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Thomas Guilbert - One of the best experts on this subject based on the ideXlab platform.
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pan PPAR Agonist iva337 is effective in experimental lung fibrosis and pulmonary hypertension
Annals of the Rheumatic Diseases, 2017Co-Authors: Jerome Avouac, Irena Konstantinova, Christophe Guignabert, Sonia Pezet, Jeremy Sadoine, Thomas Guilbert, Anne Cauvet, Jeanmichel Luccarini, Jeanlouis JunienAbstract: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.
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pan PPAR Agonist iva337 is effective in prevention and treatment of experimental skin fibrosis
Annals of the Rheumatic Diseases, 2015Co-Authors: Nadira Ruzehaji, Jerome Avouac, Sonia Pezet, Thomas Guilbert, Camelia Frantz, Matthieu PonsoyeAbstract:Background The pathogenesis of systemic sclerosis (SSc) involves a distinctive triad of autoimmune, vascular and inflammatory alterations resulting in fibrosis. Evidence suggests that peroxisome proliferator-activated receptors (PPARs) play an important role in SSc-related fibrosis and their Agonists may become effective therapeutic targets. Objective To determine the expression of PPARs in human fibrotic skin and investigate the effects of IVA337, a pan PPAR Agonist, in in vitro and in vivo models of fibrosis. Methods The antifibrotic effects of IVA337 were studied using a bleomycin-induced mouse model of dermal fibrosis. The in vivo effect of IVA337 on wound closure and inflammation were studied using an excisional model of wound healing. Results Low levels of PPARα and PPARγ were detected in the skin of patients with SSc compared with controls. In mice, IVA337 was associated with decreased extracellular matrix (ECM) deposition and reduced expression of phosphorylated SMAD2/3—intracellular effector of transforming growth factor (TGF)-β1. Although the antifibrotic effect of pan PPAR was similar to that of PPARγ Agonist alone, a significant downregulation of several markers of inflammation was associated with IVA337. Despite its anti-inflammatory and antifibrotic properties, IVA337 did not interfere with wound closure. In vitro effects of IVA337 included attenuation of transcription of ECM genes and alteration of canonical and non-canonical TGF-β signalling pathways. Conclusions These findings indicate that simultaneous activation of all three PPAR isoforms exerts a dampening effect on inflammation and fibrosis, making IVA337 a potentially effective therapeutic candidate in the treatment of fibrotic diseases including SSc.
Jeanlouis Junien - One of the best experts on this subject based on the ideXlab platform.
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pan PPAR Agonist lanifibranor improves portal hypertension and hepatic fibrosis in experimental advanced chronic liver disease
Journal of Hepatology, 2021Co-Authors: Zoe Boyerdiaz, Jeanlouis Junien, Pierre Broqua, Claude Robert, Guillaume Wettstein, Peio Aristuzabalza, Maria Andresrozas, Marti Ortegaribera, Anabel Fernandeziglesias, Jaime BoschAbstract:Background & aims In advanced chronic liver disease (ACLD), deregulated hepatic necroinflammatory processes play a key role in the development of liver microvascular dysfunction, fibrogenesis, and increased hepatic vascular tone, resulting in progression of ACLD and portal hypertension. Given the current lack of an effective treatment, we aimed to characterise the effects of the pan-peroxisome proliferator-activated receptor (pan-PPAR) Agonist lanifibranor in 2 preclinical models of ACLD, as well as in liver cells from patients with ACLD. Methods Cirrhotic rats (thioacetamide or common bile duct ligation; TAA or cBDL) randomly received lanifibranor (100 mg/kg/day, po) or vehicle for 14 days (n = 12/group). PPAR expression, systemic and hepatic haemodynamics, presence of ascites, liver sinusoidal endothelial cell (LSEC) phenotype, hepatic stellate cell (HSC) activation, serum transaminases and albumin, hepatic macrophage infiltration, cytokine expression, and liver fibrosis were determined. Hepatic cells were isolated from the livers of patients with cirrhosis and their phenotype was evaluated after treatment with either lanifibranor