Myeloperoxidase-DNA complex: a marker and combined target for Pseudomonas aeruginosa-associated bronchiectasis.

Pseudomonas aeruginosa (P. aeruginosa)-associated bronchiectasis remains a clinical challenge due to lacking diagnostic biomarkers and targeted therapies. This multi-dimensional (clinical-cell-animal) study investigated the myeloperoxidase (MPO)-DNA complex, a marker of neutrophil extracellular traps (NETs), and the combination of AZD5904 (an MPO inhibitor) and DNase I (a NETs-DNA degrader). Key findings include: First, integrated evidence from bronchoalveolar lavage fluid analysis and immunofluorescence identified the MPO-DNA complex as a biomarker significantly associated with P. aeruginosa-associated bronchiectasis severity (e.g., lung lobe involvement, Bronchiectasis Severity Index). Mendelian randomization (MR) analysis revealed a potential causal link with bronchiectasis risk but not with several other chronic respiratory diseases. Second, in cellular models, P. aeruginosa PAO1-induced NETs were associated with epithelial damage, as evidenced by the upregulation of reactive oxygen species, malondialdehyde, interleukin-1β, and interleukin-6, and the reduction of BEAS-2B cell viability. Third, in P. aeruginosa-infected bronchiectasis rat models, AZD5904 combined with DNase I alleviated lung pathology, inflammation, and NETs accumulation more effectively than monotherapy. This study suggests the MPO-DNA complex as a potential biomarker and pathogenic factor associated with disease severity, and proposes a dual-target combined intervention strategy worthy of further preclinical investigation for P. aeruginosa-associated bronchiectasis.