肺动脉高压（Pulmonary arterial hypertension，PAH)）是以肺动脉平滑肌细胞增生，管腔狭窄、闭塞，肺血管阻力进行性升高，最终导致右心衰竭，甚至死亡的一类疾病。然而，PAH的发病机制至今仍不明确。过去20年，随着PAH靶向治疗药物的应用，PAH患者的预后较过去有了明显改善，但预后仍十分恶劣。目前针对PAH治疗的药物主要以血管扩张效应为主，对肺血管重构的影响有限。想要进一步改善PAH患者的预后，研发以抑制肺血管重构为主的药物是未来PAH治疗的方向。近年来，研究表明炎症和免疫紊乱在PAH的发病中具有重要作用。我们在前期的研究发现，IL-6/STAT3信号通路介导了肺血管重构，IL-6与BMPRⅡ存在相互拮抗效应。然而，IL-6的上游信号分子和IL-6介导BMPRⅡ的机制并不清楚。本研究有助于揭示PAH的发病机制，为防治PAH血管重构提供新靶点。

Pulmonary arterial hypertension (PAH) is characterized by uncontrolled proliferation of pulmonary arterial smooth muscle cells (PASMCs), pulmonary vascular remodeling (PVR), narrowed or (and) occluded lumen, progressive pulmonary vascular resistance, eventual right heart failure, and death. However, the pathogenesis of PAH is not fully understood. In the past 20 years, the prognosis of these population had been improved due to the application of PAH targeted therapies. But the outcome of long-term in patients with idiopathic PAH remains unacceptably low. Current PAH therapies primarily stimulate pulmonary vasodilation to decrease pulmonary vascular resistance, having low specificity in providing an anti-proliferative effect to control PVR. Novel therapeutic strategies are required to specifically target the biological pathways of PVR. In recent years, studies have shown that inflammation and immune disorders have an important role in the pathogenesis of PAH. We found that IL-6/STAT3 signaling pathway is involved in the pathogenesis of PVR and there is mutual antagonistic effect between IL-6 and bone morphogenetic protein receptor II (BMPRII) in our previous study. However, the upstream signaling molecules modulate the expression of IL-6 and the downstream signaling molecules of IL-6 mediated BMPRII are unclear. The present study will reveal the potential pathogenesis of PAH and provide new therapeutic targets for the prevention and treatment of vascular remodeling in the PAH.

肺动脉高压(pulmonary arterial hypertension,PAH)是以血管收缩、血管平滑肌增生、血管重塑及原位血栓形成为主要病变特征，引起肺动脉压力和肺血管阻力进行性升高，最终导致右心功能受损、甚至死亡的严重疾病，预后极差。随着前列环素类似物、内皮素受体拮抗剂、磷酸二酯酶5型抑制剂等靶向药物的应用，PAH的治疗取得了重大进步，中国医学科学院阜外医院十一·五PAH注册登记研究显示患者1年、2年、3年存活率仍只有84.1%、73.7%和70.6%，结局仍不理想。根本原因在于目前针对PAH治疗的药物主要以血管扩张效应为主，对肺血管重构的作用非常有限，如何有效预防和逆转肺血管重塑成为PAH研究的重要方向。本研究通过建立野百合碱 (monocrotaline, MCT)诱导的肺动脉高压大鼠模型探究NF-κB和TGF-β1信号是否参与了肺动脉高压的发生，并分别探究其抑制剂PDTC和SB525334对于肺血管重构的影响，此外从细胞水平进一步探究NF-κB /TGF-β1信号同IL-6、STAT3、miR-21和BMPRII之间的内在联系，以阐明肺动脉高压的发病机制，以期为防治PAH血管重构的药物筛选提供新靶点。本研究表明MCT大鼠3周已有显著的肺动脉高压，4周更为严重，表现为mPAP、PASP和RVSP的显著升高，IL-6/STAT3和miR-21表达明显上调，BMPR2水平显著降低，NF-κB抑制剂PDTC和TGF-β1选择性受体抑制剂SB525334均可以显著降低上述血流动力学指标，病理学HE染色和免疫荧光双染均证实肺血管中层的肥厚程度明显减轻，表明NF-κB /TGF-β1信号参与了肺血管重构， NF-κB /TGF-β1信号通路可作为治疗PAH的潜在靶点。在本项目的资助下，1篇中文文章待投稿，国内会议投稿2篇，国际ESC会议投稿1篇。