or vehicle. Results TAA-cirrhotic rats receiving lanifibranor showed significantly lower portal pressure compared with vehicle-treated animals (-15%; p = 0.003) without decreasing portal blood flow, indicating improved hepatic vascular resistance. Moreover, lanifibranor-treated TAA-rats showed decreased ascites, improved LSEC and HSC phenotypes, ameliorated hepatic microvascular function, reduced hepatic inflammation, and significant fibrosis regression (-32%; p = 0.020). These findings were confirmed in the cBDL rat model as well as in human liver cells from patients with cirrhosis, which exhibited phenotypic improvement upon treatment with lanifibranor. Conclusions Lanifibranor ameliorates fibrosis and portal hypertension in preclinical models of decompensated cirrhosis. Promising results in human hepatic cells further support its clinical evaluation for the treatment of ACLD. Lay summary Advanced chronic liver disease (ACLD) constitutes a serious public health issue for which safe and effective treatments are lacking. This study shows that lanifibranor improves portal hypertension and liver fibrosis, 2 key elements of the pathophysiology of ACLD, in preclinical models of the disease. Evaluation of lanifibranor in liver cells from patients with ACLD further supports its beneficial effects.
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Pan-PPAR Agonist lanifibranor improves portal hypertension and hepatic fibrosis in experimental advanced chronic liver disease.
Journal of hepatology, 2020Co-Authors: Zoe Boyer-diaz, Jeanlouis Junien, Pierre Broqua, Peio Aristu-zabalza, María Andrés-rozas, Claude Robert, Martí Ortega-ribera, Anabel Fernández-iglesias, Guillaume Wettstein, Jaime BoschAbstract:Abstract Background Aims In advanced chronic liver disease (ACLD), de-regulated hepatic necroinflammatory processes play a key role in the development of liver microvascular dysfunction, fibrogenesis, and increased hepatic vascular tone, resulting in progression of ACLD and portal hypertension. Given the current lack of an effective treatment, we aimed at characterizing the effects of the pan-peroxisome proliferator-activated receptors (pan-PPAR) Agonist lanifibranor in two pre-clinical models of ACLD, as well as in liver cells from patients with ACLD. Methods Cirrhotic rats (thioacetamide or common bile duct ligation; TAA or cBDL) randomly received lanifibranor (100mg/kg/day, po) or vehicle for 14 days (n=12/group). PPAR expression, systemic and hepatic hemodynamics, presence of ascites, liver sinusoidal endothelial cells (LSEC) phenotype, hepatic stellate cells (HSC) activation, serum transaminases and albumin, hepatic macrophage infiltration, cytokine expression, and liver fibrosis were determined. Hepatic cells were isolated from livers from cirrhotic patients and their phenotype was evaluated after treatment with lanifibranor or vehicle. Results TAA-cirrhotic rats receiving lanifibranor showed significantly lower portal pressure than vehicle-treated animals (-15%) without decreasing portal blood flow, indicating improved hepatic vascular resistance. Moreover, lanifibranor-treated TAA-rats showed decreased ascites, improved phenotype of LSEC and HSC, ameliorated hepatic microvascular function, reduced hepatic inflammation, and significant fibrosis regression (-32%). These findings were confirmed in the cBDL rat model, as well as in human liver cells from cirrhotic patients, which exhibited a phenotypic improvement upon treatment with lanifibranor. Conclusions This study demonstrates that lanifibranor exerts clear beneficial effects in pre-clinical models of decompensated cirrhosis, which lead to amelioration in fibrosis and portal hypertension. Our results in human hepatic cells isolated from cirrhotic patients further encourage its clinical evaluation for the treatment of ACLD.
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pan PPAR Agonist iva337 is effective in experimental lung fibrosis and pulmonary hypertension
Annals of the Rheumatic Diseases, 2017Co-Authors: Jerome Avouac, Irena Konstantinova, Christophe Guignabert, Sonia Pezet, Jeremy Sadoine, Thomas Guilbert, Anne Cauvet, Jeanmichel Luccarini, Jeanlouis JunienAbstract: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.
