Pan-PPAR agonist IVA337 is effective in experimental lung fibrosis and pulmonary hypertension
Pan-PPAR agonist IVA337 is effective in experimental lung fibrosis and pulmonary hypertension
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DOI：
10.1136/annrheumdis-2016-210821
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发表时间：
2017-11-01
影响因子：
27.4
通讯作者：
Allanore, Yannick
中科院分区：
文献类型：
--
作者：
Avouac, Jerome;Konstantinova, Irena;Allanore, Yannick
目的 评估全过氧化物酶体增殖物激活受体 (PPAR) 激动剂 IVA337 在临床前小鼠肺纤维化和相关肺动脉高压 (PH) 模型中的抗纤维化作用。方法 IVA337 在博来霉素诱导的肺纤维化小鼠模型和 Fra-2 转基因小鼠中进行了评估，后者的特点是非特异性间质性肺炎和严重的肺动脉血管重塑，导致肺纤维化。 PH值。小鼠每天经口灌胃接受两剂 IVA337（30 mg/kg 或 100 mg/kg）或媒介物，持续长达 4 周。结果表明，与接受 30 mg/kg IVA337 或媒介物的小鼠相比，100 mg/kg 剂量的 IVA337 可以显着保护两种小鼠模型免受肺纤维化的发展。与载体治疗的小鼠相比，博莱霉素模型的组织学评分显着降低了 61%，Fra-2 转基因小鼠的组织学评分显着降低了 50%，肺总羟脯氨酸浓度分别降低了 28% 和 48%。 100 mg/kg 的 IVA337 还显着降低了两种小鼠模型病变肺部的纤维化标记物水平。此外，IVA337 通过改善血流动力学测量和血管重塑，显着缓解 Fra-2 转基因小鼠的 PH。在原代人肺成纤维细胞中，IVA337 以剂量依赖性方式抑制 TGF-β 诱导的成纤维细胞向肌成纤维细胞的转变以及 PDGF 介导的成纤维细胞增殖。 结论 我们证明，用 100 mg/kg IVA337 治疗可预防两种互补动物模型中的肺纤维化，并显着减弱 Fra-2 小鼠模型中的 PH。这些发现证实，泛 PPAR 激动剂 IVA337 是治疗这些心肺疾病的有吸引力的候选药物。
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-beta 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.