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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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Lung function following long and short term airway challenges.(a) Following OVA sensitisation and short or long term OVA challenges or after sham sensitisation and long or short term PBS challenges, airway responsiveness to MCh was assessed 48 hours after final airway challenge and then weekly for 8 weeks. Mean±SEM of Penh values at 50 mg/ml MCh are shown for the first 4 weeks only from 3 independent experiments (n≥12). No differences between groups were detected after week 4. (b) Baseline Penh values were assessed during the same measurements. Mean±SEM from 5 independent experiments are illustrated (n≥15). Significant differences: * long term OVA challenges versus PBS control, +short term OVA challenges versus PBS control, levels of significance: */+ p<0,01, **/++ p<0,001.
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pone-0001575-g001: Lung function following long and short term airway challenges.(a) Following OVA sensitisation and short or long term OVA challenges or after sham sensitisation and long or short term PBS challenges, airway responsiveness to MCh was assessed 48 hours after final airway challenge and then weekly for 8 weeks. Mean±SEM of Penh values at 50 mg/ml MCh are shown for the first 4 weeks only from 3 independent experiments (n≥12). No differences between groups were detected after week 4. (b) Baseline Penh values were assessed during the same measurements. Mean±SEM from 5 independent experiments are illustrated (n≥15). Significant differences: * long term OVA challenges versus PBS control, +short term OVA challenges versus PBS control, levels of significance: */+ p<0,01, **/++ p<0,001.

Mentions: Following short term as well as long term OVA challenges in OVA sensitised mice, AHR of comparable magnitude developed. 48 hours after the last challenge maximal Penh values at 50 mg/ml MCh were 7.38±0.72 and 6.74±0.37 for long term and short term challenges respectively, compared to 3.96±0.26 in PBS challenged controls. After short term challenges AHR resolved within one week, while it persisted for 2 weeks after long term challenges (Fig 1a). In addition, baseline Penh values in the absence of provocation were significantly increased 48 hours after OVA challenges in both treatment groups compared to mice challenged with PBS (Fig 1b). Interestingly, in contrast to AHR, baseline Penh values remained elevated for up to 6 weeks following long term challenges, while they normalised within a week after short term challenges (Fig 1b).


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)

Lung function following long and short term airway challenges.(a) Following OVA sensitisation and short or long term OVA challenges or after sham sensitisation and long or short term PBS challenges, airway responsiveness to MCh was assessed 48 hours after final airway challenge and then weekly for 8 weeks. Mean±SEM of Penh values at 50 mg/ml MCh are shown for the first 4 weeks only from 3 independent experiments (n≥12). No differences between groups were detected after week 4. (b) Baseline Penh values were assessed during the same measurements. Mean±SEM from 5 independent experiments are illustrated (n≥15). Significant differences: * long term OVA challenges versus PBS control, +short term OVA challenges versus PBS control, levels of significance: */+ p<0,01, **/++ p<0,001.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2215329&req=5

pone-0001575-g001: Lung function following long and short term airway challenges.(a) Following OVA sensitisation and short or long term OVA challenges or after sham sensitisation and long or short term PBS challenges, airway responsiveness to MCh was assessed 48 hours after final airway challenge and then weekly for 8 weeks. Mean±SEM of Penh values at 50 mg/ml MCh are shown for the first 4 weeks only from 3 independent experiments (n≥12). No differences between groups were detected after week 4. (b) Baseline Penh values were assessed during the same measurements. Mean±SEM from 5 independent experiments are illustrated (n≥15). Significant differences: * long term OVA challenges versus PBS control, +short term OVA challenges versus PBS control, levels of significance: */+ p<0,01, **/++ p<0,001.
Mentions: Following short term as well as long term OVA challenges in OVA sensitised mice, AHR of comparable magnitude developed. 48 hours after the last challenge maximal Penh values at 50 mg/ml MCh were 7.38±0.72 and 6.74±0.37 for long term and short term challenges respectively, compared to 3.96±0.26 in PBS challenged controls. After short term challenges AHR resolved within one week, while it persisted for 2 weeks after long term challenges (Fig 1a). In addition, baseline Penh values in the absence of provocation were significantly increased 48 hours after OVA challenges in both treatment groups compared to mice challenged with PBS (Fig 1b). Interestingly, in contrast to AHR, baseline Penh values remained elevated for up to 6 weeks following long term challenges, while they normalised within a week after short term challenges (Fig 1b).

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