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Azurocidin-1 Links Bronchiectasis Severity and Exacerbations Through Impairment of Epithelial Defence and is Targeted by Dipeptidyl Peptidase-1 Inhibition
24 Pages Posted: 18 Mar 2025
More...Abstract
Background: Dipeptidyl peptidase-1 (DPP1) inhibitors prevent the activation of neutrophil serine proteases and reduce exacerbations in people with bronchiectasis. We identified a novel effect of DPP1 inhibitors in reducing the neutrophil pseudoenzyme Azurocidin-1 (AZU1). The role of AZU1 in bronchiectasis has not been previously investigated.
Methods: In two European observational cohorts of patients with bronchiectasis, sputum AZU1 was correlated with clinical severity and exacerbations. A posthoc analysis of the phase-2 WILLOW trial of brensocatib vs placebo was used to assess the effect of DPP1 inhibition on AZU1 in the airway. A patient cohort and an experimental rhinovirus challenge study was used to extend findings to COPD.
Findings and Interpretation: Sputum AZU1 was associated with bronchiectasis severity index (p<0.0001), FEV1 (p<0.0001) and exacerbation frequency (p<0.0001 n=197). In an independent cohort, AZU1 was associated with radiological severity, symptoms and bacterial infection. Bronchiectasis patients with bacterial and viral exacerbations had elevated levels of AZU1. These findings were extended to COPD where sputum AZU1 was related to COPD severity, and in patients challenged with rhinovirus A16, AZU1 was increased at day 9 post challenge (p<0.001). In vitro AZU1 impairs ciliary function and epithelial integrity indicating a mechanism by which AZU1 drives disease pathogenesis.In the WILLOW trial, AZU1 was the most downregulated protein with brensocatib treatment. Over 24 weeks, AZU1 was markedly reduced by DPP1 inhibition (p<0.0001).
Conclusion: AZU1 is identified as a novel marker of disease severity in bronchiectasis, is associated with bacterial infection and exacerbation, and is targeted by DPP1 inhibition.
Keywords: bronchiectasis, COPD, inflammation, neutrophil, mucociliary clearance, chronic respiratory disease, mechanism, respiratory epithelium, microbiome, human challenge model, rhinovirus, phase 2 trial
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