PuSH - Publication Server of Helmholtz Zentrum München: An <em>ex vivo</em> model to induce early fibrosis-like changes in human precision-cut lung slices.

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Alsafadi, H.N. ; Staab-Weijnitz, C.A. ; Lehmann, M. ; Lindner, M.* ; Peschel, B. ; Königshoff, M. ; Wagner, D.E.

An ex vivo model to induce early fibrosis-like changes in human precision-cut lung slices.

Am. J. Physiol. Lung Cell Mol. Physiol. 312, L896-L902 (2017)

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IPF is a devastating chronic interstitial lung disease (ILD) characterized by lung tissue scarring and high morbidity. Lung epithelial injury, myofibroblast activation, and deranged repair are believed to be key processes involved in disease onset and progression but the exact molecular mechanisms behind IPF remain unclear. Several drugs have been shown to slow disease progression, but treatments which halt or reverse IPF progression have not been identified. Ex vivo models of human lung have been proposed for drug discovery, one of which is precision-cut lung slices (PCLS). Although PCLS production from IPF explants is possible, IPF explants are rare and typically represent end-stage disease. Here we present a novel model of early fibrosis-like changes in human PCLS derived from patients without ILD/IPF using a combination of profibrotic growth factors and signaling molecules. Fibrotic-like changes of PCLS were qualitatively analyzed by histology and immunofluorescence and quantitatively by WST1, RT-qPCR, WB, and ELISA. PCLS remained viable after 5 days of treatment and fibrotic gene expression (FN1, SERPINE1, COL1A1, CTGF, MMP7 and ACTA2) increased as early as 24h of treatment, with increases in protein levels at 48 hours and increased deposition of extracellular matrix. Alveolar epithelium reprogramming was evident by decreases in SFTPC and loss of HOPX In summary, using human-derived PCLS from patients without ILD/IPF, we established a novel ex vivo model which displays characteristics of early fibrosis and could be used to evaluate novel therapies and study early-stage IPF pathomechanisms.

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