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AP-1 Subunit Overexpression Drives a Non-Allergic Asthma Phenotype in Mice
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A1299 - AP-1 Subunit Overexpression Drives a Non-Allergic Asthma Phenotype in Mice
Author Block: L. M. Marsh1, A. Gungl2, V. Biasin3, A. Olschewski3, G. Kwapiszewska1; 1Lung Vasculature Research, Ludwig Boltzmann Institute, Graz, Austria, 2Medical University of Graz, Graz, Austria, 3Lung Vascular Research, Ludwig Boltzmann Institute, Graz, Austria.
RATIONALE: Asthma is a complex chronic inflammatory disease characterised by airway inflammation, remodelling and hyperresponsiveness (AHR). Members of the AP-1 family of transcription factors have been shown to play important roles in the activation of the immune system and the control of cellular responses. Here we have investigated the role of one of the lesser known AP-1 family members, Fra2 in experimental asthma.
METHODS and RESULTS: Gene profiling of lung homogenates from mice overexpressing Fra2 (TG) compared to wildtype (WT) controls revealed a high abundance of genes associated with asthma and mucus production. In line with this finding TG mice exhibited increased airway remodelling, seen as peribronchial collagen deposition and smooth muscle thickening, and mucus production. TG mice possessed a time-dependent increase of inflammatory cells in the lung, predominately consisting of eosinophils and T cells. Cell recruitment was concomitant with increased expression of Th2 cytokines including IL-13 and also eotaxin. Furthermore, TG mice possessed AHR in response to increasing doses of methacholine. Blocking of IL-13 signalling decreased phosphorylation of Stat3 and ameliorated AHR, mucus secretion and eotaxin production, whereas airway remodelling and Th2 cytokine levels remained elevated in TG mice. Anti-inflammatory steroid treatment led to an overall improvement of lung function and AHR, as well as airway remodelling.
CONCLUSION: Here we show for the first time that the AP-1 family member Fra2 has an important implication in the development of asthma and describe a novel model for non-allergic asthma mimicking key features of the disease, such as airway inflammation, remodelling and hyperresponsiveness.
This study was funded in part by the Austrian Science Fund (FWF): P278488-B23
Author Block: L. M. Marsh1, A. Gungl2, V. Biasin3, A. Olschewski3, G. Kwapiszewska1; 1Lung Vasculature Research, Ludwig Boltzmann Institute, Graz, Austria, 2Medical University of Graz, Graz, Austria, 3Lung Vascular Research, Ludwig Boltzmann Institute, Graz, Austria.
RATIONALE: Asthma is a complex chronic inflammatory disease characterised by airway inflammation, remodelling and hyperresponsiveness (AHR). Members of the AP-1 family of transcription factors have been shown to play important roles in the activation of the immune system and the control of cellular responses. Here we have investigated the role of one of the lesser known AP-1 family members, Fra2 in experimental asthma.
METHODS and RESULTS: Gene profiling of lung homogenates from mice overexpressing Fra2 (TG) compared to wildtype (WT) controls revealed a high abundance of genes associated with asthma and mucus production. In line with this finding TG mice exhibited increased airway remodelling, seen as peribronchial collagen deposition and smooth muscle thickening, and mucus production. TG mice possessed a time-dependent increase of inflammatory cells in the lung, predominately consisting of eosinophils and T cells. Cell recruitment was concomitant with increased expression of Th2 cytokines including IL-13 and also eotaxin. Furthermore, TG mice possessed AHR in response to increasing doses of methacholine. Blocking of IL-13 signalling decreased phosphorylation of Stat3 and ameliorated AHR, mucus secretion and eotaxin production, whereas airway remodelling and Th2 cytokine levels remained elevated in TG mice. Anti-inflammatory steroid treatment led to an overall improvement of lung function and AHR, as well as airway remodelling.
CONCLUSION: Here we show for the first time that the AP-1 family member Fra2 has an important implication in the development of asthma and describe a novel model for non-allergic asthma mimicking key features of the disease, such as airway inflammation, remodelling and hyperresponsiveness.
This study was funded in part by the Austrian Science Fund (FWF): P278488-B23
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