ψψP<0.01; ***P<0.001. In (f), * indicates statistical comparison between elastase + RV and PBS + RV groups and ψ indicates comparison between elastase + RV and elastase + UV groups.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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Figure 6: Single-dose elastase treatment induces lung function changesMice were challenged intranasally with a single dose of elastase or PBS as control. Ten days later, mice were infected intranasally with RV1B or UV-inactivated RV1B (UV). At day 1 after RV challenge, forced manoeuvre techniques and Flexivent were used to assess lung function parameters including (a) FRC, (b) TLC, (c) dynamic compliance, (d) tissue damping and (e) lung hysteresis. (f) AHR was measured by whole-body plethysmography at day 1 post-infection. (a–e) n=10 mice/group, two independent experiments combined. Data analysis by one-way ANOVA and Bonferroni post-hoc test (f) n=8 mice/group, two independent experiments combined. Data analysis by two-way ANOVA and Bonferroni post-hoc test. *P<0.05; **/ψψP<0.01; ***P<0.001. In (f), * indicates statistical comparison between elastase + RV and PBS + RV groups and ψ indicates comparison between elastase + RV and elastase + UV groups.
Mentions: Assessment of lung function parameters in the single-dose elastase model showed abnormalities consistent with human COPD including increased FRC, TLC and increased dynamic lung compliance associated with elastase administration (elastase + UV compared with PBS + UV-treated mice; Figures 6a–6c). We did not observe any additional effect of RV infection on these abnormal parameters at day 1 post-challenge with no increases in FRC, TLC or dynamic compliance observed in elastase + RV- compared with elastase + UV-treated mice (Figures 6a–6c). There were no significant effects of elastase treatment and/or RV infection on tissue damping or lung hysteresis (Figures 6d and 6e). We also assessed AHR measured as PenH using whole-body plesmythography at 24 h post-RV challenge. Neither RV infection nor elastase treatment alone caused increased AHR compared with PBS + UV-treated controls. However, mice exposed to single-dose elastase followed by RV infection had significantly increased PenH at the highest dose of methacholine compared with PBS + RV- or elastase + UV-treated mice (Figure 6f).

Bottom Line: 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.

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