Abstract

This article aims to investigate the effects of recombinant pyrin domain (RPYD) on airway inflammation and remodeling in mice with chronic asthma. The chronic asthma BALB/c mouse model was first sensitized by ovalbumin (OVA) and then challenged by OVA nebulization. RPYD or dexamethasone was given before OVA challenge. Our results showed that RPYD significantly inhibited the increase of total cell number, eosinophils, neutrophils and lymphocytes in bronchoalveolar lavage fluid (BALF) induced by OVA, and reduced the infiltration of inflammatory cells, the proliferation of goblet cells and collagen deposition. In addition, RPYD inhibited the mRNA and protein levels of α-smooth muscle actin (α-SMA), transforming growth factor (TGF)-β1, Jagged1, Notch1, Hes1 and Smad3, as well as Smad3 phosphorylation. TGFβ1 down-regulated the level of E-cadherin and promoted the expression of α-SMA, thus inducing epithelial-mesenchymal transition (EMT) in bronchial epithelial cells. We found that RPYD reduced EMT by inhibiting TGFβ1/smad3 and Jagged1/Notch1 signaling pathways. Further overexpression of NICD showed that under the stimulation of TGFβ1, NICD enhanced the phosphorylated Smad3 and nuclear Smad3, accompanied by the increased expression of Notch1 target gene Hes1. In contrast, after treatment with smad3 siRNA, the expression of Hes1 was down regulated as the decrease of Smad3, which indicates that there is crosstalk between smad3 and NICD on Hes1 expression. In conclusion, RPYD reduces airway inflammation, improves airway remodeling and reduces EMT in chronic asthmatic mice by inhibiting the crosstalk between TGFβ1/smad3 and Jagged1/Notch1 signaling pathways.

Highlights

  • Bronchial asthma is a chronic airway inflammation that involves multiple cells

  • We explored the effects of recombinant pyrin domain (RPYD) on chronic airway inflammation and airway remodeling in chronic asthma

  • We found that RPYD significantly reduced the number of inflammatory cells and the release of inflammatory factors in bronchoalveolar lavage fluid (BALF) and reduced the inflammatory response around the airways

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Summary

Introduction

Bronchial asthma is a chronic airway inflammation that involves multiple cells (including eosinophils, macrophages, lymphocytes, neutrophils, etc.). Damage to epithelial cells and the proliferation of bronchial smooth muscle cells may eventually develop into airway remodeling (Li et al, 2019). Epithelial-mesenchymal transition (EMT) is important during the airway remodeling of asthma. Abnormally expressed TGF-β1 induces epithelial cell damage, promotes neovascularization, and induces epithelial cell differentiation, promoting collagen deposition and the development of EMT (Qu et al, 2012; Ojiaku et al, 2017). Phosphorylated receptor activated-Smad (including Smad, Smad3) oligomerizes with Smad and is transferred into the nucleus to promote the expression of transcription factors (such as Snail2/Slug, Twist family, etc.), promoting the development of EMT (Kim et al, 2018; Tsubakihara and Moustakas, 2018)

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