Human precision-cut lung slices generated from excess donor lungs as a model for IPF and drug screening

Idiopathic pulmonary fibrosis (IPF) is a devastating disease with a poor prognosis and no cure. Unfortunately, over 90% of drugs fail in clinical trials for IPF due to difficulty in translating promising drugs from animal models. Human precision-cut lung slices (hPCLS) have gained increasing interest as a possible means to model IPF. An early-like stage of IPF can be induced via a fibrosis cocktail (FC) in hPCLS generated from tumor-free cancer resections to study disease and pharmacological approaches. A drawback of using PCLS from tumor-free lung cancer resections is that the tissue can be deranged (e.g. aberrant immune cells and secreted factors), which may contribute to the fibrotic response ex vivo. In the current study, we hypothesized that hPCLS generated from excess donor lung tissue could be used as a more physiologic option. hPCLS were generated from 4 excess donor lungs and treated with FC for up to 120 hours. To obtain non-biased gene expression data, we utilized RNA-seq using an RNA isolation protocol we recently developed. FC induced a fibrotic-like response after 48 hours which increased further with time. Genes associated with matrix remodeling (e.g.FN1, COL1A1, and MMP7) and Wnt-signaling (e.g.WNT2, WNT5B, WNT10A, NKD1, and AXIN2) increased, whereas genes associated with distal epithelial cell markers (e.g.SFTPC and HOPX) decreased. Genes associated with epithelial subtypes in IPF (e.g.KRT17) increased. In addition, hPCLS were treated with two novel drugs, one in pre-clinical testing and one currently in Phase II clinical trials for IPF. Each drug induced differential amelioration of fibrotic gene expression, assessed by RNA-seq. hPCLS generated from excess donor lungs and treated with FC are a promising model of IPF and to study potential therapies.