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; Christopher M. Evans

doi:10.1038/s41467-020-20499-0

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. ThelinChristopher M. Evans

School of Medicine

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Article number	249
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-20499-0
State	Published - Dec 2021

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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Morgan, L. E., Jaramillo, A. M., Shenoy, S. K., Raclawska, D., Emezienna, N. A., Richardson, V. L., Hara, N., Harder, A. Q., NeeDell, J. C., Hennessy, C. E., El-Batal, H. M., Magin, C. M., Grove Villalon, D. E., Duncan, G., Hanes, J. S., Suk, J. S., Thornton, D. J., Holguin, F., Janssen, W. J., ... Evans, C. M. (2021). Disulfide disruption reverses mucus dysfunction in allergic airway disease. Nature communications, 12(1), [249]. https://doi.org/10.1038/s41467-020-20499-0

Disulfide disruption reverses mucus dysfunction in allergic airway disease. / 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.; Evans, Christopher M.

In: Nature communications, Vol. 12, No. 1, 249, 12.2021.

Research output: Contribution to journal › Article › peer-review

Morgan, LE, Jaramillo, AM, Shenoy, SK, Raclawska, D, Emezienna, NA, Richardson, VL, Hara, N, Harder, AQ, NeeDell, JC, Hennessy, CE, El-Batal, HM, Magin, CM, Grove Villalon, DE, Duncan, G, Hanes, JS , Suk, JS, Thornton, DJ, Holguin, F, Janssen, WJ, Thelin, WR & Evans, CM 2021, 'Disulfide disruption reverses mucus dysfunction in allergic airway disease', Nature communications, vol. 12, no. 1, 249. https://doi.org/10.1038/s41467-020-20499-0

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. ; Evans, Christopher M. / Disulfide disruption reverses mucus dysfunction in allergic airway disease. In: Nature communications. 2021 ; Vol. 12, No. 1.

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title = "Disulfide disruption reverses mucus dysfunction in allergic airway disease",

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.",

author = "Morgan, {Leslie E.} and Jaramillo, {Ana M.} and Shenoy, {Siddharth K.} and Dorota Raclawska and Emezienna, {Nkechinyere A.} and Richardson, {Vanessa L.} and Naoko Hara and Harder, {Anna Q.} and NeeDell, {James C.} and Hennessy, {Corinne E.} and El-Batal, {Hassan M.} and Magin, {Chelsea M.} and {Grove Villalon}, {Diane E.} and Gregg Duncan and Hanes, {Justin S.} and Suk, {Jung Soo} and Thornton, {David J.} and Fernando Holguin and Janssen, {William J.} and Thelin, {William R.} and Evans, {Christopher M.}",

note = "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).",

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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.

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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.

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