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

Exposure to ambient Ozone (O(3)) 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 O(3)-induced epithelial cell injury, inflammation, and airway hyperreactivity, which are discussed herein. The current data suggest that O(3)-induced oxidative stress is a central event-inducing oxeiptotic cell death pathway. O(3)-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 O(3) in leukocyte and non-leukocyte populations, driving sterile innate immune response. Chronic inflammatory response to O(3), 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 O(3)-damage sensing and signaling pathways to lung cells and thereby highlight potential hotspots of O(3) responses. Deeper insights into these pathological pathways might be helpful for the identification of novel therapeutic targets and strategies.

• Russo, R. C.
• Togbe, D.
• Couillin, I.
• Segueni, N.
• Han, L.
• Quesniaux, V. F. J.
• Stoeger, T.
• Ryffel, B.