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Lookup NU author(s): Professor Anthony De SoyzaORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2026 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Background: Dipeptidyl peptidase-1 (DPP1) inhibitors prevent the activation of neutrophil serine proteases and reduce exacerbations in people with bronchiectasis. We previously identified a novel effect of DPP1 inhibitors in reducing the neutrophil pseudoenzyme azurocidin-1 (AZU1). The aim of this study was to investigate the role of AZU1 in the pathophysiology of bronchiectasis. Methods: Sputum AZU1 concentrations were analysed in multiple cohorts. These consisted of two observational cohorts of patients with bronchiectasis (EMBARC BRIDGE cohort 1 and cohort 2) and a cohort of patients with chronic obstructive pulmonary disease (COPD; TARDIS COPD cohort) to correlate AZU1 with disease severity and exacerbations. A rhinovirus challenge study was used to investigate AZU1 concentrations during experimental exacerbation in COPD, people who smoke, and controls. A post-hoc analysis of the phase 2 WILLOW trial of brensocatib versus placebo was used to assess the effect of DPP1 inhibition on airway AZU1. Findings: Higher AZU1 sputum concentration was associated with increased bronchiectasis disease severity index (p<0·0001), decreased percentage predicted forced expiratory volume in 1 second (r=–0·4662, p<0·001), and increased exacerbation frequency (p<0·0019; EMBARC cohort 1, n=197). AZU1 was associated with radiological severity (Reiff score), symptoms (quality of life bronchiectasis respiratory symptom score), and bacterial infection (sputum microbiology and 16S microbiome alpha diversity; highest levels of AZU1 were found in airway samples with Pseudomonas aeruginosa; p<0·0001; EMBARC cohort 2, n=144). Bronchiectasis patients with bacterial and viral exacerbations had increased concentrations of AZU1 (p=0·0003; n=96). These findings were extended to COPD, in which AZU1 was related to COPD severity (COPD cohort, n=101), and in patients with COPD challenged with rhinovirus A16, AZU1 was increased at day 9 post-challenge (p<0·001; n=9). In-vitro AZU1 impaired ciliary function and epithelial integrity, suggesting a mechanism by which AZU1 drives disease pathogenesis. In a post-hoc analysis of the WILLOW trial, AZU1 was the most downregulated protein with brensocatib treatment (brensocatib 10 mg, n=71; brensocatib 25 mg, n=73; and placebo, n=71). Over 24 weeks, AZU1 was significantly reduced by DPP1 inhibition (p<0·0001). Interpretation: AZU1 was identified as a novel marker of disease severity in bronchiectasis, associated with bacterial infection and exacerbation, and targeted by DPP1 inhibition. Funding: EMBARC3 and Insmed.
Author(s): Shoemark A, Johnson ED, Shuttleworth M, Schwiening M, Hull R, Stobo J, Abo-Leyah H, Finch S, Pollock J, Huang JTJ, Richardson H, Perea L, McIntosh E, Cant E, Galloway R, Choi H, de Soyza A, Spinou A, Ringshausen FC, Lorent N, Mallia P, Johnston SL, Gierlinski M, Goeminne P, Loebinger MR, Hua Gao Y, Chotirmall SH, Dhar R, Haworth C, Altenburg J, Blasi F, Polverino E, Shteinberg M, Strickson S, Cipolla D, Teper A, Fernandez C, Shih VH, Mange K, Singanayagam A, Aliberti S, Sibila O, Long MB, Chalmers JD
Publication type: Article
Publication status: Published
Journal: The Lancet Respiratory Medicine
Year: 2026
Pages: Epub ahead of print
Online publication date: 24/04/2026
Acceptance date: 02/04/2018
Date deposited: 12/05/2026
ISSN (print): 2213-2600
ISSN (electronic): 2213-2619
Publisher: Elsevier Ltd
URL: https://doi.org/10.1016/S2213-2600(25)00334-0
DOI: 10.1016/S2213-2600(25)00334-0
Data Access Statement: Data from this study, which is held by the European Bronchiectasis Network (EMBARC) is available through an application process available on the EMBARC website (https://www.bronchiectasis.net/accessing-embarc-samples-data/)
PubMed id: 42044645
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