Ozone-induced lung injury and inflammation: Pathways and therapeutic targets for pulmonary diseases caused by air pollutants

Abstract

Exposure to ambient Ozone (O₃) air pollution directly causes by its oxidative properties, respiratory epithelial cell injury, and cell death, which promote inflammation and hyperreactivity, posing a significant public health concern. Recent clinical and experimental studies have made strides in elucidating the mechanisms underlying O₃-induced epithelial cell injury, inflammation, and airway hyperreactivity, which are discussed herein. The current data suggest that O₃-induced oxidative stress is a central event-inducing oxeiptotic cell death pathway. O₃-induced epithelial barrier damage and cell death, triggering the release of alarmins and damage-associated molecular patterns (DAMPs), with subsequent endogenous activation of Toll-like receptors (TLRs), DNA sensing pathways, and inflammasomes, activating interleukin-1-Myd88 inflammatory pathway with the production of a range of chemokines and cytokines. This cascade orchestrates lung tissue-resident cell activation in response to O₃ in leukocyte and non-leukocyte populations, driving sterile innate immune response. Chronic inflammatory response to O₃, by repeated exposures, supports a mixed phenotype combining asthma and emphysema, in which their exacerbation by other particulate pollutants potentially culminates in respiratory failure. We use data from lung single-cell transcriptomics to map genes of O₃-damage sensing and signaling pathways to lung cells and thereby highlight potential hotspots of O₃ responses. Deeper insights into these pathological pathways might be helpful for the identification of novel therapeutic targets and strategies.