Recombinant Pyrin Domain Protein Attenuates Airway Inflammation and Alleviates Epithelial-Mesenchymal Transition by Inhibiting Crosstalk Between TGFβ1 and Notch1 Signaling in Chronic Asthmatic Mice

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 epithelialmesenchymal 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.

The miR‐124‐3p regulates the allergic airway inflammation and remodeling in an ovalbumin‐asthmatic mouse model by inhibiting S100A4

“…The TGF‐β1/Smad2 signaling pathway was previously reported to be involved in asthma‐related fibroblast‐to‐myofibroblast transition 38 . Additionally, a study in China showed that in rodent asthma models, TGF‐β1/SMAD and Jagged1/Notch1 signaling pathways are regulated by recombinant pyrin domain protein to suppress asthmatic airway inflammation and airway remodeling 39 …”

“…38 Additionally, a study in China showed that in rodent asthma models, TGF-β1/SMAD and Jagged1/Notch1 signaling pathways are regulated by recombinant pyrin domain protein to suppress asthmatic airway inflammation and airway remodeling. 39 There were some limitations to this study that should be considered when interoperating the results. First, this study only explored the function of miR-124-3p and its interaction with S100A4 in asthmatic inflammation and EMT.…”

Approach for Elucidating the Molecular Mechanism of Epithelial to Mesenchymal Transition in Fibrosis of Asthmatic Airway Remodeling Focusing on Cl− Channels

“…Furthermore, the RhoA/ROCK signaling pathway has also contributed to EMT in OVA-induced asthmatic model mice [ 64 ]. Wang et al reported that inhibition of the crosstalk between the TGF-β1/Smad3 and Jagged1/Notch1 signaling pathways attenuates EMT in OVA-induced asthmatic model mice [ 65 ]. These data mean that complex synergistic interactions between the TGF-β1/Smad3 and Jagged1/Notch1 signaling pathways facilitate EMT.…”

Anti-Inflammatory and Anti-Remodelling Potential of Ethanol Extract Rhodomyrtus Tomentosa in Combination of Asthma and Coal Dust Models

“…In addition, flavonoids in Dracocephalum peregrinum L. inhibit the signal transforming growth factor-beta-1 (TGF-β1) (14). The TGF-β1 molecule is an inflammatory cytokine associated with fibrosis (one of the parameters of lung tissue remodelling) in asthma (15). That plants that contain flavonoids and saponins have the potential to be used as anti-inflammatory and antiremodelling in asthma.…”