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op0081 pan PPAR Agonist iva337 is effective in the prevention of experimental lung fibrosis and pulmonary hypertension
Annals of the Rheumatic Diseases, 2017Co-Authors: Jerome Avouac, Irena Konstantinova, Christophe Guignabert, Sonia Pezet, Jeremy Sadoine, Anne Cauvet, Jeanmichel Luccarini, Jeanlouis Junien, G Thomas, Pierre BroquaAbstract:Background Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors known to modulate fibrosis. The pan-PPAR Agonist IVA337 recently demonstrated efficacy in prevention and treatment of experimental skin fibrosis (1). Objectives Our objective was to evaluate the antifibrotic effects of 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 characterized by non-specific interstitial pneumonia and severe vascular remodeling of pulmonary arteries leading to PH. Mice received 2 doses of IVA337 (30 mg/kg or 100 mg/kg) or vehicle administered by daily oral gavage up to 4 weeks. Results Both 30 mg/kg and 100 mg/kg doses of IVA337 were well tolerated in all mouse models. IVA337 demonstrated at a dose of 100 mg/kg a marked protection from the development of lung fibrosis induced by bleomycin compared to mice receiving 30 mg/kg of IVA337 or vehicle. Indeed, IVA337 (100 mg/kg) strongly reduced by 61% and 28% tissue density on histological measurements and total lung hydroxyproline concentrations, respectively, as compared to vehicle. IVA337 at 100 mg/kg also significantly decreased col1, col3 and fibronectin in lesional lungs. Similarly, Fra-2 transgenic mice treated with 100 mg/kg of IVA337 displayed reduced lung density (20% vs. vehicle) and significant increase of functional residual capacity (30% vs. vehicle) when assessed by chest micro-CT imaging. These results were emphasized by a 50% reduction of the Ascroft fibrosis score (Figure 1A) and by a 48% reduction of hydroxyproline concentrations upon IVA337 (100 mg/kg) compared to vehicle treated mice. Successful targeting of the TGF-b signaling axis was observed in both mouse models upon treatment with 100 mg/kg of IVA337. 100 mg/kg IVA337 also significantly reduced T cell and B cell infiltration in lesional lungs of Fra-2 transgenic mice. Regarding vessel remodeling and related pulmonary hypertension, treatment with 100 mg/kg of IVA337 led to a substantial attenuation of right ventricular systolic pressure and right ventricular hypertrophy compared to mice receiving the vehicle (Figure 1B and 1C). Furthermore, IVA337 given at 100 mg/kg markedly reduced medial wall thickness (Figure 1D) and the number of muscularized distal pulmonary arteries. In vitro in primary human lung fibroblasts, IVA337 inhibited in a dose-dependent manner TGFβ-mediated fibroblasts to myofibroblasts transition and PDGF-mediated proliferation. Conclusions 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 systemic sclerosis both, for skin and key cardiovascular complications. References Ruzehaji et al, Ann Rheum Dis 2016;75(12):2175–2183. Disclosure of Interest J. Avouac: None declared, I. Konstantinova Employee of: INVENTIVA, C. Guignabert: None declared, J. Sadoine: None declared, G. Thomas: None declared, S. Pezet: None declared, A. Cauvet: None declared, L. Tu: None declared, J. M. Luccarini Employee of: INVENTIVA, J. L. Junien Consultant for: INVENTIVA, P. Broqua Employee of: INVENTIVA, Y. Allanore Grant/research support from: Inventiva
Jerome Avouac - One of the best experts on this subject based on the ideXlab platform.
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pan PPAR Agonist iva337 is effective in experimental lung fibrosis and pulmonary hypertension
Annals of the Rheumatic Diseases, 2017Co-Authors: Jerome Avouac, Irena Konstantinova, Christophe Guignabert, Sonia Pezet, Jeremy Sadoine, Thomas Guilbert, Anne Cauvet, Jeanmichel Luccarini, Jeanlouis JunienAbstract: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.
