TY - JOUR
T1 - Disulfide disruption reverses mucus dysfunction in allergic airway disease
AU - Morgan, Leslie E.
AU - Jaramillo, Ana M.
AU - Shenoy, Siddharth K.
AU - Raclawska, Dorota
AU - Emezienna, Nkechinyere A.
AU - Richardson, Vanessa L.
AU - Hara, Naoko
AU - Harder, Anna Q.
AU - NeeDell, James C.
AU - Hennessy, Corinne E.
AU - El-Batal, Hassan M.
AU - Magin, Chelsea M.
AU - Grove Villalon, Diane E.
AU - Duncan, Gregg
AU - Hanes, Justin S.
AU - Suk, Jung Soo
AU - Thornton, David J.
AU - Holguin, Fernando
AU - Janssen, William J.
AU - Thelin, William R.
AU - Evans, Christopher M.
N1 - Funding Information:
This study was funded by NIH grants HL080396 (C.E. and C.M.) and ES023384 (C.E.), HL130938 (C.E. and W.J.), HL125169 (J.H.); by U.S. Department of Defense grants W81XWH-17-1-0597 (C.E.), W81XWH-19-1-0172 (C.E.), and PR192068 (C.M.); Cystic Fibrosis Foundation grants EVANS18IO (C.E.), JARAMI20F0 (A.J.), and HANES16XX0 (J.H.); the National Science Foundation NSF CAREER 1941401 (C.M.), and by the Medical Research Council grant MR/R002800/1 (D.T).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-020-20499-0
DO - 10.1038/s41467-020-20499-0
M3 - Article
C2 - 33431872
AN - SCOPUS:85099221630
VL - 12
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 249
ER -