Transcriptional Effects of Ozone and Impact on Airway Inflammation - PubMed (original) (raw)
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Transcriptional Effects of Ozone and Impact on Airway Inflammation
Sharon Mumby et al. Front Immunol. 2019.
Abstract
Epidemiological and challenge studies in healthy subjects and in individuals with asthma highlight the health impact of environmental ozone even at levels considered safe. Acute ozone exposure in man results in sputum neutrophilia in 30% of subjects particularly young children, females, and those with ongoing cardiopulmonary disease. This may be associated with systemic inflammation although not in all cases. Chronic exposure amplifies these effects and can result in the formation of asthma-like symptoms and immunopathology. Asthmatic patients who respond to ozone (responders) induce a greater number of genes in bronchoalveolar (BAL) macrophages than healthy responders with up-regulation of inflammatory and immune pathways under the control of cytokines and chemokines and the enhanced expression of remodeling and repair programmes including those associated with protease imbalances and cell-cell adhesion. These pathways are under the control of several key transcription regulatory factors including nuclear factor (NF)-κB, anti-oxidant factors such as nuclear factor (erythroid-derived 2)-like 2 NRF2, the p38 mitogen activated protein kinase (MAPK), and priming of the immune system by up-regulating toll-like receptor (TLR) expression. Murine and cellular models of acute and chronic ozone exposure recapitulate the inflammatory effects seen in humans and enable the elucidation of key transcriptional pathways. These studies emphasize the importance of distinct transcriptional networks in driving the detrimental effects of ozone. Studies indicate the critical role of mediators including IL-1, IL-17, and IL-33 in driving ozone effects on airway inflammation, remodeling and hyperresponsiveness. Transcription analysis and proof of mechanisms studies will enable the development of drugs to ameliorate the effects of ozone exposure in susceptible individuals.
Keywords: acute ozone exposure; chronic ozone exposure; gene expression; immune cell recruitment; pro-inflammatory signaling.
Figures
Figure 1
Mechanisms of ozone-induced transcriptome activation in the airway. Schematic diagram indicating that ozone dissolves in the epithelial lining fluid of susceptible individuals to produce reactive oxygen species (ROS) and modified lipids. These act on the epithelial cells to activate a number of key intracellular and cell surface pathways leading to the induction of the mRNA for cytokines, growth factors, and remodeling enzymes. As a result, there is an acute effect on the recruitment and activation of innate immune cells and on epithelial barrier function and mucus production. These acute effects of ozone may impact on the levels of inflammatory mediators and cells in the blood. Airway inflammation may be directly, or indirectly, associated with airway hyperresponsiveness (AHR). Prolonged ozone exposure has a greater remodeling effect and can result in emphysema. Together, both acute and chronic ozone exposure results in increased hospitalisations due to lung exacerbations or attacks, decreased quality of life (QoL) in at-risk individuals and a large healthcare cost for the individual and for society.
Figure 2
Effect of ozone and N-acetyl cysteine (NAC) on the enrichment of gene signature for fibrotic pathways within murine lungs. Using a bioinformatic technique called gene set variation analysis (GSVA) it is possible to interrogate transcriptomic arrays or RNA-sequencing data for the presence of gene signatures that are unique for specific pathways and or cell types. These signatures may be available from the literature or from online resources or be self-generated. The results show the enrichment scores (ES), a summary of the mRNA expression of all the genes in each signature across the whole data with a range of −1 to +1. Six weeks ozone exposure (2.5 ppm, 3 h/2 days a week) enriches for markers of fibrosis including bleomycin exposure (A), activated fibroblasts (B) and transforming growth factor (TGF)β gene expression (C) compared with air. The analysis also reveals enrichment for individual cell types such as CD8+ T-cells (D) and key remodeling pathways such as the glycolysis (E) and HIPPO (F) pathways. The ES for each of these signatures is reversed by co-treatment with N-acetyl cysteine (NAC, 100 mg/kg i.p.). Data is obtained from the experiments reported in Yang et al. (83). Data are presented as individual data points with box-and-whisker plots showing median and interquartile range. **p < 0.01; ***p < 0.001; ****p < 10−5.
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