Disulfide disruption reverses mucus dysfunction in allergic airway disease.

Autor: Morgan LE; Department of Medicine, School of Medicine, University of Colorado, Aurora, CO, USA., Jaramillo AM; Department of Medicine, School of Medicine, University of Colorado, Aurora, CO, USA., Shenoy SK; Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.; Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Raclawska D; Department of Medicine, School of Medicine, University of Colorado, Aurora, CO, USA., Emezienna NA; Department of Medicine, School of Medicine, University of Colorado, Aurora, CO, USA.; Department of Obstetrics and Gynecology, Howard University College of Medicine, Washington, DC, USA., Richardson VL; Department of Medicine, School of Medicine, University of Colorado, Aurora, CO, USA., Hara N; Department of Medicine, School of Medicine, University of Colorado, Aurora, CO, USA., Harder AQ; Department of Medicine, School of Medicine, University of Colorado, Aurora, CO, USA., NeeDell JC; Department of Medicine, School of Medicine, University of Colorado, Aurora, CO, USA., Hennessy CE; Department of Medicine, School of Medicine, University of Colorado, Aurora, CO, USA., El-Batal HM; Department of Bioengineering, College of Engineering, Design, and Computing, University of Colorado, Denver | Anschutz Medial Campus, Denver, CO, USA., Magin CM; Department of Medicine, School of Medicine, University of Colorado, Aurora, CO, USA.; Department of Bioengineering, College of Engineering, Design, and Computing, University of Colorado, Denver | Anschutz Medial Campus, Denver, CO, USA., Grove Villalon DE; Parion Sciences, Inc., Durham, NC, USA., Duncan G; Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.; Fischell Department of Bioengineering, School of Engineering University of Maryland, College Park, MD, USA., Hanes JS; Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.; Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.; Department of Pharmacology & Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.; Department of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA., Suk JS; Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.; Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.; Department of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA., Thornton DJ; Wellcome Trust Centre for Cell-Matrix Research and the Lydia Becker Institute of Immunology and Inflammation, School of Biological Sciences, The University of Manchester, Manchester, UK., Holguin F; Department of Medicine, School of Medicine, University of Colorado, Aurora, CO, USA., Janssen WJ; Department of Medicine, School of Medicine, University of Colorado, Aurora, CO, USA.; Department of Medicine National Jewish Health, Denver, CO, USA.; Department of Immunology and Microbiology, School of Medicine, University of Colorado, Aurora, CO, USA., Thelin WR; Parion Sciences, Inc., Durham, NC, USA., Evans CM; Department of Medicine, School of Medicine, University of Colorado, Aurora, CO, USA. Christopher.Evans@cuanschutz.edu.; Department of Immunology and Microbiology, School of Medicine, University of Colorado, Aurora, CO, USA. Christopher.Evans@cuanschutz.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2021 Jan 11; Vol. 12 (1), pp. 249. Date of Electronic Publication: 2021 Jan 11.
DOI: 10.1038/s41467-020-20499-0
Abstrakt: Airway mucus is essential for lung defense, but excessive mucus in asthma obstructs airflow, leading to severe and potentially fatal outcomes. Current asthma treatments have minimal effects on mucus, and the lack of therapeutic options stems from a poor understanding of mucus function and dysfunction at a molecular level and in vivo. Biophysical properties of mucus are controlled by mucin glycoproteins that polymerize covalently via disulfide bonds. Once secreted, mucin glycopolymers can aggregate, form plugs, and block airflow. Here we show that reducing mucin disulfide bonds disrupts mucus in human asthmatics and reverses pathological effects of mucus hypersecretion in a mouse allergic asthma model. In mice, inhaled mucolytic treatment loosens mucus mesh, enhances mucociliary clearance, and abolishes airway hyperreactivity (AHR) to the bronchoprovocative agent methacholine. AHR reversal is directly related to reduced mucus plugging. These findings establish grounds for developing treatments to inhibit effects of mucus hypersecretion in asthma.
Databáze: MEDLINE