TY - JOUR
T1 - Murine Precision-cut Intestinal Slices as a Potential Screening Tool for Antifibrotic Drugs
AU - Iswandana, Raditya
AU - Pham, Bao Tung
AU - Suriguga, Su
AU - Luangmonkong, Theerut
AU - Van Wijk, Louise A.
AU - Jansen, Yvette J.M.
AU - Oosterhuis, Dorenda
AU - Maria Mutsaers, Henricus Antonius
AU - Olinga, Peter
N1 - Funding Information:
Research sponsored by the Crohn's & Colitis Foundation.
Funding Information:
Received for publications December 20, 2018; Editorial Decision December 12, 2019. From the *Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, the Netherlands; †Faculty of Pharmacy, Universitas Indonesia, Depok, Indonesia; ‡Department of Pharmaceutics, Hanoi University of Pharmacy, Hanoi, Vietnam; §Department of Pharmacology, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand; ¶Department of Clinical Medicine, Aarhus University, Aarhus, Denmark #These authors contributed equally. Supported by: This work is supported by funding from De Nederlandse organisatie voor gezondheidsonderzoek en zorginnovatie (ZonMw); the Netherlands (Grant 114025003). Address correspondence to: Professor Peter Olinga, Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, the Netherlands. E-mail: p.olinga@rug.nl. © 2020 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and repro-duction in any medium, provided the original work is properly cited. For commer-cial re-use, please contact journals.permissions@oup.com doi: 10.1093/ibd/izz329 Published online 14 January 2020
Publisher Copyright:
© 2020 Crohn's & Colitis Foundation. Published by Oxford University Press on behalf of Crohn's & Colitis Foundation.
PY - 2020/4/11
Y1 - 2020/4/11
N2 - 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.
AB - 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.
KW - antifibrotic compounds
KW - intestinal fibrosis
KW - platelet-derived growth factor inhibitors
KW - precision-cut intestinal slices
KW - transforming growth factor-β1 inhibitors
UR - http://www.scopus.com/inward/record.url?scp=85083623678&partnerID=8YFLogxK
U2 - 10.1093/ibd/izz329
DO - 10.1093/ibd/izz329
M3 - Article
C2 - 31943022
AN - SCOPUS:85083623678
SN - 1078-0998
VL - 26
SP - 678
EP - 686
JO - Inflammatory Bowel Diseases
JF - Inflammatory Bowel Diseases
IS - 5
ER -