Background/Purpose: Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease of unknown etiology; the most critical event in the evolution of fibrosis is the appearance of activated myofibroblasts. Mast cells (MC) mediate a variety of inflammatory and fibrotic conditions, but their role in IPF is unclear. We examined whether MCs play a critical role in the development of pulmonary fibrosis.

Methods: Lung tissue was examined using histology and immunohistochemistry. Bioptic material was obtained from the involved lung tissue of 18 IPF patients. As control samples, we used 8 noncancerous lung sections from patients who had undergone surgery for lung cancer. We used immunohistochemistry to identify and quantify tryptase-positive MCs, prolyl-4-hydroxylase β-positive fibroblasts, and alpha-smooth muscle actin (α-SMA)-positive myofibroblasts. Co-culture of human mast cell line 1 (HMC-1) with pulmonary fibroblasts was performed in a transwell system. Fibroblasts cultured with HMC-1 cells for 7 days were cytospun and expression of α-SMA, a marker of myofibroblast differentiation, was examined by immunohistochemistry. α-SMA gene (Acta2) expression in fibroblasts, and IL-6, TGF-β, and bFGF in HMC-1 cells and fibroblasts were evaluated by RT-qPCR.

Results:

MCs were significantly more numerous in IPF than control lung tissue. MCs were usually in close proximity to pulmonary fibroblasts and myofibroblasts. Up-regulation of α-SMA in fibroblasts during co-culture with MCs was confirmed by immunohistochemistry; Acta2 mRNA was also significantly elevated. In co-cultures of fibroblasts and HMC-1 cells, IL-6, TGF-b, and bFGF expression increased in the HMC-1 cells and IL-6 and TGF-b expression increased in the fibroblasts. These observations suggest an amplification loop is generated between MCs and fibroblasts, enhancing production of pro-fibrotic factors.