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


RESULTS
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.
Koerner-Rettberg
Cordula
C
Children's Hospital, Ruhr University of Bochum, Bochum, Germany.
Doths
Sandra
S
Stroet
Anke
A
Schwarze
Jürgen
J
D000485:Allergens / Q000276:immunology; D000818:Animals; D001249:Asthma / Q000473:pathology* / Q000503:physiopathology; D002908:Chronic Disease; D005355:Fibrosis; D007249:Inflammation / Q000209:etiology*; D015848:Interleukin-5 / Q000096:biosynthesis; D008168:Lung / Q000503:physiopathology*; D008218:Lymphocytosis; D051379:Mice; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis
D000485:Allergens; D015848:Interleukin-5; D053773:Transforming Growth Factor beta1