Cytochrome P450 1A protects against hyperbaric oxygen-induced lung injury by regulating neutrophil extracellular trap formation

Although hyperbaric oxygen (HBO) therapy is a clinically established intervention for various pathological conditions, excessive oxygen exposure can induce acute lung injury (ALI), the underlying mechanisms of which remain elusive. In this study, we demonstrate that neutrophil extracellular traps (NETs) contribute to the pathogenesis of HBO-induced ALI. HBO exposure upregulates pulmonary expression of CYP1A1 and CYP1A2, two isoforms of the cytochrome P450 (CYP) 1A subfamily. Genetic deletion of both CYP1A1 and CYP1A2 exacerbates, whereas the CYP1A inducer attenuates NET formation and ALI in HBO-exposed mice. Mechanistically, HBO-induced upregulation of CYP1A protects against lung injury by suppressing oxidative stress-driven NET formation via an NRF2(nuclear factor erythroid 2-related factor 2)-dependent pathway. Notably, the inhibitory effect of the CYP1A/NRF2 signaling axis on NET formation is mediated indirectly through its antioxidant actions in alveolar epithelial cells, rather than via direct modulation of neutrophils, thereby establishing an antioxidative microenvironment that limits NET formation. Our findings reveal a novel protective mechanism whereby activation of the CYP1A/NRF2 pathway mitigates HBO-induced lung injury through regulation of intercellular crosstalk between alveolar epithelial cells and neutrophils within the oxidative milieu.