Gasdermin-D调节骨髓来源巨噬细胞炎症因子释放促进心梗后心脏纤维化及相关机制研究

心肌梗死后无菌炎症的持续发生可诱导心脏组织过度纤维化，导致心脏重构，是导致心梗后充血性心力衰竭的显著危险因素。骨髓来源巨噬细胞通过调控炎症因子释放，在心梗后的炎症反应中发挥着极为关键的作用。Gasdermin-D（GSDMD）作为焦亡通路上关键分子，活化后直接介导巨噬细胞对IL-1β、IL-18等炎症因子的释放，导致成纤维细胞活化。因此我们推测，抑制GSDMD功能可能降低心梗后骨髓巨噬细胞募集及炎症因子释放，抑制成纤维细胞过度激活，改善心梗后心脏重构及心功能水平。本研究采用GSDMD基因敲除小鼠，并行骨髓移植构建嵌合体小鼠，进一步构建心梗模型，拟证实GSDMD通过调控骨髓巨噬细胞影响心梗后炎症反应及组织纤维化，探索相关分子机制，寻找有效的干预靶点改善心梗后心室重构、心衰的预后。

The continuous occurrence of aseptic inflammation after myocardial infarction can induce excessive fibrosis in heart tissue and lead to cardiac remodeling, which is a significant risk factor for congestive heart failure after myocardial infarction. Bone marrow derived macrophages play a key role in the inflammatory response after myocardial infarction by regulating the release of inflammatory factors. Gasdermin-d (GSDMD), as a key molecule in the pyroptosis pathway, directly mediates the release of IL-1 β, IL-18 and other inflammatory factors by macrophages, which directly lead to the activation of fibroblasts. Therefore, we speculate that inhibition of GSDMD function may reduce the recruitment of bone marrow macrophages and the release of inflammatory factors after myocardial infarction, inhibit the excessive activation of fibroblasts, and improve the level of cardiac remodeling and cardiac function after myocardial infarction. This research used GSDMD gene knockout mice and bone marrow transplantation to construct chimeric mice and myocardial infarction model, intends to confirm that GSDMD can affect the inflammatory response and tissue fibrosis after myocardial infarction by regulating bone marrow macrophages, explore the relevant molecular mechanisms, and find effective intervention targets to improve the prognosis of ventricular remodeling and heart failure after myocardial infarction.