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Murine Precision-cut Intestinal Slices as a Potential Screening Tool for Antifibrotic Drugs
Raditya Iswandana1,2, Bao Tung Pham1,3, Su Suriguga1
1Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, the Netherlands.
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.
Insights
Intestinal fibrosis in Crohn's disease was studied using precision-cut intestinal slices. Sunitinib effectively reduced fibrosis markers, showing potential for treating intestinal fibrosis.
Area of Science:
- Gastroenterology
- Drug Discovery
- Fibrosis Research
Background:
- Intestinal fibrosis is a key characteristic of Crohn's disease.
- Investigating antifibrotic compounds is crucial for managing this condition.
Purpose of the Study:
- To evaluate the efficacy of antifibrotic compounds in a preclinical model.
- To assess the impact of TGF-β and PDGF pathways on intestinal fibrosis.
Main Methods:
- Utilized murine precision-cut intestinal slices cultured for 48 hours.
- Assessed gene and protein expression of fibrosis markers (Col1α1, Hsp47, Fn2, Pai-1).
- Tested antifibrotic drugs targeting TGF-β and PDGF pathways at non-toxic concentrations.
Main Results:
- Precision-cut intestinal slices remained viable and showed increased fibrosis markers during culture.
- Transforming growth factor β (TGF-β) stimulated fibrogenesis; platelet-derived growth factor (PDGF) did not.
- Pirfenidone, LY2109761, and sunitinib significantly reduced fibrosis markers; sunitinib showed notable effects on protein expression and procollagen excretion.
Conclusions:
- Precision-cut intestinal slices serve as a viable preclinical tool for antifibrotic drug screening.
- Sunitinib demonstrated significant reduction in fibrosis markers, indicating its therapeutic potential for intestinal fibrosis.