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op0081 pan PPAR Agonist iva337 is effective in the prevention of experimental lung fibrosis and pulmonary hypertension
Annals of the Rheumatic Diseases, 2017Co-Authors: Jerome Avouac, Irena Konstantinova, Christophe Guignabert, Sonia Pezet, Jeremy Sadoine, Anne Cauvet, Jeanmichel Luccarini, Jeanlouis Junien, G Thomas, Pierre BroquaAbstract:Background Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors known to modulate fibrosis. The pan-PPAR Agonist IVA337 recently demonstrated efficacy in prevention and treatment of experimental skin fibrosis (1). Objectives Our objective was to evaluate the antifibrotic effects of 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 characterized by non-specific interstitial pneumonia and severe vascular remodeling of pulmonary arteries leading to PH. Mice received 2 doses of IVA337 (30 mg/kg or 100 mg/kg) or vehicle administered by daily oral gavage up to 4 weeks. Results Both 30 mg/kg and 100 mg/kg doses of IVA337 were well tolerated in all mouse models. IVA337 demonstrated at a dose of 100 mg/kg a marked protection from the development of lung fibrosis induced by bleomycin compared to mice receiving 30 mg/kg of IVA337 or vehicle. Indeed, IVA337 (100 mg/kg) strongly reduced by 61% and 28% tissue density on histological measurements and total lung hydroxyproline concentrations, respectively, as compared to vehicle. IVA337 at 100 mg/kg also significantly decreased col1, col3 and fibronectin in lesional lungs. Similarly, Fra-2 transgenic mice treated with 100 mg/kg of IVA337 displayed reduced lung density (20% vs. vehicle) and significant increase of functional residual capacity (30% vs. vehicle) when assessed by chest micro-CT imaging. These results were emphasized by a 50% reduction of the Ascroft fibrosis score (Figure 1A) and by a 48% reduction of hydroxyproline concentrations upon IVA337 (100 mg/kg) compared to vehicle treated mice. Successful targeting of the TGF-b signaling axis was observed in both mouse models upon treatment with 100 mg/kg of IVA337. 100 mg/kg IVA337 also significantly reduced T cell and B cell infiltration in lesional lungs of Fra-2 transgenic mice. Regarding vessel remodeling and related pulmonary hypertension, treatment with 100 mg/kg of IVA337 led to a substantial attenuation of right ventricular systolic pressure and right ventricular hypertrophy compared to mice receiving the vehicle (Figure 1B and 1C). Furthermore, IVA337 given at 100 mg/kg markedly reduced medial wall thickness (Figure 1D) and the number of muscularized distal pulmonary arteries. In vitro in primary human lung fibroblasts, IVA337 inhibited in a dose-dependent manner TGFβ-mediated fibroblasts to myofibroblasts transition and PDGF-mediated proliferation. Conclusions 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 systemic sclerosis both, for skin and key cardiovascular complications. References Ruzehaji et al, Ann Rheum Dis 2016;75(12):2175–2183. Disclosure of Interest J. Avouac: None declared, I. Konstantinova Employee of: INVENTIVA, C. Guignabert: None declared, J. Sadoine: None declared, G. Thomas: None declared, S. Pezet: None declared, A. Cauvet: None declared, L. Tu: None declared, J. M. Luccarini Employee of: INVENTIVA, J. L. Junien Consultant for: INVENTIVA, P. Broqua Employee of: INVENTIVA, Y. Allanore Grant/research support from: Inventiva
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pan PPAR Agonist iva337 is effective in prevention and treatment of experimental skin fibrosis
Annals of the Rheumatic Diseases, 2015Co-Authors: Nadira Ruzehaji, Jerome Avouac, Sonia Pezet, Thomas Guilbert, Camelia Frantz, Matthieu PonsoyeAbstract:Background The pathogenesis of systemic sclerosis (SSc) involves a distinctive triad of autoimmune, vascular and inflammatory alterations resulting in fibrosis. Evidence suggests that peroxisome proliferator-activated receptors (PPARs) play an important role in SSc-related fibrosis and their Agonists may become effective therapeutic targets. Objective To determine the expression of PPARs in human fibrotic skin and investigate the effects of IVA337, a pan PPAR Agonist, in in vitro and in vivo models