可溶性DR5通过TLR4调节巨噬细胞极化降低心肌缺血再灌注损伤的机制研究

心肌缺血再灌注损伤（MIRI）是可能引起猝死的治疗急性心肌梗死等心血管疾病的一大障碍。驻留在心脏的大量巨噬细胞向M1型极化是尚未引起足够重视的MIRI爆发的主要因素之一。本项目前期研究结果显示，已被发现能够在不同种炎症相关疾病中快速抑制细胞凋亡的可溶性DR5能够显著抑制巨噬细胞向M1型极化，并且能够调控参与了MIRI、M1型极化和炎症反应等过程，还能启动NFκB通路的TLR4。因此本项目提出假说：可溶性DR5可通过TLR4调节巨噬细胞极化抑制MIRI。基于本假说，我们首先直接在体外、体内MIRI模型中观察可溶性DR5的保护作用，然后先调控TLR4表达量再造模，以及进一步在给药后加入NFκB抑制剂观察作用效果，从而深入了解可溶性DR5通过TLR4/NFκB通路调节巨噬细胞极化改善MIRI的作用机制。本项目为MIRI的发病机制和临床药物治疗提供了更丰富的理论依据，具有重要的战略意义和应用价值。

Myocardial ischemia reperfusion injury (MIRI) is a major obstacle in the treatment of cardiovascular diseases such as acute myocardial infarction that may cause sudden death. The M1-type polarization of a large number of macrophages resident in the heart is one of the main factors contributing to the outbreak of MIRI which has not taken seriously. Our previous studies have shown that soluble DR5, which has been found to inhibit apoptosis rapidly in various inflammation-related diseases, can significantly inhibit the M1-type polarization of macrophages and regulate TLR4, which is involved in MIRI, M1-type polarization and inflammatory response and can activate the NFκB pathway. Therefore, this project proposed the hypothesis that: soluble DR5 can inhibit MIRI by regulating macrophage polarization through TLR4. Based on this hypothesis, we first directly observed the protective effect of soluble DR5 in vitro and in vivo MIRI models. Then we regulate TLR4 expression before inducing MIRI. Further, we add the NF kappa B inhibition after soluble DR5 treatment to observe the effect, in order to deeply understand the mechanism of soluble DR5 regulating macrophage polarization through TLR4/NFκB pathway to improve MIRI. This project provides a richer theoretical basis for the pathogenesis and clinical drug therapy of MIRI, and has important strategic significance and application value.