A model of human lung fibrogenesis for the assessment of anti-fibrotic strategies in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with limited therapeutic options. K(Ca)3.1 ion channels play a critical role in TGF beta 1-dependent pro-fibrotic responses in human lung myofibroblasts. We aimed to develop a human lung parenchymal model of fibrogenesis and test the efficacy of the selective K(Ca)3.1 blocker senicapoc. 2 mm(3) pieces of human lung parenchyma were cultured for 7 days in DMEM +/- TGF beta 1 (10 ng/ml) and pro-fibrotic pathways examined by RT-PCR, immunohistochemistry and collagen secretion. Following 7 days of culture with TGF beta 1, 41 IPF-and fibrosis-associated genes were significantly upregulated. Immunohistochemical staining demonstrated increased expression of ECM proteins and fibroblast-specific protein after TGF beta 1-stimulation. Collagen secretion was significantly increased following TGF beta 1-stimulation. These pro-fibrotic responses were attenuated by senicapoc, but not by dexamethasone. This 7 day ex vivo model of human lung fibrogenesis recapitulates pro-fibrotic events evident in IPF and is sensitive to K(Ca)3.1 channel inhibition. By maintaining the complex cell-cell and cell-matrix interactions of human tissue, and removing crossspecies heterogeneity, this model may better predict drug efficacy in clinical trials and accelerate drug development in IPF. K(Ca)3.1 channels are a promising target for the treatment of IPF.