Resolution of Inflammation in Heart Failure Post-Myocardial Infarction

心肌梗死(MI)后的心力衰竭(HF)是发病率和死亡率的重要原因。识别 限制心肌梗死后左心室(LV)不良重构的事件将提供治疗靶点 防止、减缓或逆转向心衰的进展。MI启动免疫细胞的“进入”信号，包括 中性粒细胞，如果不加以控制，会导致不受控制的促炎活动，进而导致心衰。我们的 心肌梗塞后的研究表明，脾通过心脾协调炎症的消退。 路径。这些发现揭示了临床上迫切需要建立脾的作用机制。 调解这一决议。以前人们认为炎症的消退是一个惰性的过程，但 新出现的数据证实，这是一个由专门的亲拆分分子(SPM)管理的活跃过程。 源自omega-3和omega-6脂肪酸。我们在HF环境下的R00研究证实，脾 产生不同的SPM，包括心肌梗塞后的脂氧素、溶血素和松脂素，以及外源治疗 解决素d1(Rvd1)以心脾的方式清除炎症。我们发现外源性Rvd1清除了 中性粒细胞通过激活中性粒细胞表达的甲酰肽受体2(FPR2)发挥抗炎作用 心肌梗死后的左心室和脾。在小鼠身上使用Rvd1进行的概念验证研究提供了基础 用于研究溶血素介导的慢性心力衰竭的作用机制。这些数据暗示着激活 中性粒细胞受体在促进心肌梗死后炎症有效消退信号中的作用。至 为了实现我们在MI后恢复阶段激活免疫细胞的总体目标，我们建议建立：1) Rvd1在慢性心力衰竭炎症消退中的作用；2)这一“输出”信号的激活是否 足以通过FPR2基因敲除小鼠取消RvD1的作用和结果来解决心力衰竭后的炎症 3)RvD1对心脾轴中性粒细胞表达CD10的新作用机制。 由我们在计算机计算建模方面的创新建议。我们在老鼠身上的初步研究证实了 Rvd1在急性心力衰竭中的作用现在，我们提出了一项机制研究，以扩大硅胶、体外和急性心力衰竭(白天)的研究。 5)慢性心力衰竭的结局(第28天)，这是翻译的关键，并表明心力衰竭患者的生存受益。 非免疫抑制促分解疗法是一种未得到满足的医学需求，有可能成为第一个 控制慢性炎症和延缓心脾功能衰竭的有效疗法。这些研究 将在配体受体特异性途径中识别免疫细胞特异性脂质介体的新靶点，而不是 而不是抗体或细胞因子特异性抑制，这可能会增强患者的治疗应用 在未来5-6年内发生HF。

Heart failure (HF) after myocardial infarction (MI) is a significant cause of morbidity and mortality. Identifying the events that limit adverse remodeling of the left ventricle (LV) post-MI will provide therapeutic targets to prevent, slow, or reverse progression to HF. MI initiates the “get-in” signal for immune cells including neutrophils, which if unchecked causes uncontrolled pro-inflammatory activity that in turn leads to HF. Our post-MI studies suggest that spleen coordinates the resolution of inflammation through a cardiosplenic pathway. These findings reveal an urgent clinical need to establish the mechanisms by which the spleen mediates this resolution. It was previously believed that resolution of inflammation is an inert process, but emerging data confirms that this is an active process managed by specialized pro-resolving molecules (SPMs) derived from omega-3 and omega-6 fatty acids. Our R00 study in an HF setting confirms that the spleen produces various SPMs, including lipoxins, resolvins, and maresins post-MI, and exogenous treatment with resolvin D1 (RvD1) clears inflammation in a cardiosplenic manner. We discovered that exogenous RvD1 clears neutrophils and resolves inflammation by activating neutrophil-expressed formyl peptide receptor 2 (FPR2) in the left ventricle and spleen post-MI. This proof-of-concept study using RvD1 in mice provides the foundation for investigation of the resolvins-mediated mechanism of action in chronic HF. These data implicate activation of neutrophil receptors in promoting the “get-out” signal for effective resolution of inflammation post-MI. To achieve our overall goal of activating immune cells in the healing phase after MI, we propose to establish: 1) the role of RvD1 in resolution of inflammation in chronic HF; 2) whether activation of this “get-out” signal is enough to resolve post-MI inflammation in HF using FPR2 knockout mice to abolish RvD1 action and resultant HF; and 3) the novel mechanism of action of RvD1 on neutrophil-expressed CD10 in the cardiosplenic axis, as suggested by our innovative in silico computational modeling. Our initial studies in mice have confirmed the role of RvD1 in acute HF. Now, we propose a mechanistic study to extend in silico, ex vivo, and acute HF (day 5) outcomes to chronic HF (day 28), which is key for translation and to indicate survival benefit to HF patients. Non-immunosuppressive pro-resolving therapy is an unmet medical need and has the potential to be the first ever effective therapy to control chronic inflammation and delay HF in a cardiosplenic manner. These studies will identify immune cell-specific novel targets for lipid mediators in a ligand-receptor-specific pathway, rather than antibody or cytokine-specific inhibition, which will likely enhance therapeutic applications in patients with HF within the next 5-6 years.