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Reduced lung function in a chronic asthma model is associated with prolonged inflammation, but independent of peribronchial fibrosis.

Koerner-Rettberg C, Doths S, Stroet A, Schwarze J - PLoS ONE (2008)

Bottom Line: Further, long term challenges led to prolonged and intense airway inflammation with marked lymphocytosis, but moderate eosinophilia, sustained IL-5 production and ovalbumin-specific IgG2a antibodies, the latter suggesting a Th1 component to the immune response.In contrast, following short term challenges airway inflammation was dominated by eosinophils and associated with a strong, but transient IL-13 response.They are more closely associated with intense airway inflammation, marked lymphocytosis, prolonged IL-5 and TGF-beta1 production in the airways and a Th1 immune response.

View Article: PubMed Central - PubMed

Affiliation: Children's Hospital, Ruhr University of Bochum, Bochum, Germany.

ABSTRACT

Background: In asthma, mechanisms contributing to chronicity remain to be determined. Recent models of sensitisation with prolonged airway allergen challenges reproduce typical features of chronic asthma. However, the interplay between inflammation, structural changes and lung function is poorly understood. This study was performed to delineate functional, structural and immunological airway changes after cessation of long term challenges to elucidate factors contributing to the development of prolonged lung function changes.

Methodology/principal findings: Mice sensitised systemically were consecutively challenged intranasally with ovalbumin for two or eight weeks. After the end of challenges, lung function, airway inflammation, features of airway remodelling, local T-cell cytokines and systemic ovalbumin-specific antibodies were monitored. Long term challenges resulted in airway hyperresponsiveness lasting 2 weeks and reduced baseline lung function for 6 weeks after their cessation. In contrast, these changes resolved within one week after short term challenges. Prolonged transforming growth factor beta (TGF-beta)1 production and marked peribronchial fibrosis were only induced by long term challenges. Importantly, fibrosis became apparent only after the onset of lung function changes and outlasted them. Further, long term challenges led to prolonged and intense airway inflammation with marked lymphocytosis, but moderate eosinophilia, sustained IL-5 production and ovalbumin-specific IgG2a antibodies, the latter suggesting a Th1 component to the immune response. In contrast, following short term challenges airway inflammation was dominated by eosinophils and associated with a strong, but transient IL-13 response.

Conclusions: Prolonged lung function changes after long term allergen challenges seem to develop and resolve independently of the persistent peribronchial fibrosis. They are more closely associated with intense airway inflammation, marked lymphocytosis, prolonged IL-5 and TGF-beta1 production in the airways and a Th1 immune response.

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Cytokines in BAL fluid after long and short term airway challenges.Following OVA sensitisation and short or long term OVA challenges or after sham sensitisation and long or short term PBS challenges, concentrations of (a) IL-5, (b) IL-13 and (c) activated TGF-β1were measured in BAL fluid by ELISA 3 days to 8 weeks after final airway challenge, n≥15 per group from 5 independent experiments. Significant differences: * OVA challenges versus PBS controls, +long term versus short term OVA challenges, */+ p<0.05, **/++ p<0.01, ***/+++ p<0.001.
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pone-0001575-g004: Cytokines in BAL fluid after long and short term airway challenges.Following OVA sensitisation and short or long term OVA challenges or after sham sensitisation and long or short term PBS challenges, concentrations of (a) IL-5, (b) IL-13 and (c) activated TGF-β1were measured in BAL fluid by ELISA 3 days to 8 weeks after final airway challenge, n≥15 per group from 5 independent experiments. Significant differences: * OVA challenges versus PBS controls, +long term versus short term OVA challenges, */+ p<0.05, **/++ p<0.01, ***/+++ p<0.001.

Mentions: Th2 cytokines (IL-4, IL-5 and IL-13), which dominate many murine models of short term airway sensitisation, Th1cytokines (IFN-γ and IL-12), as well as IL-10, a cytokine associated with regulatory immune responses, were measured in BAL fluid by ELISA. Both short and long term OVA challenges induced increased levels of IL-5 and IL-13, however with marked differences between the two protocols (Fig 4a, b). Three days after final challenges, IL-13 dominated the response to short term challenges, while IL-5 was the dominant cytokine induced by prolonged challenges. IL-13 rapidly fell to undetectable levels by 2 weeks after challenges regardless of the protocol. IL-5 levels in contrast, persisted and even rose further 4 weeks after the final challenge in the long term challenge protocol, whereas the small increases in IL-5 after short term challenges were transient. IL-4 was only detected in minimal levels in both challenge protocols (data not shown). In addition to the Th2 cytokines, IFN-γ (up to 540 pg/ml) was induced 4 weeks after long term challenges in 25% of mice. This response failed to reach statistical significance, but IFN-γ was never detected after short term challenges. There were no significant changes in IL-10 and IL-12 levels in BAL fluid between challenge protocols (data not shown).


