Precision-cut lung slices from bleomycin treated animals as a model for testing potential therapies for idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a complex lung disease with incompletely understood pathophysiology. Effectiveness of available medicines is limited and the need for new and improved therapies remains. Due to complexity of the disease, it is difficult to develop predictable in vitro models. In this study we have described precision-cut lung slices (PCLS) prepared from bleomycin treated mice as an in vitro model for testing of novel compounds with antifibrotic activity. We have shown that PCLS during in vitro incubation retain characteristics of bleomycin model with increased expression of fibrosis related genes ACTA2 (α-smooth muscle actin), COL1A1 (collagen 1), FN1 (fibronectin 1), MMP12 (matrix metalloproteinase 12) and TIMP1 (tissue inhibitor of metalloproteinases). To further evaluate PCLS as an in vitro model, we have tested ALK5 inhibitor SB525334 which was previously shown to attenuate fibrosis in in vivo bleomycin model and nintedanib which is the FDA approved treatment for IPF. SB525334 and nintedanib inhibited expression of fibrosis related genes in PCLS from bleomycin treated mice. In addition, comparable activity profile of SB525334 was achieved in PCLS and in vivo model. Altogether these results suggest that PCLS may be a suitable in vitro model for compound testing during drug development process.

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S1476 SB525334 SB525334 is a potent and selective inhibitor of TGFβ receptor I (ALK5) with IC50 of 14.3 nM in a cell-free assay, 4-fold less potent to ALK4 than ALK5 and inactive to ALK2, 3, and 6. (73) (8)

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