of fibrosis. Methods The antifibrotic effects of IVA337 were studied using a bleomycin-induced mouse model of dermal fibrosis. The in vivo effect of IVA337 on wound closure and inflammation were studied using an excisional model of wound healing. Results Low levels of PPARα and PPARγ were detected in the skin of patients with SSc compared with controls. In mice, IVA337 was associated with decreased extracellular matrix (ECM) deposition and reduced expression of phosphorylated SMAD2/3—intracellular effector of transforming growth factor (TGF)-β1. Although the antifibrotic effect of pan PPAR was similar to that of PPARγ Agonist alone, a significant downregulation of several markers of inflammation was associated with IVA337. Despite its anti-inflammatory and antifibrotic properties, IVA337 did not interfere with wound closure. In vitro effects of IVA337 included attenuation of transcription of ECM genes and alteration of canonical and non-canonical TGF-β signalling pathways. Conclusions These findings indicate that simultaneous activation of all three PPAR isoforms exerts a dampening effect on inflammation and fibrosis, making IVA337 a potentially effective therapeutic candidate in the treatment of fibrotic diseases including SSc.
Pierre Broqua - One of the best experts on this subject based on the ideXlab platform.
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pan PPAR Agonist lanifibranor improves portal hypertension and hepatic fibrosis in experimental advanced chronic liver disease
Journal of Hepatology, 2021Co-Authors: Zoe Boyerdiaz, Jeanlouis Junien, Pierre Broqua, Claude Robert, Guillaume Wettstein, Peio Aristuzabalza, Maria Andresrozas, Marti Ortegaribera, Anabel Fernandeziglesias, Jaime BoschAbstract:Background & aims In advanced chronic liver disease (ACLD), deregulated hepatic necroinflammatory processes play a key role in the development of liver microvascular dysfunction, fibrogenesis, and increased hepatic vascular tone, resulting in progression of ACLD and portal hypertension. Given the current lack of an effective treatment, we aimed to characterise the effects of the pan-peroxisome proliferator-activated receptor (pan-PPAR) Agonist lanifibranor in 2 preclinical models of ACLD, as well as in liver cells from patients with ACLD. Methods Cirrhotic rats (thioacetamide or common bile duct ligation; TAA or cBDL) randomly received lanifibranor (100 mg/kg/day, po) or vehicle for 14 days (n = 12/group). PPAR expression, systemic and hepatic haemodynamics, presence of ascites, liver sinusoidal endothelial cell (LSEC) phenotype, hepatic stellate cell (HSC) activation, serum transaminases and albumin, hepatic macrophage infiltration, cytokine expression, and liver fibrosis were determined. Hepatic cells were isolated from the livers of patients with cirrhosis and their phenotype was evaluated after treatment with either lanifibranor or vehicle. Results TAA-cirrhotic rats receiving lanifibranor showed significantly lower portal pressure compared with vehicle-treated animals (-15%; p = 0.003) without decreasing portal blood flow, indicating improved hepatic vascular resistance. Moreover, lanifibranor-treated TAA-rats showed decreased ascites, improved LSEC and HSC phenotypes, ameliorated hepatic microvascular function, reduced hepatic inflammation, and significant fibrosis regression (-32%; p = 0.020). These findings were confirmed in the cBDL rat model as well as in human liver cells from patients with cirrhosis, which exhibited phenotypic improvement upon treatment with lanifibranor. Conclusions Lanifibranor ameliorates fibrosis and portal hypertension in preclinical models of decompensated cirrhosis. Promising results in human hepatic cells further support its clinical evaluation for the treatment of ACLD. Lay summary Advanced chronic liver disease (ACLD) constitutes a serious public health issue for which safe and effective treatments are lacking. This study shows that lanifibranor improves portal hypertension and liver fibrosis, 2 key elements of the pathophysiology of ACLD, in preclinical models of the disease. Evaluation of lanifibranor in liver cells from patients with ACLD further supports its beneficial effects.
