白介素-11介导肺动脉高压血管外膜重构的机制研究

外膜重构是肺血管重构重要基础，在肺动脉高压发生、发展中发挥“由外向内”的调节作用。有效抑制成纤维细胞表型转化、增殖和细胞外基质沉积是控制外膜重构的关键。结合前期工作和已有报道，我们推测：TGF-β1上调IL-11表达，并经其介导肺血管外膜成纤维细胞表型转化、增殖和细胞外基质沉积。为此，我们拟较系统地开展IL-11介导血管外膜重构的研究。主要内容包括：检测肺动脉高压患者IL-11含量、TGF-β1含量与活性，初步探讨IL-11与肺动脉高压相关性；构建肺动脉高压动物模型，采用过表达、基因沉默及抑制剂多种组合方法，明确IL-11信号通路在调控肺血管外膜重构中的作用；离体培养外膜成纤维细胞，采用多层面、多视角的正、反向干预，明确IL-11对成纤维细胞表型转化、增殖及基质分泌的影响及机制。项目完成将为解析肺血管外膜重构的分子机制、探索针对肺动脉高压血管外膜重构的新靶点提供部分理论基础和初步实验依据。

Adventitia remodeling is the important foundation of pulmonary vascular remodeling, which plays an "outside-in" regulatory role in the occurrence and development of pulmonary arterial hypertension. Effective inhibition of phenotypic transformation, proliferation and extracellular matrix deposition of fibroblasts is the key to controlling the remodeling of the adventitia. Based on our previous work and published reports, we speculated that TGF-β1 can up-regulate the expression of IL-11 and mediate the phenotypic transformation, proliferation and extracellular matrix deposition of pulmonary vascular adventitia fibroblasts. Therefore, we plan to systematically carry out the study on vascular remodeling mediated by IL-11. The main contents included: (1) To discuss the correlation between IL-11 and pulmonary hypertension by detecting content and activity of IL-11, TGF-β1 in patients with pulmonary hypertension. (2) To clarify the role of IL-11 signaling pathway in the regulation of vascular adventitia remodeling, we build animal models of pulmonary hypertension, using multiple combinations of over-expression and knock-down of IL-11 and inhibitors. (3) To clarify the influence of IL-11 on phenotypic transformation, proliferation and matrix secretion of fibroblasts and the mechanism, in vitro with culturing adventitia fibroblasts, and using multifaceted positive and negative intervention. The completion of the project will provide partial theoretical basis and preliminary experimental basis for the analysis of the molecular mechanism of pulmonary vascular adventitia remodeling and the exploration of new targets for pulmonary arterial hypertension vascular adventitia remodeling.