The polymeric mucin Muc5ac is required for allergic airway hyperreactivity

  • Nat Commun. 2015 Feb 17:6:6281. doi: 10.1038/ncomms7281.
Christopher M Evans  1 ,  Dorota S Raclawska  1 ,  Fani Ttofali  1 ,  Deborah R Liptzin  2 ,  Ashley A Fletcher  1 ,  Daniel N Harper  1 ,  Maggie A McGing  1 ,  Melissa M McElwee  3 ,  Olatunji W Williams  4 ,  Elizabeth Sanchez  3 ,  Michelle G Roy  3 ,  Kristen N Kindrachuk  5 ,  Thomas A Wynn  5 ,  Holger K Eltzschig  6 ,  Michael R Blackburn  7 ,  Michael J Tuvim  3 ,  William J Janssen  8 ,  David A Schwartz  1 ,  Burton F Dickey  3
Affiliations
  • 1. Department of Medicine, University of Colorado School of Medicine, 12700 E 19th Avenue, Mailstop 8611, Research Complex 2, Room 3121, Aurora, Colorado 80045, USA.
  • 2. Department of Pediatrics, University of Colorado School of Medicine, 13123 East 16th Avenue, B-395, Aurora, Colorado 80045, USA.
  • 3. Department of Pulmonary Medicine, University of Texas, MD Anderson Cancer Center, PO Box 301402, Houston, Texas 77030, USA.
  • 4. Pediatrics, Peyton Manning Children's Hospital, 8402 Harcourt Road, Suite 731, Indianapolis, Indiana 46260, USA.
  • 5. Immunopathogenesis Section, Program in Barrier Immunity and Repair, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Room 4071, MSC 6606, Bethesda, Maryland 20892-6606, USA.
  • 6. Department of Anesthesiology, University of Colorado School of Medicine, 12700 E 19th Avenue, Mailstop B112, Research Complex 2, Room 7124, Aurora, Colorado 80045, USA.
  • 7. Department of Biochemistry and Molecular Biology, The University of Texas-Houston Medical School, 6431 Fannin, Houston, Texas 77030, USA.
  • 8. 1] Department of Medicine, University of Colorado School of Medicine, 12700 E 19th Avenue, Mailstop 8611, Research Complex 2, Room 3121, Aurora, Colorado 80045, USA [2] Department of Medicine, National Jewish Health, 1400 Jackson Street, Denver, Colorado 80206, USA.
PMID: 25687754 DOI: 10.1038/ncomms7281
Abstract

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.