Abstract
BackgroundMucin disulfide cross-links mediate pathologic mucus formation in muco-obstructive lung diseases. MUC-031, a novel thiol-modified carbohydrate compound, cleaves disulfides to cause mucolysis. The aim of this study was to determine the mucolytic and therapeutic effects of MUC-031 in sputum from patients with cystic fibrosis (CF) and mice with muco-obstructive lung disease (βENaC-Tg mice).MethodsWe compared the mucolytic efficacy of MUC-031 and existing mucolytics (N-acetylcysteine (NAC) and recombinant human deoxyribonuclease I (rhDNase)) using rheology to measure the elastic modulus (G′) of CF sputum, and we tested effects of MUC-031 on airway mucus plugging, inflammation and survival in βENaC-Tg mice to determine its mucolytic efficacyin vivo.ResultsIn CF sputum, compared to the effects of rhDNase and NAC, MUC-031 caused a larger decrease in sputum G′, was faster in decreasing sputum G′ by 50% and caused mucolysis of a larger proportion of sputum samples within 15 min of drug addition. Compared to vehicle control, three treatments with MUC-031 in 1 day in adult βENaC-Tg mice decreased airway mucus content (16.8±3.2versus7.5±1.2 nL·mm−2, p<0.01) and bronchoalveolar lavage cells (73 833±6930versus47 679±7736 cells·mL−1, p<0.05). Twice-daily treatment with MUC-031 for 2 weeks also caused decreases in these outcomes in adult and neonatal βENaC-Tg mice and reduced mortality from 37% in vehicle-treated βENaC-Tg neonates to 21% in those treated with MUC-031 (p<0.05).ConclusionMUC-031 is a potent and fast-acting mucolytic that decreases airway mucus plugging, lessens airway inflammation and improves survival in βENaC-Tg mice. These data provide rationale for human trials of MUC-031 in muco-obstructive lung diseases.
Funder
Bundesministerium für Bildung und Forschung
Deutsche Forschungsgemeinschaft
National Heart, Lung, and Blood Institute
Publisher
European Respiratory Society (ERS)
Subject
Pulmonary and Respiratory Medicine
Cited by
18 articles.
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