The pan-PPAR agonist lanifibranor reduces development of lung fibrosis and attenuates cardiorespiratory manifestations in a transgenic mouse model of systemic sclerosis

Emma Derrett-Smith,Olivier Lacombe,Voon H Ong,Rachel K Hoyles,Irena Konstantinova,Xu Shiwen,Jean Louis Junien,Pierre Broqua,Kristina E N Clark,Christopher P Denton,David J Abraham

doi:10.1186/s13075-021-02592-x

Abstract

BackgroundThe TβRII∆k-fib transgenic (TG) mouse model of scleroderma replicates key fibrotic and vasculopathic complications of systemic sclerosis through fibroblast-directed upregulation of TGFβ signalling. We have examined peroxisome proliferator-activated receptor (PPAR) pathway perturbation in this model and explored the impact of the pan-PPAR agonist lanifibranor on the cardiorespiratory phenotype.MethodsPPAR pathway gene and protein expression differences from TG and WT sex-matched littermate mice were determined at baseline and following administration of one of two doses of lanifibranor (30 mg/kg or 100 mg/kg) or vehicle administered by daily oral gavage up to 4 weeks. The prevention of bleomycin-induced lung fibrosis and SU5416-induced pulmonary hypertension by lanifibranor was explored.ResultsGene expression data were consistent with the downregulation of the PPAR pathway in the TβRII∆k-fib mouse model. TG mice treated with high-dose lanifibranor demonstrated significant protection from lung fibrosis after bleomycin and from right ventricular hypertrophy following induction of pulmonary hypertension by SU5416, despite no significant change in right ventricular systolic pressure.ConclusionsIn the TβRII∆k-fib mouse strain, treatment with 100 mg/kg lanifibranor reduces the development of lung fibrosis and right ventricular hypertrophy induced by bleomycin or SU5416, respectively. Reduced PPAR activity may contribute to the exaggerated fibroproliferative response to tissue injury in this transgenic model of scleroderma and its pulmonary complications.

Highlights

The TβRII∆k-fib transgenic (TG) mouse model of scleroderma replicates key fibrotic and vasculopathic complications of systemic sclerosis through fibroblast-directed upregulation of transforming growth factor β (TGFβ) signalling
peroxisome proliferator-activated receptor (PPAR) gene expression is altered in whole skin, lung, and explanted cells of TβRII∆k‐fib mice For individual substrate Ribodeoxynu‐ cleic acid (RNA) analysed, the number of genes were whole lung (n = 3), adult skin fibroblasts (n = 2), neonatal skin fibroblasts (n = 4), neonatal lung fibroblasts (n = 3) and adult vascular smooth muscle cells (n = 11)
Our findings suggest that lanifibranor may attenuate right ventricular hypertrophy or fibrosis in this transgenic model but further studies would be required to confirm this and explore the interplay between the cardiac, vascular and pulmonary phenotype of the mice, just as these factors are relevant in assessment and treatment of systemic sclerosis

Summary

Introduction

The TβRII∆k-fib transgenic (TG) mouse model of scleroderma replicates key fibrotic and vasculopathic complications of systemic sclerosis through fibroblast-directed upregulation of TGFβ signalling. The transgene stabilises endogenous wildtype receptor complexes leading to increased expression of the corresponding murine TβRII on fibroblasts that causes upregulated ligand-dependent TGFβ signalling in the skin and other connective tissues. This mouse strain develops constitutive skin fibrosis [3] and a structural vasculopathy [6] with vessel wall fibrosis. Administration of bleomycin leads to persistent and severe lung fibrosis when compared to unbuffered saline in transgenic (TG) mice or bleomycin in wildtype (WT) mice [4]

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