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Pan-PPAR Agonist lanifibranor improves portal hypertension and hepatic fibrosis in experimental advanced chronic liver disease.
Journal of hepatology, 2020Co-Authors: Zoe Boyer-diaz, Jeanlouis Junien, Pierre Broqua, Peio Aristu-zabalza, María Andrés-rozas, Claude Robert, Martí Ortega-ribera, Anabel Fernández-iglesias, Guillaume Wettstein, Jaime BoschAbstract:Abstract Background Aims In advanced chronic liver disease (ACLD), de-regulated hepatic necroinflammatory processes play a key role in the development of liver microvascular dysfunction, fibrogenesis, and increased hepatic vascular tone, resulting in progression of ACLD and portal hypertension. Given the current lack of an effective treatment, we aimed at characterizing the effects of the pan-peroxisome proliferator-activated receptors (pan-PPAR) Agonist lanifibranor in two pre-clinical models of ACLD, as well as in liver cells from patients with ACLD. Methods Cirrhotic rats (thioacetamide or common bile duct ligation; TAA or cBDL) randomly received lanifibranor (100mg/kg/day, po) or vehicle for 14 days (n=12/group). PPAR expression, systemic and hepatic hemodynamics, presence of ascites, liver sinusoidal endothelial cells (LSEC) phenotype, hepatic stellate cells (HSC) activation, serum transaminases and albumin, hepatic macrophage infiltration, cytokine expression, and liver fibrosis were determined. Hepatic cells were isolated from livers from cirrhotic patients and their phenotype was evaluated after treatment with lanifibranor or vehicle. Results TAA-cirrhotic rats receiving lanifibranor showed significantly lower portal pressure than vehicle-treated animals (-15%) without decreasing portal blood flow, indicating improved hepatic vascular resistance. Moreover, lanifibranor-treated TAA-rats showed decreased ascites, improved phenotype of LSEC and HSC, ameliorated hepatic microvascular function, reduced hepatic inflammation, and significant fibrosis regression (-32%). These findings were confirmed in the cBDL rat model, as well as in human liver cells from cirrhotic patients, which exhibited a phenotypic improvement upon treatment with lanifibranor. Conclusions This study demonstrates that lanifibranor exerts clear beneficial effects in pre-clinical models of decompensated cirrhosis, which lead to amelioration in fibrosis and portal hypertension. Our results in human hepatic cells isolated from cirrhotic patients further encourage its clinical evaluation for the treatment of ACLD.
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op0081 pan PPAR Agonist iva337 is effective in the prevention of experimental lung fibrosis and pulmonary hypertension
Annals of the Rheumatic Diseases, 2017Co-Authors: Jerome Avouac, Irena Konstantinova, Christophe Guignabert, Sonia Pezet, Jeremy Sadoine, Anne Cauvet, Jeanmichel Luccarini, Jeanlouis Junien, G Thomas, Pierre BroquaAbstract:Background Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors known to modulate fibrosis. The pan-PPAR Agonist IVA337 recently demonstrated efficacy in prevention and treatment of experimental skin fibrosis (1). Objectives Our objective was to evaluate the antifibrotic effects of 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 characterized by non-specific interstitial pneumonia and severe vascular remodeling of pulmonary arteries leading to PH. Mice received 2 doses of IVA337 (30 mg/kg or 100 mg/kg) or vehicle administered by daily oral gavage up to 4 weeks. Results Both 30 mg/kg and 100 mg/kg doses of IVA337 were well tolerated in all mouse models. IVA337 demonstrated at a dose of 100 mg/kg a marked protection from the development of lung fibrosis induced by bleomycin compared to mice receiving 30 mg/kg of IVA337 or vehicle. Indeed, IVA337 (100 mg/kg) strongly reduced by 61% and 28% tissue density on histological measurements and total lung hydroxyproline concentrations, respectively, as compared to vehicle. IVA337 