Murine Precision-cut Intestinal Slices as a Potential Screening Tool for Antifibrotic Drugs

Raditya Iswandana, Bao Tung Pham, Su Suriguga, Theerut Luangmonkong, Louise A. Van Wijk, Yvette J.M. Jansen, Dorenda Oosterhuis, Henricus Antonius Maria Mutsaers, Peter Olinga

Research output: Contribution to journalArticle

Abstract

Background: Intestinal fibrosis is a hallmark of Crohn's disease. Here, we investigated the impact of several putative antifibrotic compounds on the expression of fibrosis markers using murine precision-cut intestinal slices. Methods: Murine precision-cut intestinal slices were cultured for 48 hours in the presence of profibrotic and/or antifibrotic compounds. The fibrotic process was studied on gene and protein level using procollagen 1a1 (Col1α1), heat shock protein 47 (Hsp47), fibronectin (Fn2), and plasminogen activator inhibitor-1 (Pai-1). The effects of potential antifibrotic drugs mainly inhibiting the transforming growth factor β (TGF-β) pathway (eg, valproic acid, tetrandrine, pirfenidone, SB203580, and LY2109761) and compounds mainly acting on the platelet-derived growth factor (PDGF) pathway (eg, imatinib, sorafenib, and sunitinib) were assessed in the model at nontoxic concentrations. Results: Murine precision-cut intestinal slices remained viable for 48 hours, and an increased expression of fibrosis markers was observed during culture, including Hsp47, Fn2, and Pai-1. Furthermore, TGF-β1 stimulated fibrogenesis, whereas PDGF did not have an effect. Regarding the tested antifibrotics, pirfenidone, LY2109761, and sunitinib had the most pronounced impact on the expression of fibrosis markers, both in the absence and presence of profibrotic factors, as illustrated by reduced levels of Col1α1, Hsp47, Fn2, and Pai-1 after treatment. Moreover, sunitinib significantly reduced Hsp47 and Fn2 protein expression and the excretion of procollagen 1. Conclusions: Precision-cut intestinal slices can successfully be used as a potential preclinical screening tool for antifibrotic drugs. We demonstrated that sunitinib reduced the expression of several fibrosis markers, warranting further evaluation of this compound for the treatment of intestinal fibrosis.

Original languageEnglish
Pages (from-to)678-686
Number of pages9
JournalInflammatory Bowel Diseases
Volume26
Issue number5
DOIs
Publication statusPublished - 11 Apr 2020

Keywords

  • antifibrotic compounds
  • intestinal fibrosis
  • platelet-derived growth factor inhibitors
  • precision-cut intestinal slices
  • transforming growth factor-β1 inhibitors

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    Iswandana, R., Pham, B. T., Suriguga, S., Luangmonkong, T., Van Wijk, L. A., Jansen, Y. J. M., Oosterhuis, D., Maria Mutsaers, H. A., & Olinga, P. (2020). Murine Precision-cut Intestinal Slices as a Potential Screening Tool for Antifibrotic Drugs. Inflammatory Bowel Diseases, 26(5), 678-686. https://doi.org/10.1093/ibd/izz329