Azurocidin-1 as a mediator of bronchiectasis severity, epithelial defence, and target of dipeptidyl peptidase-1 inhibition: an international, multicohort study.
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Shoemark Amelia, Johnson Emma D, Shuttleworth Morven, Schwiening Max, Hull Rebecca, Stobo Jamie, Abo-Leyah Hani, Finch Simon, Pollock Jennifer, Huang Jeffrey T J, Richardson Hollian, Perea Lidia, McIntosh Eve, Cant Erin, Galloway Rachel, Choi Hayoung, de Soyza Anthony, Spinou Arietta, Ringshausen Felix C, Lorent Natalie, Mallia Patrick, Johnston Sebastian L, Gierlinski Marek, Goeminne Pieter, Loebinger Michael R, Hua Gao Yong, Chotirmall Sanjay H, Dhar Raja, Haworth Charles, Altenburg Josje, Blasi Francesco, Polverino Eva, Shteinberg Michal, Strickson Sam, Cipolla David, Teper Ariel, Fernandez Carlos, Shih Vivian H, Mange Kevin, Singanayagam Aran, Aliberti Stefano, Sibila Oriol, Long Merete B, Chalmers James D
Аннотация
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.