Ozone as a Driver of Lung Inflammation and Innate Immunity, and as a Model for Lung Disease

Abstract

The articles in this series will remind readers of the increasing importance of ozone as an important component of air pollution that contributes to mortality and disease progression (1–3). Ground level ozone is created by chemical reactions in the presence of sunlight between oxides of nitrogen (NOx) and volatile organic compounds (VOC) that are both emitted as pollutants from cars, power plants, industrial boilers, refineries, chemical plants, and other sources. Levels of ozone are most likely to reach unhealthy levels on hot sunny days in urban areas, although high levels may also be observed during winter months. Ozone can also be transported long distances by wind into non-urban areas. The effects of ozone on health are relatively well-known. Exposure to ozone can cause difficulty to breathe, shortness of breath and discomfort on breathing, cough and sore-throat presumably due to an inflammation and damage to the upper and lower airways. Ozone exposure can aggravate lung conditions such as asthma and COPD, causing acute deterioration of these conditions that necessitate emergency treatments (4, 5). As such, ozone exposure is likely to cause increased school absences, days off work, medication use, visits to doctors and emergency rooms, and hospital admissions. Ozone is highly reactive, eliciting rapid and dose-dependent disruption of the respiratory barrier. It impacts many cell types in the lung and activates specific signaling cascades, eliciting responses including cellular damage, enhanced apoptosis, cytokine production, recruitment of inflammatory cells, and subsequent tissue repair. Oxidative stress is a conserved mechanism that contributes to numerous environmental lung injuries. Ozone, as a principal mediator of oxidative stress in both the intracellular and extracellular compartments, has become a clinically-relevant model to understand the mechanisms underlying biological responses to oxidative stress (6, 7). Oxidation products are either directly toxic and can cause injury to lung tissue or they can function as exogenous ligands via binding to cell surface receptors and thereby triggering intracellular inflammatory and/or apoptotic signaling pathways (8). Thus, ozone‐induced oxidant stress modifies several known cell‐signaling mechanisms: activation of innate immune signaling pathways, upregulation of antioxidant genes, and enhanced release of damage‐associated molecular pattern molecules (DAMPs) (9, 10). Oxidative stress also decreases the clearance of pathogens by impairing antimicrobial function of effector cells including suppressing alveolar macrophage phagocytosis, enhancing macrophage and neutrophil apoptosis, and increasing the susceptibility of epithelial cells to influenza infection.