Ozone Preexposure Exacerbates Septic Lung Injury Through ADAR1 Modulation and Pyroptosis Activation

Chronic ozone exposure in urban environments compromises lung function, predisposing individuals to severe sepsis outcomes from common infections. Pyroptosis, a type of programmed cell death, is implicated in sepsis and lung injury, and its regulation is crucial for understanding disease severity. We focused on pyroptosis due to its role in inflammation, tissue damage, and organ dysfunction in septic patients, as well as its link to ozone exposure through inflammasome activation. To elucidate the underlying molecular mechanisms, we integrated bioinformatics and experimental approaches. We analyzed public genomic data repositories to identify pyroptosis-related genes and those linked to sepsis and ozone-induced lung injury. Three pyroptosis-related genes (caspase-1, interleukin-1β, and gasdersmin D) were upregulated, while adenosine deaminase acting on RNA 1 (ADAR1) was downregulated. To validate these findings, mice were exposed to ozone followed by lipopolysaccharide-induced sepsis. After 12 hours, lung tissue damage, inflammation, and pyroptosis were assessed. Two-way ANOVA revealed significant LPS × ozone interactions, with one-way ANOVA showing dose-dependent ozone effects on inflammation and pyroptosis. Results confirmed the bioinformatics predictions, showing ADAR1 levels initially increased in septic mice but declined with ozone exposure. Concurrently, ozone exacerbated caspase-1-mediated pyroptosis in lung tissue. Our findings demonstrate that ozone preexposure worsens septic lung injury by modulating ADAR1 and pyroptosis. By elucidating the ADAR1-pyroptosis interplay, this study highlights a novel mechanism contributing to the pathogenesis of ozone-induced lung injury in sepsis, revealing ADAR1 as a key regulatory molecule.