at 100 mg/kg also significantly decreased col1, col3 and fibronectin in lesional lungs. Similarly, Fra-2 transgenic mice treated with 100 mg/kg of IVA337 displayed reduced lung density (20% vs. vehicle) and significant increase of functional residual capacity (30% vs. vehicle) when assessed by chest micro-CT imaging. These results were emphasized by a 50% reduction of the Ascroft fibrosis score (Figure 1A) and by a 48% reduction of hydroxyproline concentrations upon IVA337 (100 mg/kg) compared to vehicle treated mice. Successful targeting of the TGF-b signaling axis was observed in both mouse models upon treatment with 100 mg/kg of IVA337. 100 mg/kg IVA337 also significantly reduced T cell and B cell infiltration in lesional lungs of Fra-2 transgenic mice. Regarding vessel remodeling and related pulmonary hypertension, treatment with 100 mg/kg of IVA337 led to a substantial attenuation of right ventricular systolic pressure and right ventricular hypertrophy compared to mice receiving the vehicle (Figure 1B and 1C). Furthermore, IVA337 given at 100 mg/kg markedly reduced medial wall thickness (Figure 1D) and the number of muscularized distal pulmonary arteries. In vitro in primary human lung fibroblasts, IVA337 inhibited in a dose-dependent manner TGFβ-mediated fibroblasts to myofibroblasts transition and PDGF-mediated proliferation. Conclusions 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 systemic sclerosis both, for skin and key cardiovascular complications. References Ruzehaji et al, Ann Rheum Dis 2016;75(12):2175–2183. Disclosure of Interest J. Avouac: None declared, I. Konstantinova Employee of: INVENTIVA, C. Guignabert: None declared, J. Sadoine: None declared, G. Thomas: None declared, S. Pezet: None declared, A. Cauvet: None declared, L. Tu: None declared, J. M. Luccarini Employee of: INVENTIVA, J. L. Junien Consultant for: INVENTIVA, P. Broqua Employee of: INVENTIVA, Y. Allanore Grant/research support from: Inventiva
Sonia Pezet - One of the best experts on this subject based on the ideXlab platform.
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pan PPAR Agonist iva337 is effective in experimental lung fibrosis and pulmonary hypertension
Annals of the Rheumatic Diseases, 2017Co-Authors: Jerome Avouac, Irena Konstantinova, Christophe Guignabert, Sonia Pezet, Jeremy Sadoine, Thomas Guilbert, Anne Cauvet, Jeanmichel Luccarini, Jeanlouis JunienAbstract: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.
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op0081 pan PPAR Agonist iva337 is effective in the prevention of experimental lung fibrosis and pulmonary hypertension
Annals of the Rheumatic Diseases, 2017Co-Authors: Jerome Avouac, Irena Konstantinova, Christophe Guignabert, Sonia Pezet, Jeremy Sadoine, Anne Cauvet, Jeanmichel Luccarini, Jeanlouis Junien, G Thomas, Pierre BroquaAbstract:Background Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors known to modulate fibrosis. The pan-PPAR Agonist IVA337 recently demonstrated efficacy in prevention and treatment of experimental skin fibrosis (1). Objectives Our objective was to evaluate the antifibrotic effects of 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 characterized by non-specific interstitial pneumonia and severe vascular remodeling of pulmonary arteries leading to PH. Mice received 2 doses of IVA337 (30 mg/kg or 100 mg/kg) or vehicle administered by daily oral gavage up to 4 weeks. Results Both 30 mg/kg and 100 mg/kg doses of IVA337 were well tolerated in all mouse models. IVA337 demonstrated at a dose of 100 mg/kg a marked protection from the development of lung fibrosis induced by bleomycin compared to mice receiving 30 mg/kg of IVA337 or vehicle. Indeed, IVA337 (100 mg/kg) strongly reduced by 61% and 28% tissue density on histological measurements and total lung hydroxyproline concentrations, respectively, as compared to vehicle. IVA337 at 100 mg/kg also significantly decreased col1, col3 and fibronectin in lesional lungs. Similarly, Fra-2 transgenic mice treated with 100 mg/kg of IVA337 displayed reduced lung density (20% vs. vehicle) and significant increase of functional residual capacity (30% vs. vehicle) when assessed by chest micro-CT imaging. These results were emphasized by a 50% reduction of the Ascroft fibrosis score (Figure 1A) and by a 48% reduction of hydroxyproline concentrations upon IVA337 (100 mg/kg) compared to vehicle treated mice. Successful targeting of the TGF-b signaling axis was observed in both mouse models upon treatment with 100 mg/kg of IVA337. 