Reduced Lung Function in a Chronic Asthma Model Is Associated with Prolonged Inflammation, but Independent of Peribronchial Fibrosis

Cordula Koerner-Rettberg,Anke Stroet,Jürgen Schwarze,Sandra Doths,Jacques Zimmer

doi:10.1371/journal.pone.0001575

Abstract

BackgroundIn 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 FindingsMice 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-β)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.ConclusionsProlonged 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-β1 production in the airways and a Th1 immune response.

Highlights

Asthma affects more than 10% of children in industrialized countries [1] and results in considerable morbidity and mortality
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-b1 production in the airways and a Th1 immune response
Mouse models of allergic airway sensitisation with short term allergen challenges have elucidated mechanisms of acute inflammatory and functional responses like airway eosinophilia and transient airway hyperresponsiveness (AHR) but failed to induce characteristic features of chronic asthma, such as airway wall remodelling, including sub-epithelial fibrosis [3] and muscular hypertrophy [4], and long term changes in lung function, all of which can be seen in models with prolonged airway challenges [5,6,7,8,9,10,11,12,13,14]

Summary

Introduction

Asthma affects more than 10% of children in industrialized countries [1] and results in considerable morbidity and mortality. Mouse models of allergic airway sensitisation with short term allergen challenges have elucidated mechanisms of acute inflammatory and functional responses like airway eosinophilia and transient airway hyperresponsiveness (AHR) (reviewed by Kumar [2]) but failed to induce characteristic features of chronic asthma, such as airway wall remodelling, including sub-epithelial fibrosis [3] and muscular hypertrophy [4], and long term changes in lung function, all of which can be seen in models with prolonged airway challenges [5,6,7,8,9,10,11,12,13,14]. 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

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Discussion

Conclusion