TY -的T1 -吸入seralutinib有力的功效在肺动脉高血压模型JF -欧洲呼吸杂志》乔和J - 10.1183/13993003.02356 -2021欧元六世- 60 - 6 SP - 2102356 AU -安娜Galkin盟Ravikumar Sitapara AU -布莱恩·克莱蒙斯盟爱德华多·加西亚AU -迈克尔·肯尼迪AU -大卫Guimond盟-劳拉·l·卡特AU -阿什利Douthitt AU -罗宾Osterhout盟Aneta Gandjeva AU -黛博拉睡非盟-路易莎Salter-Cid AU -鲁宾·m·立筋盟-劳伦斯s Zisman Y1 - 2022/12/01 UR - //www.qdcxjkg.com/content/60/6/2102356.abstract N2 -背景信号通过血小板源生长因子受体(PDGFR)集落刺激因子1受体(CSF1R)和桅杆/干细胞生长因子受体工具包(c - kit)中扮演着一个关键的角色在肺动脉高血压(PAH)。我们检查的临床疗效吸入seralutinib,一个独特的小分子PDGFR / CSF1R PAH / c - kit激酶抑制剂在临床开发,一个概念验证激酶抑制剂相比,伊马替尼。方法Seralutinib和伊马替尼效力和选择性进行了比较。吸入seralutinib药物动力学/药效学研究在健康老鼠。疗效评估在两种大鼠模型的多环芳烃:SU5416 /缺氧(SU5416 / H)和野百合碱全肺切除术(MCTPN)。对炎性细胞因子/信号检测的影响。PDGFR CSF1R和c - kit免疫组织化学在老鼠和人类PAH肺样本和微rna (microRNA) SU5416 / H模型进行分析。结果Seralutinib强有力地抑制PDGFRα/β,CSF1R和c - kit。吸入seralutinib表现出剂量依赖性抑制肺PDGFR和c - kit信号,增加了骨形态形成蛋白受体2型(BMPR2)。Seralutinib改善心肺血流动力学参数和减少小肺动脉muscularisation和右心室肥大模型。SU5416 / H模型中,seralutinib改善心肺血流动力学参数,恢复肺BMPR2蛋白质含量和减少n端pro-brain利钠肽(中位数水平以上病人),超过伊马替尼。定量免疫组织化学在人类肺癌PAH样本演示PDGFR增加,CSF1R和c - kit。 miRNA analysis revealed candidates that could mediate seralutinib effects on BMPR2.Conclusions Inhaled seralutinib was an effective treatment of severe PAH in two animal models, with improved cardiopulmonary haemodynamic parameters, a reduction in NT-proBNP, reverse remodelling of pulmonary vascular pathology and improvement in inflammatory biomarkers. Seralutinib showed greater efficacy compared to imatinib in a preclinical study.Seralutinib is an inhaled, small-molecule kinase inhibitor that targets PDGFRα/β, CSF1R and c-KIT, and upregulates BMPR2 protein expression; these pathways play important roles in PAH. The efficacy of seralutinib is demonstrated in two animal models of PAH. https://bit.ly/3wObkEN ER -