肥大细胞活化是肺血管结构重构的重要病理基础，然而肥大细胞活化的调节机制尚未阐明。本课题前期研究发现内源性二氧化硫（SO2）为心血管新的气体信号分子，在此基础上拟从肥大细胞内源性调控切入，检测肥大细胞中内源性SO2生成及其酶促调控，揭示肥大细胞存在内源性SO2体系；阐明低氧小鼠肺血管管周肥大细胞活化及内源性SO2体系的动态变化规律；在动物及细胞水平采用基因操作上调/下调肥大细胞内源性SO2，结合肥大细胞稳定剂/激活剂干预，揭示内源性SO2通过抑制肥大细胞活化，进而拮抗肺血管结构重构；以腺苷酸环化酶(AC)为切入点，结合AC抑制剂/激动剂干预，揭示SO2通过激活AC途径抑制肥大细胞活化；采用质谱分析及巯基次磺化探针，结合次磺化位点的定点突变，阐明SO2激活AC的分子机制和靶点。以期揭示肥大细胞内源性SO2拮抗肺血管结构重构的新机制，为探索基于肥大细胞活化的肺动脉高压治疗策略提供新思路、新靶点。

Mast cell activation is an important pathologic basis of pulmonary vascular structural remodeling. However, the regulatory mechanisms for mast cell activation remain unclear. Based on our previous findings that endogenous sulfur dioxide is a novel cardiovascular gasotransmitter, the study targets the endogenous regulation of mast cell activation. Endogenous sulfur dioxide generation and its enzymatic reaction are to be detected in mast cells for demonstrating the existence of endogenous sulfur dioxide pathway in mast cells. The changes in perivascular mast cell activation and mast cell-derived sulfur dioxide pathway are to be examined in the hypoxic mice. The applicant plans to demonstrate that endogenous sulfur dioxide inhibits pulmonary vascular structural remodeling by preventing mast cell activation with the help of gene manipulation to down-regulate or up-regulate endogenous sulfur dioxide pathway in animals and mast cells and with the mast cell stabilizing agents or agonists as well. Targeting adenylate cyclase (AC), with the use of AC inhibitor or agonist, the applicant attempts to disclose that sulfur dioxide inhibits mast cell activation by activating AC pathway. By using mass spectrometry, sulfenylating probe and sulfenylating site-directed mutation, the investigator aims to explore the molecular mechanisms for AC activation by sulfur dioxide and its targeting sites. In the study, the investigator intends to show the novel mechanisms by which endogenous sulfur dioxide inhibits pulmonary vascular structural remodeling so as to provide with the new ideas and novel acting target of the mast cell activation-based therapeutic strategy for pulmonary hypertension.