Mast cells and fibroblasts work in concert to aggravate pulmonary fibrosis: role of transmembrane SCF and the PAR-2/PKC-α/Raf-1/p44/42 signaling pathway

Am J Pathol. 2013 Jun;182(6):2094-108. doi: 10.1016/j.ajpath.2013.02.013. Epub 2013 Apr 4.


Mast cell (MC) accumulation has been demonstrated in the lungs of idiopathic pulmonary fibrosis (IPF) patients. Mediators released from MCs may regulate tissue remodeling processes, thereby contributing to IPF pathogenesis. We investigated the role of MC-fibroblast interaction in the progression of lung fibrosis. Increased numbers of activated MCs, in close proximity to fibroblast foci and alveolar type II cells, were observed in IPF lungs. Correspondingly elevated tryptase levels were detected in IPF lung tissue samples. Coculture of human lung MCs with human lung fibroblasts (HLFs) induced MC activation, as evinced by tryptase release, and stimulated HLF proliferation; IPF HLFs exhibited a significantly higher growth rate, compared with control. Tryptase stimulated HLF growth in a PAR-2/PKC-α/Raf-1/p44/42-dependent manner and potentiated extracellular matrix production, but independent of PKC-α, Raf-1, and p44/42 activities. Proproliferative properties of tryptase were attenuated by knockdown or pharmacological inhibition of PAR-2, PKC-α, Raf-1, or p44/42. Expression of transmembrane SCF, but not soluble SCF, was elevated in IPF lung tissue and in fibroblasts isolated from IPF lungs. Coculture of IPF HLFs with MCs enhanced MC survival and proliferation. These effects were cell-contact dependent and could be inhibited by application of anti-SCF antibody or CD117 inhibitor. Thus, fibroblasts and MCs appear to work in concert to perpetuate fibrotic processes and so contribute to lung fibrosis progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Communication / physiology
  • Cell Count
  • Cell Degranulation / physiology
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Coculture Techniques
  • Dose-Response Relationship, Drug
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Fibroblasts / physiology*
  • Humans
  • Lung / metabolism
  • Lung / pathology
  • Mast Cells / metabolism
  • Mast Cells / physiology*
  • Protein Kinases / physiology
  • Pulmonary Fibrosis / metabolism
  • Pulmonary Fibrosis / pathology*
  • Receptor, PAR-2 / physiology
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Stem Cell Factor / physiology
  • Tryptases / pharmacology
  • Tryptases / physiology


  • Receptor, PAR-2
  • Stem Cell Factor
  • Protein Kinases
  • Tryptases