100 mg/kg IVA337 also significantly reduced T cell and B cell infiltration in lesional lungs of Fra-2 transgenic mice. Regarding vessel remodeling and related pulmonary hypertension, treatment with 100 mg/kg of IVA337 led to a substantial attenuation of right ventricular systolic pressure and right ventricular hypertrophy compared to mice receiving the vehicle (Figure 1B and 1C). Furthermore, IVA337 given at 100 mg/kg markedly reduced medial wall thickness (Figure 1D) and the number of muscularized distal pulmonary arteries. In vitro in primary human lung fibroblasts, IVA337 inhibited in a dose-dependent manner TGFβ-mediated fibroblasts to myofibroblasts transition and PDGF-mediated proliferation. Conclusions 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 systemic sclerosis both, for skin and key cardiovascular complications. References Ruzehaji et al, Ann Rheum Dis 2016;75(12):2175–2183. Disclosure of Interest J. Avouac: None declared, I. Konstantinova Employee of: INVENTIVA, C. Guignabert: None declared, J. Sadoine: None declared, G. Thomas: None declared, S. Pezet: None declared, A. Cauvet: None declared, L. Tu: None declared, J. M. Luccarini Employee of: INVENTIVA, J. L. Junien Consultant for: INVENTIVA, P. Broqua Employee of: INVENTIVA, Y. Allanore Grant/research support from: Inventiva
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pan PPAR Agonist iva337 is effective in prevention and treatment of experimental skin fibrosis
Annals of the Rheumatic Diseases, 2015Co-Authors: Nadira Ruzehaji, Jerome Avouac, Sonia Pezet, Thomas Guilbert, Camelia Frantz, Matthieu PonsoyeAbstract:Background The pathogenesis of systemic sclerosis (SSc) involves a distinctive triad of autoimmune, vascular and inflammatory alterations resulting in fibrosis. Evidence suggests that peroxisome proliferator-activated receptors (PPARs) play an important role in SSc-related fibrosis and their Agonists may become effective therapeutic targets. Objective To determine the expression of PPARs in human fibrotic skin and investigate the effects of IVA337, a pan PPAR Agonist, in in vitro and in vivo models of fibrosis. Methods The antifibrotic effects of IVA337 were studied using a bleomycin-induced mouse model of dermal fibrosis. The in vivo effect of IVA337 on wound closure and inflammation were studied using an excisional model of wound healing. Results Low levels of PPARα and PPARγ were detected in the skin of patients with SSc compared with controls. In mice, IVA337 was associated with decreased extracellular matrix (ECM) deposition and reduced expression of phosphorylated SMAD2/3—intracellular effector of transforming growth factor (TGF)-β1. Although the antifibrotic effect of pan PPAR was similar to that of PPARγ Agonist alone, a significant downregulation of several markers of inflammation was associated with IVA337. Despite its anti-inflammatory and antifibrotic properties, IVA337 did not interfere with wound closure. In vitro effects of IVA337 included attenuation of transcription of ECM genes and alteration of canonical and non-canonical TGF-β signalling pathways. Conclusions These findings indicate that simultaneous activation of all three PPAR isoforms exerts a dampening effect on inflammation and fibrosis, making IVA337 a potentially effective therapeutic candidate in the treatment of fibrotic diseases including SSc.