Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Institute of Public Health Studies, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Brazil.
Br J Pharmacol. 2019 Dec;176(23):4462-4473. doi: 10.1111/bph.14807. Epub 2019 Dec 5.
Pulmonary arterial hypertension (PAH) is a progressive disease associated with high morbidity and mortality, despite advances in medical therapy. We compared the effects of infigratinib (NVP-BGJ398), a new FGF receptor-1 inhibitor, with or without the PDE-5 inhibitor sildenafil, on vascular function and remodelling as well as on gene expression of signal transducers for receptors of TGF-β (Smads-1/2/4) and transcription factor of endothelial-mesenchymal transition (Twist-1) in established experimental PAH. Types I and III pro-collagen and TGF-β expressions in lung fibroblasts were analysed in vitro after the different treatments.
PAH was induced in male Wistar rats with monocrotaline. 14 days later, treatments [sildenafil (SIL), infigratinib (INF) or their combination (SIL+INF)] were given for another 14 days. On Day 28, echocardiography and haemodynamic assays were performed, and lungs and pulmonary vessels were removed for analysis by histology, immunohistochemistry and RT-PCR. Fibroblasts prepared from PAH lungs were also analysed for TGF-β and pro-collagen.
Only the combination of infigratinib and sildenafil significantly improved right ventricular systolic pressure and vascular remodelling parameters (right ventricular hypertrophy, smooth muscle α-actin, vessel wall thickness, and vascular collagen content). Infigratinib may act by reducing gene expression of Smads-1/4 and Twist-1 in lung tissue, as well as TGF-β and types I and III pro-collagen in lung fibroblasts.
In this model of monocrotaline-induced PAH, the combination of the new inhibitor of FGF receptor-1, infigratinib, and sildenafil effectively improved haemodynamics and decreased vascular remodelling.
尽管在医学治疗方面取得了进展，但肺动脉高压（PAH）仍是一种与高发病率和死亡率相关的进行性疾病。我们比较了新型成纤维细胞生长因子受体-1 抑制剂英菲格拉替尼（NVP-BGJ398）与或不与磷酸二酯酶-5 抑制剂西地那非联用对已建立的实验性 PAH 中血管功能和重塑以及 TGF-β 受体信号转导物（Smads-1/2/4）和内皮-间充质转化转录因子（Twist-1）的基因表达的影响。在体外，分析了不同处理后肺成纤维细胞中 I 型和 III 型前胶原和 TGF-β 的表达。
用野百合碱诱导雄性 Wistar 大鼠发生 PAH。14 天后，给予不同的治疗（西地那非（SIL）、英菲格拉替尼（INF）或二者联用（SIL+INF））14 天。第 28 天，进行超声心动图和血流动力学检测，并取出肺和肺血管进行组织学、免疫组织化学和 RT-PCR 分析。还分析了来自 PAH 肺的成纤维细胞中的 TGF-β 和前胶原。
只有英菲格拉替尼和西地那非的联合应用才能显著改善右心室收缩压和血管重塑参数（右心室肥厚、平滑肌α-肌动蛋白、血管壁厚度和血管胶原含量）。英菲格拉替尼可能通过降低肺组织中 Smads-1/4 和 Twist-1 的基因表达以及肺成纤维细胞中 TGF-β 和 I 型和 III 型前胶原的基因表达来发挥作用。
在野百合碱诱导的 PAH 模型中，新型成纤维细胞生长因子受体-1 抑制剂英菲格拉替尼与西地那非的联合应用可有效改善血液动力学并减少血管重塑。
