Th17细胞/IL-17调控p38-MAPK信号通路在结缔组织病相关肺动脉高压发病中的作用

Connective tissue disease related pulmonary arterial hypertension (CTD-PAH) is regarded as a disease characterized by complicated pathogenesis and poor prognosis. Recent evidences suggested that the abnormal proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) are involved in the development of CTD-PAH. Moreover, our previous study found that Th17 cells elevated in CTD-PAH patients and IL-17+ cells extensive infiltrated around the pulmonary artery in the PAH rats. However, the mechanism of Th17/IL-17 in CTD-PAH remains unclear. In our present study, we first observe the effect of Th17/IL-17 on monocrotaline induced PAH in rats who can imitate the CTD-PAH. Second, after stimulation of IL-17 or anti-IL-17, we investigate the effects of IL-17 on the rat PASMCs and confirm the significance of p38-MAPK signal by RNA interference and p38-MAPK inhibitor. Thus, it will reveal the role of Th17/IL-17 in CTD-PAH via p38-MAPK signal and provide the new treatment target in CTD-PAH.

结缔组织病相关肺动脉高压（CTD-PAH）发病复杂，治疗有限，预后较差，探索病机寻找新治疗靶点有重要价值。肺动脉平滑肌细胞（PASMCs）异常增殖和迁移被认为是疾病发生的重要环节。我们前期发现，CTD-PAH患者外周血Th17细胞升高，大鼠肺血管壁IL-17+细胞增多，但Th17/IL-17影响CTD-PAH的机制不明。故本课题首先以野百合碱建立CTD-PAH大鼠模型，IL-17或其拮抗剂进行干预，从整体、器官水平明确Th17/IL-17对PAH的影响；其次，IL-17或其拮抗剂体外刺激大鼠PASMCs，并利用p38-MAPK拮抗剂及RNAi技术抑制p38-MAPK表达，分析IL-17对PASMCs迁移、增殖及合成能力的影响，探索IL-17对p38-MAPK通路的调控作用。本研究将从多层次充分揭示Th17/IL-17调控p38-MAPK通路在CTD-PAH发生中的作用，为治疗提供新思路。

结缔组织病相关肺动脉高压（CTD-PAH）发病复杂，治疗有限，预后较差，探索病机寻找新治疗靶点有重要价值。肺动脉平滑肌细胞（PASMCs）异常增殖和迁移被认为是疾病发生的重要环节。本课题发现CTD-PAH大鼠肺血管壁IL-17+细胞浸润增多，并利用不同浓度IL-17体外刺激大鼠PASMCs，随着IL-17浓度的增加，PASMCs迁移和增殖的能力逐渐增加；PASMCs合成ICAM-1及IL-6的水平随着刺激时间的延长逐渐升高，培养48小时，随着IL-17浓度的增加，ICAM-1及IL-6浓度逐渐升高。在PASMCs培养过程中，p-38的表达随IL-17浓度的增加而受到抑制。综上，本研究揭示Th17/IL-17可能通过调控p38-MAPK信号通路促进PASMCs增殖、迁移、合成炎症因子，从而促进CTD-PAH的发生发展，IL-17拮抗剂有望改善CTD-PAH的进展及预后。