Regulatory Effects of Nur77 on Airway Remodeling and ASMC Proliferation in House Dust Mite-Induced Asthma

Kun Wang,Huiming Yin,Wei Gao,Qiang Li,Yan Shang,Yanan He,Muyun Wang,Rajeshwary Ghosh

doi:10.1155/2020/4565246

Abstract

Airway remodeling played a vital role in the development of asthma, and airway smooth muscle (ASM) mass was its hallmark. However, few strategies targeting ASM remodeling were developed in treating asthma. Nur77 was the transcription factor nuclear receptor involved in the pathogenesis of several lung diseases. Nur77 distribution and expression were determined in an HDM-mediated allergic asthma model. Its effect on airway hyperresponsiveness (AHR), chronic inflammation, and ASM remodeling in asthmatic mice was evaluated using a lentivirus-mediated shRNA. Possible mechanisms were explored by examining Nur77 actions and its underlying pathways in primary human AMC cells (ASMCs). In this study, we reported that Nur77 expression was mainly distributed along ASM and increased in lungs of HDM-challenged mice. Nur77 depletion by lentivirus-mediated shRNA ameliorated AHR, chronic inflammation, goblet cell hyperplasia, and airway remodeling in the asthmatic mouse model. By means of primary human ASMC, we discovered that Nur77 upregulation by HDM stimulation promoted cell proliferation and ROS production, as well as reduced antioxidant gene expression. These alterations might associate with MFN2/MAPK/AKT pathways. These findings broadened our understanding of airway remodeling and ASMC proliferation, which might provide a novel therapeutic target for asthma patients.

Highlights

Bronchial asthma is a common chronic respiratory disease with features of inflammatory cell activation, reversible obstruction, hyperresponsiveness, and remodeling of the airway
We discovered reduced phosphorylation of AKT in asthmatic airway smooth muscle cells (ASMCs) regulated by nuclear receptor 77 (Nur77) depletion (Figure 5(i))
By means of primary human ASMC, we discovered that intercellular Nur77 was upregulated in response to HDM exposure

Summary

Introduction

Bronchial asthma (or asthma) is a common chronic respiratory disease with features of inflammatory cell activation, reversible obstruction, hyperresponsiveness, and remodeling of the airway. It is sweeping the world, and nearly 25 million people suffer from the disease, which is responsible for over 5000 deaths per year [1, 2]. Airway remodeling plays a pivotal role in the natural history of asthma [3] It is characterized by thickened epithelium with goblet cell hyperplasia, more fibrotic airway smooth muscle (ASM) layer with increased cell numbers, and altered extracellular matrix (ECM) deposition [4]. In spite of great efforts to alleviate airway remodeling in the last decades, few therapeutic options have proved effective to restrict or reverse this

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