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

Abstract

Background Idiopathic pulmonary fibrosis (IPF) is a progressive and invariably lethal interstitial lung disease with little effective therapy. Animal models potentially help with understanding disease mechanisms, but to-date, the commonly used bleomycin mouse model of lung fibrosis has failed to predict drug efficacy in IPF. We hypothesise that human lung tissue stimulated with pro-fibrotic mediators will provide a more accurate physiological representation for the assessment of anti-fibrotic strategies in IPF. Methods 2mm 3 pieces of human lung parenchyma were cultured for 7 days in DMEM±TGFβ1 (10ng/ml) and pro-fibrotic pathways examined by RT-PCR, immunohistochemistry and collagen secretion. The effects of K Ca 3.1 channel blockers, on inhibiting TGFβ1-induced fibrogenesis were examined. Results Following 7 days of culture with TGFβ1, over 20 genes were upregulated including αSMA, collagen 1, integrin β1 and MMP2. Immunohistochemical staining demonstrated increased expression of collagen type I, αSMA, fibroblast markers after TGFβ1 exposure when compared to control tissue. Collagen secretion was significantly increased following TGFβ1 stimulation. These pro-fibrotic responses were inhibited by K Ca 3.1 channel blockade. Conclusions Human lung explants may provide an alternative to the use of animals for the study of fibrotic mechanisms and novel drug interventions in IPF. In maintaining the complex cell-cell and cell-matrix interactions of human tissue, this model may better predict drug efficacy in clinical trials. This study also supports the view that K Ca 3.1 channels are a promising target for the treatment of IPF. This abstract has been presented previously at the European Respiratory Society9s Lung Science Conference in March 2016 .