A kinase inhibitor screen identifies signaling pathways regulating mucosal growth during otitis media

PLoS One. 2020 Aug 6;15(8):e0235634. doi: 10.1371/journal.pone.0235634. eCollection 2020.

Abstract

Otitis media, the most common disease of childhood, is characterized by extensive changes in the morphology of the middle ear cavity. This includes hyperplasia of the mucosa that lines the tympanic cavity, from a simple monolayer of squamous epithelium into a greatly thickened, respiratory-type mucosa. The processes that control this response, which is critical to otitis media pathogenesis and recovery, are incompletely understood. Given the central role of protein phosphorylation in most intracellular processes, including cell proliferation and differentiation, we screened a library of kinase inhibitors targeting members of all the major families in the kinome for their ability to influence the growth of middle ear mucosal explants in vitro. Of the 160 inhibitors, 30 were found to inhibit mucosal growth, while two inhibitors enhanced tissue proliferation. The results suggest that the regulation of infection-mediated tissue growth in the ME mucosa involves multiple cellular processes that span the kinome. While some of the pathways and processes identified have been previously implicated in mucosa hyperplasia others are novel. The results were used to generate a global model of growth regulation by kinase pathways. The potential for therapeutic applications of the results are discussed.

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

  • Animals
  • Cell Proliferation / drug effects*
  • Drug Evaluation, Preclinical
  • Haemophilus influenzae / pathogenicity
  • High-Throughput Screening Assays
  • Humans
  • Hyperplasia / drug therapy
  • Hyperplasia / microbiology
  • Hyperplasia / pathology
  • Mice
  • Mucous Membrane / drug effects
  • Mucous Membrane / microbiology
  • Mucous Membrane / pathology
  • Otitis Media / drug therapy*
  • Otitis Media / microbiology
  • Otitis Media / pathology
  • Phosphorylation / drug effects
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Serine-Threonine Kinases / metabolism*
  • Rats
  • Signal Transduction / drug effects*
  • Tissue Culture Techniques

Substances

  • Protein Kinase Inhibitors
  • Protein Serine-Threonine Kinases