Abstract
Background: Asthma is a complex chronic inflammatory disease characterised by airway inflammation, remodelling and hyperresponsiveness (AHR). Members of the AP-1 transcription factor family play important roles in the activation of the immune system and the control of cellular responses; however, their role in the development of asthma has not been well studied. We aimed to investigate the role of the lesser known AP-1 family member, Fra2 in experimental asthma.Methods: Phenotypic characterisation and gene expression profiling was performed on Fra2 (TG) overexpressing and wild-type mice. The efficacy of therapeutic interventions in regulating the Fra2 phenotype was determined.Results: Transcriptional profiling of TG mice revealed a high abundance of regulated genes associated with airway remodelling, inflammation and mucus production. A concomitant increase in peribronchial collagen deposition, smooth muscle thickening and mucus production was observed. TG mice possessed increased inflammatory infiltration in the lung, predominantly consisting of eosinophils and T-cells and elevated expression of Th2 cytokines and eotaxin. Furthermore, TG mice possessed severe AHR in response to increasing doses of methacholine. Glucocorticoid treatment led to a partial improvement of the asthma phenotype, whereas blockade of IL-13 via neutralising antibodies ameliorated AHR and mucus production, but had no effect on collagen deposition.Conclusion: We here describe a novel model for non-allergic asthma that does not require the application of exogenous allergens, which mimics several key features of the disease, such as airway inflammation, remodelling and hyperresponsiveness. Fra2 may represent a key molecule coordinating multiple aspects of asthma pathogenesis.
Highlights
Asthma is a chronic lung disease that affects over 300 million people worldwide [1]
We previously observed that Fra2 overexpression in mice causes age-dependent lung remodelling and peribronchial inflammation (Figure E1) [31]
To understand how Fra-2 gives rise to these pathological changes, we performed gene expression profiling in 16 week-old Fra2 TG mice and wild-type mouse (WT) littermates (Figure 1A)
Summary
Airway remodelling manifests as mucus cell metaplasia, smooth muscle thickening and sub-epithelial fibrosis, which gives rise to airway obstruction and hyperresponsiveness (AHR) [2]. Fra Overexpressing Mice Develop Asthma allergic response [3]. IL-4 is important in the initiation of allergic responses (Th2 cell proliferation or IgE synthesis), while IL-13 is more important for the effector phase (induction of AHR, mucus production and airway smooth muscle hyperplasia) [5]. Asthma is a complex chronic inflammatory disease characterised by airway inflammation, remodelling and hyperresponsiveness (AHR). Members of the AP-1 transcription factor family play important roles in the activation of the immune system and the control of cellular responses; their role in the development of asthma has not been well studied. We aimed to investigate the role of the lesser known AP-1 family member, Fra in experimental asthma
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