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

J Clin Invest. 2012 Dec;122(12):4555-68. doi: 10.1172/JCI64896. Epub 2012 Nov 26.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Binding Sites
  • Cells, Cultured
  • Chloride Channels / genetics
  • Chloride Channels / metabolism
  • Chloride Channels / physiology
  • Crystallography, X-Ray
  • Drug Design
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism*
  • Gene Expression Regulation
  • Gene Knockdown Techniques
  • Humans
  • Hydrogen Bonding
  • Interleukin-13 / physiology*
  • Kinetics
  • MAP Kinase Signaling System
  • Mitogen-Activated Protein Kinase 13 / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase 13 / chemistry
  • Mitogen-Activated Protein Kinase 13 / genetics
  • Mitogen-Activated Protein Kinase 13 / metabolism
  • Models, Molecular
  • Mucins / genetics
  • Mucins / metabolism
  • Mucus / metabolism*
  • Naphthalenes / chemistry
  • Naphthalenes / pharmacology
  • Protein Binding
  • Pulmonary Disease, Chronic Obstructive / metabolism
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology
  • RNA Interference
  • Respiratory System / metabolism*
  • Respiratory System / pathology
  • Secretory Pathway / drug effects

Substances

  • BIRB 796
  • CLCA1 protein, human
  • Chloride Channels
  • Interleukin-13
  • Mucins
  • Naphthalenes
  • Pyrazoles
  • Mitogen-Activated Protein Kinase 13