Disulfide disruption reverses mucus dysfunction in allergic airway disease
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.
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.