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

Arthritis Research & Therapy

Voon H. Ong¹  Christopher P. Denton¹  Kristina E. N. Clark¹  Emma Derrett-Smith¹  Xu Shiwen¹  David J. Abraham¹  Rachel K. Hoyles²  Irena Konstantinova³  Jean Louis Junien³  Olivier Lacombe³  Pierre Broqua³ 

[1] Centre for Rheumatology and Connective Tissue Diseases, UCL Division of Medicine, Rowland Hill St., NW3 2PF, London, UK;Churchill Hospital, OX3 7LE, Oxford, UK;Inventiva, 21121, Daix, France;

关键词: Systemic sclerosis;    Animal models;    PPAR;    TGFβ;    Pulmonary hypertension;    Pulmonary fibrosis;   

DOI  :  10.1186/s13075-021-02592-x

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY