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Pcdh1 Loss Leads to a SMAD3-Dependent Increase in HDM-Induced Airway Hyperresponsiveness in Mice
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A1195 - Pcdh1 Loss Leads to a SMAD3-Dependent Increase in HDM-Induced Airway Hyperresponsiveness in Mice
Author Block: M. C. Nawijn1, U. Brouwer1, L. den Boef1, L. Hesse1, G. H. Koppelman2; 1Experimental Pulmonology and Inflammation Research, Dept Pathology and Medical Biology, GRIAC research Institute, University of Groningen, University Medical Center Groningen, Groningen, Netherlands, 2Beatrix Childrens' Hospital, University Medical center Groningen, Univ of Groningen, Groningen 9700 RB, Netherlands.
Rationale - Protocadherin-1 (Pcdh1) is a human asthma and airway hyperresponsiveness (AHR) gene expressed in bronchial epithelial cells, which contributes to maintenance and repair of epithelial barrier function. Pcdh1 binds to SMAD3 and negatively regulates the sensitivity to TGF-β induced gene expression. It is unknown whether the interaction between Pcdh1, SMAD3 and TGF-β is relevant for susceptibility to asthma in vivo. We hypothesize that the human asthma genes Pcdh1 and SMAD3 act in a single pathway leading to increased susceptibility for asthma when levels are reduced, and SMAD3 activity are increased.
Methods - We tested our hypothesis in a house dust mite (HDM) driven mouse model of allergic airway inflammation, using our unique Pcdh1 knock-out mouse model and pharmacological inhibition of SMAD3 to dissect the interactions between these asthma genes in the development of experimental asthma and AHR.
Results - We show that the Pcdh1 knock-out mouse model has increased AHR to methacholine at baseline. After three weeks of intranasal HDM challenges, Pcdh1 KO display a markedly increased AHR and airway inflammation compared to wild-type littermates. Treatment of the mice with a selective SMAD3 inhibitor for the three-week period abolished the HDM induced AHR in the Pcdh1 knock-out mice, but not in the wild-type littermate controls. Eosinophilic airway inflammation was not affected by SMAD3 inhibition.
Conclusion - These data show that loss of Pcdh1 sensitizes mice to HDM induced AHR in a SMAD3 dependent fashion. This study clearly indicates that the human asthma genes Pcdh1 and SMAD3 act in a single pathway leading to enhanced sensitivity for allergen-induced AHR. These studies also identify SMAD3 as a potential therapeutic target for intervention in asthma in individuals carrying genetic lesions in the Pcdh1/SMAD3/TGF-β pathway.
Author Block: M. C. Nawijn1, U. Brouwer1, L. den Boef1, L. Hesse1, G. H. Koppelman2; 1Experimental Pulmonology and Inflammation Research, Dept Pathology and Medical Biology, GRIAC research Institute, University of Groningen, University Medical Center Groningen, Groningen, Netherlands, 2Beatrix Childrens' Hospital, University Medical center Groningen, Univ of Groningen, Groningen 9700 RB, Netherlands.
Rationale - Protocadherin-1 (Pcdh1) is a human asthma and airway hyperresponsiveness (AHR) gene expressed in bronchial epithelial cells, which contributes to maintenance and repair of epithelial barrier function. Pcdh1 binds to SMAD3 and negatively regulates the sensitivity to TGF-β induced gene expression. It is unknown whether the interaction between Pcdh1, SMAD3 and TGF-β is relevant for susceptibility to asthma in vivo. We hypothesize that the human asthma genes Pcdh1 and SMAD3 act in a single pathway leading to increased susceptibility for asthma when levels are reduced, and SMAD3 activity are increased.
Methods - We tested our hypothesis in a house dust mite (HDM) driven mouse model of allergic airway inflammation, using our unique Pcdh1 knock-out mouse model and pharmacological inhibition of SMAD3 to dissect the interactions between these asthma genes in the development of experimental asthma and AHR.
Results - We show that the Pcdh1 knock-out mouse model has increased AHR to methacholine at baseline. After three weeks of intranasal HDM challenges, Pcdh1 KO display a markedly increased AHR and airway inflammation compared to wild-type littermates. Treatment of the mice with a selective SMAD3 inhibitor for the three-week period abolished the HDM induced AHR in the Pcdh1 knock-out mice, but not in the wild-type littermate controls. Eosinophilic airway inflammation was not affected by SMAD3 inhibition.
Conclusion - These data show that loss of Pcdh1 sensitizes mice to HDM induced AHR in a SMAD3 dependent fashion. This study clearly indicates that the human asthma genes Pcdh1 and SMAD3 act in a single pathway leading to enhanced sensitivity for allergen-induced AHR. These studies also identify SMAD3 as a potential therapeutic target for intervention in asthma in individuals carrying genetic lesions in the Pcdh1/SMAD3/TGF-β pathway.
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