Mast cells and fibroblasts work in concert to aggravate pulmonary fibrosis: role of transmembrane stem cell factor (SCF) and PAR-2/PKCalpha/Raf-1/p44/42 signaling pathway

Mast cell (MC) accumulation has been demonstrated in the lungs of idiopathic pulmonary fibrosis (IPF) patients. Mediators released from MCs may regulate tissue remodelling processes, thereby contributing to IPF pathogenesis. In this study, we investigated the role of MC-fibroblast interaction for the progression of lung fibrosis.

We observed increased number of activated MCs in IPF lungs, located in close proximity to fibroblast foci and alveolar type II cells. Correspondingly, elevated tryptase levels were detected in IPF lung tissue samples. Co-culture of human lung MCs with human lung fibroblasts (HLF) induced HLF proliferation and tryptase release from MCs. Tryptase stimulated HLF growth in a PAR-2/PKCα/Raf-1/p44/42-dependent manner and potentiated ECM production, however, independently of PKCα, Raf-1, and p44/42 activities. Proproliferative properties of tryptase were attenuated by knockdown or pharmacological inhibition of PAR-2, PKCα, Raf-1, or p44/42. Expression of transmembrane, but not soluble, stem cell factor (SCF) was elevated in IPF lung tissue and fibroblasts isolated from IPF lungs. Co-culture of IPF lung fibroblasts with MCs enhanced MC survival and proliferation. These effects were cell contact dependent and could be inhibited by application of anti-SCF antibody.

Collectively, fibroblasts and mast cells appear to work in concert to perpetuate fibrotic processes and, thus, contribute to lung fibrosis progression. Interference with the PAR-2/PKCα/Raf-1/p44/42 pathway and/or blockade of SCF could potentially be of therapeutic benefit in lung fibrosis