TY - JOUR
T1 - The polymeric mucin Muc5ac is required for allergic airway hyperreactivity
AU - Evans, Christopher M.
AU - Raclawska, Dorota S.
AU - Ttofali, Fani
AU - Liptzin, Deborah R.
AU - Fletcher, Ashley A.
AU - Harper, Daniel N.
AU - McGing, Maggie A.
AU - McElwee, Melissa M.
AU - Williams, Olatunji W.
AU - Sanchez, Elizabeth
AU - Roy, Michelle G.
AU - Kindrachuk, Kristen N.
AU - Wynn, Thomas A.
AU - Eltzschig, Holger K.
AU - Blackburn, Michael R.
AU - Tuvim, Michael J.
AU - Janssen, William J.
AU - Schwartz, David A.
AU - Dickey, Burton F.
N1 - Funding Information:
We thank G. Francis, F. Benavides and J. Parker-Thornburg for their assistance in generating mutant and congenic mice. Discussions with Dr W.M. Foster of the Duke University Medical Center were helpful in the design of our aerosol system. This work was supported by the National Institutes of Health Grants R01HL080396 and R21ES023384 (C.M.E.); R21HL120770 (D.A.S.); UH2HL123442 (C.M.E. and D.A.S.); R01HL097000 (B.F.D.); R01HL070952 (M.R.B.); R01DK097075, R01HL092188, R01HL098294 and R01HL119837 (H.K.E.); P01HL114457 (M.R.B. and H.K.E.); R01HL109517 (W.J.J.); and grants by the American Heart Association 14GRNT19990040 (C.M.E.) and the Crohn’s and Colitis Foundation of America (H.K.E.). T.A.W. was supported by the intramural research program at the National Institute of Allergy and Infectious Diseases/National Institutes of Health. Additional support was provided by National Institutes of Health Cancer Center Support Grants P30CA016672 (M.D.
PY - 2015/2/17
Y1 - 2015/2/17
N2 - In asthma, airflow obstruction is thought to result primarily from inflammation-triggered airway smooth muscle (ASM) contraction. However, anti-inflammatory and smooth muscle-relaxing treatments are often temporary or ineffective. Overproduction of the mucin MUC5AC is an additional disease feature that, while strongly associated pathologically, is poorly understood functionally. Here we show that Muc5ac is a central effector of allergic inflammation that is required for airway hyperreactivity (AHR) to methacholine (MCh). In mice bred on two well-characterized strain backgrounds (C57BL/6 and BALB/c) and exposed to two separate allergic stimuli (ovalbumin and Aspergillus extract), genetic removal of Muc5ac abolishes AHR. Residual MCh responses are identical to unchallenged controls, and although inflammation remains intact, heterogeneous mucous occlusion decreases by 74%. Thus, whereas inflammatory effects on ASM alone are insufficient for AHR, Muc5ac-mediated plugging is an essential mechanism. Inhibiting MUC5AC may be effective for treating asthma and other lung diseases where it is also overproduced.
AB - In asthma, airflow obstruction is thought to result primarily from inflammation-triggered airway smooth muscle (ASM) contraction. However, anti-inflammatory and smooth muscle-relaxing treatments are often temporary or ineffective. Overproduction of the mucin MUC5AC is an additional disease feature that, while strongly associated pathologically, is poorly understood functionally. Here we show that Muc5ac is a central effector of allergic inflammation that is required for airway hyperreactivity (AHR) to methacholine (MCh). In mice bred on two well-characterized strain backgrounds (C57BL/6 and BALB/c) and exposed to two separate allergic stimuli (ovalbumin and Aspergillus extract), genetic removal of Muc5ac abolishes AHR. Residual MCh responses are identical to unchallenged controls, and although inflammation remains intact, heterogeneous mucous occlusion decreases by 74%. Thus, whereas inflammatory effects on ASM alone are insufficient for AHR, Muc5ac-mediated plugging is an essential mechanism. Inhibiting MUC5AC may be effective for treating asthma and other lung diseases where it is also overproduced.
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U2 - 10.1038/ncomms7281
DO - 10.1038/ncomms7281
M3 - Article
C2 - 25687754
AN - SCOPUS:84923361939
SN - 2041-1723
VL - 6
JO - Nature communications
JF - Nature communications
M1 - 6281
ER -