Disulfide disruption reverses mucus dysfunction in allergic airway disease

Leslie E. Morgan, Ana M. Jaramillo, Siddharth K. Shenoy, Dorota Raclawska, Nkechinyere A. Emezienna, Vanessa L. Richardson, Naoko Hara, Anna Q. Harder, James C. NeeDell, Corinne E. Hennessy, Hassan M. El-Batal, Chelsea M. Magin, Diane E. Grove Villalon, Gregg Duncan, Justin S. Hanes, Jung Soo Suk, David J. Thornton, Fernando Holguin, William J. Janssen, William R. Thelin and Christopher M. Evans ()
Additional contact information
Leslie E. Morgan: University of Colorado
Ana M. Jaramillo: University of Colorado
Siddharth K. Shenoy: Johns Hopkins University School of Medicine
Dorota Raclawska: University of Colorado
Nkechinyere A. Emezienna: University of Colorado
Vanessa L. Richardson: University of Colorado
Naoko Hara: University of Colorado
Anna Q. Harder: University of Colorado
James C. NeeDell: University of Colorado
Corinne E. Hennessy: University of Colorado
Hassan M. El-Batal: University of Colorado
Chelsea M. Magin: University of Colorado
Diane E. Grove Villalon: Parion Sciences, Inc.
Gregg Duncan: Johns Hopkins University School of Medicine
Justin S. Hanes: Johns Hopkins University School of Medicine
Jung Soo Suk: Johns Hopkins University School of Medicine
David J. Thornton: The University of Manchester
Fernando Holguin: University of Colorado
William J. Janssen: University of Colorado
William R. Thelin: Parion Sciences, Inc.
Christopher M. Evans: University of Colorado

Nature Communications, 2021, vol. 12, issue 1, 1-9

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-020-20499-0

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