Nrf2 Activator RTA-408 Protects Against Ozone-Induced Acute Asthma Exacerbation by Suppressing ROS and γδT17 Cells

Inflammation. 2019 Oct;42(5):1843-1856. doi: 10.1007/s10753-019-01046-6.

Abstract

Ozone is a strong oxidant in air pollution that exacerbates respiratory disorders and is a major risk factor for acute asthma exacerbation. Ozone can induce reactive oxygen species (ROS) and airway neutrophilic inflammation. In addition, γδT17 cells contribute to IL-17A production upon ozone challenge, resulting in neutrophilic inflammation. It is known, however, that Nrf2 can ameliorate oxidative stress. We therefore investigated whether RTA-408, an Nrf2 activator, can attenuate airway inflammation and inhibit ROS production and whether this effect involves γδT17 cells. Balb/c mice were sensitized/challenged with ovalbumin (OVA) and followed by ozone exposure. We investigated the effect of Nrf2 activator RTA-408 on airway hyperresponsiveness, neutrophilic airway inflammation, cytokine/chemokine production, and OVA-specific IgE level in a mouse model of O3 induced asthma exacerbation. Furthermore, malondialdehyde (MDA) and glutathione (GSH) levels in lung and intracellular ROS were measured. IL-17+ γδT cell percentage by flow cytometer was determined. Nrf2 protein expression by western blot was also examined. We observed that RTA-408 attenuated ROS release during ozone-induced asthma exacerbation and suppressed neutrophil lung infiltration. RTA-408 decreased pro-inflammatory cytokine production and reduced the percentage of IL-17+ γδT cells. Thus, our results suggest that RTA-408 does attenuate airway inflammation in a murine model of ozone-induced asthma exacerbation.

Keywords: Nrf2; asthma exacerbation; oxidative stress; ozone; γδT17 cell.

MeSH terms

  • Animals
  • Asthma / chemically induced
  • Asthma / prevention & control*
  • Cell Line
  • Inflammation / drug therapy
  • Interleukin-17 / metabolism*
  • Lymphocyte Count
  • Mice
  • Mice, Inbred BALB C
  • NF-E2-Related Factor 2 / agonists*
  • Ozone / adverse effects*
  • Protective Agents / pharmacology
  • Reactive Oxygen Species / metabolism*
  • Th17 Cells / drug effects
  • Th17 Cells / pathology
  • Triterpenes / pharmacology*

Substances

  • Interleukin-17
  • NF-E2-Related Factor 2
  • Protective Agents
  • Reactive Oxygen Species
  • Triterpenes
  • Ozone
  • omaveloxolone