Disulfide disruption reverses mucus dysfunction in allergic airway disease

Authors

Leslie E. Morgan, University of Colorado Anschutz Medical Campus
Ana M. Jaramillo, University of Colorado Anschutz Medical Campus
Siddharth K. Shenoy, Wilmer Eye Institute
Dorota Raclawska, University of Colorado Anschutz Medical Campus
Nkechinyere A. Emezienna, University of Colorado Anschutz Medical Campus
Vanessa L. Richardson, University of Colorado Anschutz Medical Campus
Naoko Hara, University of Colorado Anschutz Medical Campus
Anna Q. Harder, University of Colorado Anschutz Medical Campus
James C. NeeDell, University of Colorado Anschutz Medical Campus
Corinne E. Hennessy, University of Colorado Anschutz Medical Campus
Hassan M. El-Batal, University of Colorado Denver
Chelsea M. Magin, University of Colorado Anschutz Medical Campus
Diane E. Grove Villalon, Parion Sciences, Inc.
Gregg Duncan, Wilmer Eye Institute
Justin S. Hanes, Wilmer Eye Institute
Jung Soo Suk, Wilmer Eye Institute
David J. Thornton, Wellcome Trust Centre for Cell-Matrix Research
Fernando Holguin, University of Colorado Anschutz Medical Campus
William J. Janssen, University of Colorado Anschutz Medical Campus
William R. Thelin, Parion Sciences, Inc.
Christopher M. Evans, University of Colorado Anschutz Medical Campus

Document Type

Article

Publication Date

12-1-2021

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.

Recommended Citation

Morgan, Leslie E.; Jaramillo, Ana M.; Shenoy, Siddharth K.; Raclawska, Dorota; Emezienna, Nkechinyere A.; Richardson, Vanessa L.; Hara, Naoko; Harder, Anna Q.; NeeDell, James C.; Hennessy, Corinne E.; El-Batal, Hassan M.; Magin, Chelsea M.; Grove Villalon, Diane E.; Duncan, Gregg; Hanes, Justin S.; Suk, Jung Soo; Thornton, David J.; Holguin, Fernando; Janssen, William J.; Thelin, William R.; and Evans, Christopher M., "Disulfide disruption reverses mucus dysfunction in allergic airway disease" (2021). College of Medicine Faculty Publications. 80.
https://dh.howard.edu/med_fac/80