Sinomenine Relieves Airway Remodeling By Inhibiting Epithelial-Mesenchymal Transition Through Downregulating TGF-β1 and Smad3 Expression In Vitro and In Vivo.

Hongjuan He,Zheng Wang,Jinxin Miao,Xiu-Min Li,Mingsan Miao,Lihua Cao,Zhenzhen Wang

doi:10.3389/fimmu.2021.736479

Hongjuan He, Zheng Wang + Show 5 more

Open Access

https://doi.org/10.3389/fimmu.2021.736479

Copy DOI

Abstract

Airway remodeling is associated with dysregulation of epithelial-mesenchymal transition (EMT) in patients with asthma. Sinomenine (Sin) is an effective, biologically active alkaloid that has been reported to suppress airway remodeling in mice with asthma. However, the molecular mechanisms behind this effect remain unclear. We aimed to explore the potential relationship between Sin and EMT in respiratory epithelial cells in vitro and in vivo. First, 16HBE cells were exposed to 100 μg/mL LPS and treated with 200 μg/mL Sin. Cell proliferation, migration, and wound healing assays were performed to evaluate EMT, and EMT-related markers were detected using Western blotting. Mice with OVA-induced asthma were administered 35 mg/kg or 75 mg/kg Sin. Airway inflammation and remodeling detection experiments were performed, and EMT-related factors and proteins in the TGF-β1 pathway were detected using IHC and Western blotting. We found that Sin suppressed cell migration but not proliferation in LPS-exposed 16HBE cells. Sin also inhibited MMP7, MMP9, and vimentin expression in 16HBE cells and respiratory epithelial cells from mice with asthma. Furthermore, it decreased OVA-specific IgE and IL-4 levels in serum, relieved airway remodeling, attenuated subepithelial collagen deposition, and downregulating TGF-β1and Smad3 expression in mice with asthma. Our results suggest that Sin suppresses EMT by inhibiting IL-4 and downregulating TGF-β1 and Smad3 expression.

Highlights

Asthma, a chronic inflammatory disease of the airways, is a common heterogeneous disease that affects approximately 300 million people worldwide, resulting in 250,000 deaths per year and billions of dollars in medical expenses [1, 2]
Airway epithelial cells are the primary targets for the inhaled environmental allergens and can produce Th2 innate cytokines to trigger allergic reactions [24]
The chronic exposure of repetitive environmental injury may lead to persistent activation of pathways involved in airway epithelial repair, such as epithelial to mesenchymal transition, changes in progenitor cell migration and proliferation, and abnormal redifferentiation leading to airway remodeling [25]

Summary

Introduction

A chronic inflammatory disease of the airways, is a common heterogeneous disease that affects approximately 300 million people worldwide, resulting in 250,000 deaths per year and billions of dollars in medical expenses [1, 2]. Airway remodeling refers to airway structural change that occurs in patients with asthma induced by persistent inflammation during injury and repair processes [4]. It is characterized by airway wall thickening, subepithelial collagen deposition, and excessive mucus secretion [5]. Most patients are well controlled and improved by wellestablished treatments, such as inhaled corticosteroids (ICS) and b2-adrenergic agonists. While these first-line treatments demonstrate potent anti-inflammatory effects, they are not very effective for treating airway remodeling [6]. To prevent the progression of airway remodeling in the early stages and reduce disease severity, understanding the mechanism behind airway remodeling and identifying useful therapies are urgent [9]

Objectives

Methods

Results

Conclusion