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Pan-PPAR agonist IVA337 is effective in experimental lung fibrosis and pulmonary hypertension
  1. Jerome Avouac1,2,
  2. Irena Konstantinova3,
  3. Christophe Guignabert4,5,
  4. Sonia Pezet1,
  5. Jeremy Sadoine6,
  6. Thomas Guilbert1,
  7. Anne Cauvet1,
  8. Ly Tu4,5,
  9. Jean-Michel Luccarini3,
  10. Jean-Louis Junien3,
  11. Pierre Broqua3,
  12. Yannick Allanore1,2,6
  1. 1Université Paris Descartes, Sorbonne Paris Cité, INSERM U1016, Institut Cochin, CNRS UMR8104, Paris, France
  2. 2Université Paris Descartes, Sorbonne Paris Cité , Service de Rhumatologie A, Hôpital Cochin, Paris, France
  3. 3Inventiva, Daix, France
  4. 4INSERM UMR_S 999, Le Plessis-Robinson, France
  5. 5Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France
  6. 6EA 2496 Pathologie, Imagerieet Biothérapies Orofaciales, UFR Odontologie, Université ParisDescartes and PIDV, PRES Sorbonne Paris Cité, Montrouge, France
  1. Correspondence to Dr Jerome Avouac, Service de Rhumatologie A, Hôpital Cochin, Université Paris Descartes, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France; javouac{at}me.com

Abstract

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
  • IVA337
  • PPAR.

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Footnotes

  • 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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