Ozone-Induced Oxidative Stress, Neutrophilic Airway Inflammation, and Glucocorticoid Resistance in Asthma.

Chioma Enweasor,Cameron H Flayer,Angela Haczku

doi:10.3389/fimmu.2021.631092

Abstract

Despite recent advances in using biologicals that target Th2 pathways, glucocorticoids form the mainstay of asthma treatment. Asthma morbidity and mortality remain high due to the wide variability of treatment responsiveness and complex clinical phenotypes driven by distinct underlying mechanisms. Emerging evidence suggests that inhalation of the toxic air pollutant, ozone, worsens asthma by impairing glucocorticoid responsiveness. This review discusses the role of oxidative stress in glucocorticoid resistance in asthma. The underlying mechanisms point to a central role of oxidative stress pathways. The primary data source for this review consisted of peer-reviewed publications on the impact of ozone on airway inflammation and glucocorticoid responsiveness indexed in PubMed. Our main search strategy focused on cross-referencing “asthma and glucocorticoid resistance” against “ozone, oxidative stress, alarmins, innate lymphoid, NK and γδ T cells, dendritic cells and alveolar type II epithelial cells, glucocorticoid receptor and transcription factors”. Recent work was placed in the context from articles in the last 10 years and older seminal research papers and comprehensive reviews. We excluded papers that did not focus on respiratory injury in the setting of oxidative stress. The pathways discussed here have however wide clinical implications to pathologies associated with inflammation and oxidative stress and in which glucocorticoid treatment is essential.

Highlights

O3 and glucocorticoid treatment had antagonistic effects on surfactant protein D (SP-D) expression and function in the lung, with O3 inhibiting glucocorticoid-induced sftpd transcription in vivo in mice and in vitro, in human airway epithelial cell cultures. These results indicated that glucocorticoids sustain vital functions in airway epithelium such as surfactant protein (SP)-D production, aimed at promoting immune homeostasis
Harnessing antioxidant mechanisms may have a special importance in this effort as oxidative stress has been clearly demonstrated to worsen steroid resistance in severe asthma
The pathways we discussed here are widely applicable to clinical conditions associated with inflammation and oxidative stress and in which glucocorticoid treatment is essential

Summary

INTRODUCTION

Asthma is a highly heterogenous disease that can be classified into subsets by a number of different categories. O3 and glucocorticoid treatment had antagonistic effects on SP-D expression and function in the lung, with O3 inhibiting glucocorticoid-induced sftpd transcription in vivo in mice and in vitro, in human airway epithelial cell cultures These results indicated that glucocorticoids sustain vital functions in airway epithelium such as SP-D production, aimed at promoting immune homeostasis. A 7-days treatment with LGM2605 of these macaques that received a single exposure to O3 or air (as control) prevented the O3-induced exacerbation of airway hyperresponsiveness and significantly improved baseline lung function [94] These studies highlight the significance of oxidative stress in the effect of O3 on airway hyperresponsiveness and support the idea that anti-oxidant treatment may be beneficial in glucocorticoid resistant, Th2 low asthma

CONCLUSIONS

Findings

Methods