Lung Vascular Epigenetics, Center for Infection and Genomics of the Lung (CIGL), Justus-Liebig-Universität Gießen, Aulweg 132, 35392 Giessen, Germany.
Gossamer Bio, Inc., San Diego, CA 92121, USA.
Int J Mol Sci. 2023 Aug 10;24(16):12653. doi: 10.3390/ijms241612653.
Pulmonary arterial hypertension (PAH) is a complex disorder characterized by vascular remodeling and a consequent increase in pulmonary vascular resistance. The histologic hallmarks of PAH include plexiform and neointimal lesions of the pulmonary arterioles, which are composed of dysregulated, apoptosis-resistant endothelial cells and myofibroblasts. Platelet-derived growth factor receptors (PDGFR) α and β, colony stimulating factor 1 receptor (CSF1R), and mast/stem cell growth factor receptor kit (c-KIT) are closely related kinases that have been implicated in PAH progression. In addition, emerging data indicate significant crosstalk between PDGF signaling and the bone morphogenetic protein receptor type 2 (BMPR2)/transforming growth factor β (TGFβ) receptor axis. This review will discuss the importance of the PDGFR-CSF1R-c-KIT signaling network in PAH pathogenesis, present evidence that the inhibition of all three nodes in this kinase network is a potential therapeutic approach for PAH, and highlight the therapeutic potential of seralutinib, currently in development for PAH, which targets these pathways.
肺动脉高压（PAH）是一种复杂的疾病，其特征为血管重构和肺血管阻力的相应增加。PAH 的组织学特征包括肺小动脉的丛状和新生内膜病变，其由失调的、抗细胞凋亡的内皮细胞和成纤维细胞组成。血小板衍生生长因子受体（PDGFR）α和β、集落刺激因子 1 受体（CSF1R）和肥大细胞/干细胞生长因子受体 kit（c-KIT）是密切相关的激酶，它们与 PAH 的进展有关。此外，新出现的数据表明 PDGF 信号与骨形态发生蛋白受体 2（BMPR2）/转化生长因子 β（TGFβ）受体轴之间存在显著的串扰。这篇综述将讨论 PDGFR-CSF1R-c-KIT 信号网络在 PAH 发病机制中的重要性，提出抑制该激酶网络中的所有三个节点是治疗 PAH 的一种潜在方法的证据，并强调目前正在开发的针对这些途径的治疗 PAH 的药物 seralutinib 的治疗潜力。