Reduced lung function in a chronic asthma model is associated with prolonged inflammation, but independent of peribronchial fibrosis.

Koerner-Rettberg C, Doths S, Stroet A, Schwarze J - PLoS ONE (2008)

Cytokines in BAL fluid after long and short term airway challenges.Following OVA sensitisation and short or long term OVA challenges or after sham sensitisation and long or short term PBS challenges, concentrations of (a) IL-5, (b) IL-13 and (c) activated TGF-β1were measured in BAL fluid by ELISA 3 days to 8 weeks after final airway challenge, n≥15 per group from 5 independent experiments. Significant differences: * OVA challenges versus PBS controls, +long term versus short term OVA challenges, */+ p<0.05, **/++ p<0.01, ***/+++ p<0.001.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2215329&req=5

pone-0001575-g004: Cytokines in BAL fluid after long and short term airway challenges.Following OVA sensitisation and short or long term OVA challenges or after sham sensitisation and long or short term PBS challenges, concentrations of (a) IL-5, (b) IL-13 and (c) activated TGF-β1were measured in BAL fluid by ELISA 3 days to 8 weeks after final airway challenge, n≥15 per group from 5 independent experiments. Significant differences: * OVA challenges versus PBS controls, +long term versus short term OVA challenges, */+ p<0.05, **/++ p<0.01, ***/+++ p<0.001.
Mentions: Th2 cytokines (IL-4, IL-5 and IL-13), which dominate many murine models of short term airway sensitisation, Th1cytokines (IFN-γ and IL-12), as well as IL-10, a cytokine associated with regulatory immune responses, were measured in BAL fluid by ELISA. Both short and long term OVA challenges induced increased levels of IL-5 and IL-13, however with marked differences between the two protocols (Fig 4a, b). Three days after final challenges, IL-13 dominated the response to short term challenges, while IL-5 was the dominant cytokine induced by prolonged challenges. IL-13 rapidly fell to undetectable levels by 2 weeks after challenges regardless of the protocol. IL-5 levels in contrast, persisted and even rose further 4 weeks after the final challenge in the long term challenge protocol, whereas the small increases in IL-5 after short term challenges were transient. IL-4 was only detected in minimal levels in both challenge protocols (data not shown). In addition to the Th2 cytokines, IFN-γ (up to 540 pg/ml) was induced 4 weeks after long term challenges in 25% of mice. This response failed to reach statistical significance, but IFN-γ was never detected after short term challenges. There were no significant changes in IL-10 and IL-12 levels in BAL fluid between challenge protocols (data not shown).

Bottom Line: Further, long term challenges led to prolonged and intense airway inflammation with marked lymphocytosis, but moderate eosinophilia, sustained IL-5 production and ovalbumin-specific IgG2a antibodies, the latter suggesting a Th1 component to the immune response.In contrast, following short term challenges airway inflammation was dominated by eosinophils and associated with a strong, but transient IL-13 response.They are more closely associated with intense airway inflammation, marked lymphocytosis, prolonged IL-5 and TGF-beta1 production in the airways and a Th1 immune response.

View Article: PubMed Central - PubMed

Affiliation: Children's Hospital, Ruhr University of Bochum, Bochum, Germany.

ABSTRACT

Background: In asthma, mechanisms contributing to chronicity remain to be determined. Recent models of sensitisation with prolonged airway allergen challenges reproduce typical features of chronic asthma. However, the interplay between inflammation, structural changes and lung function is poorly understood. This study was performed to delineate functional, structural and immunological airway changes after cessation of long term challenges to elucidate factors contributing to the development of prolonged lung function changes.

Methodology/principal findings: Mice sensitised systemically were consecutively challenged intranasally with ovalbumin for two or eight weeks. After the end of challenges, lung function, airway inflammation, features of airway remodelling, local T-cell cytokines and systemic ovalbumin-specific antibodies were monitored. Long term challenges resulted in airway hyperresponsiveness lasting 2 weeks and reduced baseline lung function for 6 weeks after their cessation. In contrast, these changes resolved within one week after short term challenges. Prolonged transforming growth factor beta (TGF-beta)1 production and marked peribronchial fibrosis were only induced by long term challenges. Importantly, fibrosis became apparent only after the onset of lung function changes and outlasted them. Further, long term challenges led to prolonged and intense airway inflammation with marked lymphocytosis, but moderate eosinophilia, sustained IL-5 production and ovalbumin-specific IgG2a antibodies, the latter suggesting a Th1 component to the immune response. In contrast, following short term challenges airway inflammation was dominated by eosinophils and associated with a strong, but transient IL-13 response.

Conclusions: Prolonged lung function changes after long term allergen challenges seem to develop and resolve independently of the persistent peribronchial fibrosis. They are more closely associated with intense airway inflammation, marked lymphocytosis, prolonged IL-5 and TGF-beta1 production in the airways and a Th1 immune response.

Show MeSH
Related in: MedlinePlus