IL-13-induced airway mucus production is attenuated by MAPK13 inhibition

Yael G. Alevy, Anand C. Patel, Arthur G. Romero, Dhara A. Patel, Jennifer Tucker, William T. Roswit, Chantel A. Miller, Richard F. Heier, Derek E. Byers, Tom J. Brett, Michael J. Holtzman

Research output: Contribution to journalArticle

109 Scopus citations

Abstract

Increased mucus production is a common cause of morbidity and mortality in inflammatory airway diseases, including asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis. However, the precise molecular mechanisms for pathogenic mucus production are largely undetermined. Accordingly, there are no specific and effective anti-mucus therapeutics. Here, we define a signaling pathway from chloride channel calcium-activated 1 (CLCA1) to MAPK13 that is responsible for IL-13-driven mucus production in human airway epithelial cells. The same pathway was also highly activated in the lungs of humans with excess mucus production due to COPD. We further validated the pathway by using structure-based drug design to develop a series of novel MAPK13 inhibitors with nanomolar potency that effectively reduced mucus production in human airway epithelial cells. These results uncover and validate a new pathway for regulating mucus production as well as a corresponding therapeutic approach to mucus overproduction in inflammatory airway diseases.

Original languageEnglish
Pages (from-to)4555-4568
Number of pages14
JournalJournal of Clinical Investigation
Volume122
Issue number12
DOIs
StatePublished - Dec 3 2012

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