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, trigger 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 IL-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.