Objective To evaluate the antifibrotic effects of the pan-peroxisome proliferator-activated receptor (PPAR) agonist IVA337 in preclinical mouse models of pulmonary fibrosis and related pulmonary hypertension (PH).
Methods IVA337 has been evaluated in the mouse model of bleomycin-induced pulmonary fibrosis and in Fra-2 transgenic mice, this latter being characterised by non-specific interstitial pneumonia and severe vascular remodelling of pulmonary arteries leading to PH. Mice received two doses of IVA337 (30 mg/kg or 100 mg/kg) or vehicle administered by daily oral gavage up to 4 weeks.
Results IVA337 demonstrated at a dose of 100 mg/kg a marked protection from the development of lung fibrosis in both mouse models compared with mice receiving 30 mg/kg of IVA337 or vehicle. Histological score was markedly reduced by 61% in the bleomycin model and by 50% in Fra-2 transgenic mice, and total lung hydroxyproline concentrations decreased by 28% and 48%, respectively, as compared with vehicle-treated mice. IVA337 at 100 mg/kg also significantly decreased levels of fibrogenic markers in lesional lungs of both mouse models. In addition, IVA337 substantially alleviated PH in Fra-2 transgenic mice by improving haemodynamic measurements and vascular remodelling. In primary human lung fibroblasts, IVA337 inhibited in a dose-dependent manner fibroblast to myofibroblasts transition induced by TGF-β and fibroblast proliferation mediated by PDGF.
Conclusion We demonstrate that treatment with 100 mg/kg IVA337 prevents lung fibrosis in two complementary animal models and substantially attenuates PH in the Fra-2 mouse model. These findings confirm that the pan-PPAR agonist IVA337 is an appealing therapeutic candidate for these cardiopulmonary involvements.
- pulmonary fibrosis
- pulmonary hypertension
- nuclear receptors
- systemic sclerosis
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Handling editor Tore K Kvien
Contributors Study design: JA and YA. Conduction of experiments: JA, CG, SP, JS, TG, AC and LT. Data analysis: JA, CG, SP, JS, TG, AC, LT and YA. Writing/drafting and revising the manuscript: JA, IK, CG, SP, JS, TG, AC, LT, J-ML, J-LJ, PB and YA. Final approval of the manuscript: JA, IK, CG, SP, JS, TG, AC, LT, J-ML, J-LJ, PB and YA.
Funding Fundings were supplied by INSERM, ATIP/AVENIR programme and Inventiva. Inventiva was not involved in the study design and data acquisition.
Competing interests JA has/had consultancy relationship and/or has received research funding in relationship with the treatment of systemic sclerosis from Actelion, Roche, Pfizer and Bristol-Myers Squibb. YA has/had consultancy relationship and/or has received research funding in relationship with the treatment of systemic sclerosis from Actelion, Bayer, Biogen Idec, Bristol-Myers Squibb, Genentech/Roche, Inventiva, Medac, Pfizer, Sanofi/Genzyme, Servier and UCB. IK, J-ML and PB are employed by Inventiva. J-LJ has consultancy relationship with Inventiva.
Provenance and peer review Not commissioned; externally peer reviewed.
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