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

Autor: Bao Tung Pham, Dorenda Oosterhuis, Peter Olinga, S. Suriguga, Raditya Iswandana, Henricus A. M. Mutsaers, Louise A van Wijk, Yvette J. M. Jansen, Theerut Luangmonkong
Přispěvatelé: Pharmaceutical Technology and Biopharmacy, Biopharmaceuticals, Discovery, Design and Delivery (BDDD), Groningen Institute for Organ Transplantation (GIOT)
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Platelet-derived growth factor
Drug Evaluation
Preclinical
transforming growth factor-β1 inhibitors
Pharmacology
platelet-derived growth factor inhibitors
Collagen Type I
chemistry.chemical_compound
Mice
Crohn Disease
Gastrointestinal Agents
precision-cut intestinal slices
Fibrosis
Transforming Growth Factor beta
Serpin E2
medicine
Sunitinib
intestinal fibrosis
Immunology and Allergy
Animals
Enzyme Inhibitors
HSP47 Heat-Shock Proteins
Ibdjnl/3
Heat shock protein 47
AcademicSubjects/MED00260
Platelet-Derived Growth Factor
biology
Gastroenterology
antifibrotic compounds
Pirfenidone
medicine.disease
Fibronectins
Tetrandrine
Collagen Type I
alpha 1 Chain
Intestines
chemistry
Plasminogen activator inhibitor-1
biology.protein
Platelet-derived growth factor receptor
Basic Science Research
medicine.drug
Signal Transduction
Zdroj: Inflammatory Bowel Diseases, 26(5), 678-686. LIPPINCOTT WILLIAMS & WILKINS
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, vol. 26, no. 5, pp. 678-686 . https://doi.org/10.1093/ibd/izz329
Inflammatory Bowel Diseases
ISSN: 1078-0998
DOI: 10.1093/ibd/izz329
Popis: 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.
We demonstrate that precision-cut intestinal slices are a potential suitable screening platform for antifibrotic drugs. We tested the efficacy of a broad range of putative antifibrotic drugs and identified that sunitinib reduces the expression of several fibrosis markers, warranting further evaluation of this compound for the treatment of intestinal fibrosis.
Databáze: OpenAIRE
Externí odkaz: