Resolution of Inflammation in Heart Failure Post-Myocardial Infarction

心肌梗塞后心力衰竭炎症的消退

• 批准号: 9155912
• 负责人: Ganesh V Halade
• 金额: $ 36.75万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9155912
• 关键词: Acute; Adult; American; American Heart Association; Antibodies; Binding; Blood; CD59 Antigen; Cardiac; Cell physiology; Cells; Characteristics; Chronic; Clinical; Computer Simulation; Congestive Heart Failure; Data; Disease; Docosahexaenoic Acids; Economic Burden; Emigrations; Event; FPR2 gene; Fibroblasts; Fibrosis; Flow Cytometry; Foundations; Goals; Healed; Heart; Heart failure; Human; ITGAM gene; Immune; Immunosuppressive Agents; In Vitro; Infarction; Inflammation; Inflammatory; Investigation; Knockout Mice; Lead; Left ventricular structure; Leukocytes; Ligands; Link; Lipids; Lipoxins; Maps; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Medical; Minor; Morbidity - disease rate; Mus; Myocardial Infarction; Myocardial Ischemia; Myocardium; Myofibroblast; Neprilysin; Neutrophil Activation; Omega-3 Fatty Acids; Omega-6 Fatty Acids; Outcome; Pathway interactions; Patients; Peptides; Phase; Phenotype; Population; Process; Resolution; Role; Scheme; Signal Transduction; Spleen; T-Lymphocyte; Testing; Therapeutic; Time; Translations; Ventricular Remodeling; Work; Wound Healing; base; cytokine; effective therapy; healing; improved; in vivo; indexing; innovation; lipid mediator; macrophage; monocyte; mortality; neutrophil; novel; outcome forecast; prevent; receptor; screening; statistics; therapeutic target; trafficking; treatment strategy

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.

心肌梗死（MI）后的心力衰竭（HF）是发病和死亡的重要原因。 限制心肌梗死后左心室 (LV) 不良重塑的事件将为 预防、减缓或逆转心力衰竭的进展，为免疫细胞（包括免疫细胞）发出“进入”信号。 中性粒细胞，如果不加以控制，会导致不受控制的促炎活性，进而导致心力衰竭。 心肌梗死后研究表明，脾脏通过心脾协调炎症的消退 这些发现揭示了临床迫切需要建立脾脏的机制。 以前认为炎症的消退是一个惰性过程，但是 新出现的数据证实，这是一个由专门的促解析分子 (SPM) 管理的主动过程 源自 omega-3 和 omega-6 脂肪酸，我们在 HF 环境中进行的 R00 研究证实了脾脏。 产生各种 SPM，包括脂氧素、分解素和 MI 后的 maresins，以及外源性治疗 resolvin D1 (RvD1) 以心脾方式清除炎症 我们发现外源性 RvD1 可以清除炎症。 中性粒细胞并通过激活中性粒细胞表达的甲酰肽受体 2 (FPR2) 来解决炎症 这项在小鼠中使用 RvD1 的概念验证研究提供了基础。 用于研究慢性心衰中溶解素介导的作用机制。这些数据意味着激活。 中性粒细胞受体在促进“退出”信号中的作用，以有效解决心肌梗死后的炎症。 为了实现我们在心肌梗死后的愈合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) 这种“退出”信号的激活是否是 使用 FPR2 敲除小鼠消除 RvD1 作用并产生足以解决心力衰竭的心肌梗死后炎症的方法 HF；3) RvD1 对心脾轴中性粒细胞表达的 CD10 的新作用机制，如 我们的创新计算机模型表明，我们对小鼠的初步研究已经证实了这一点。 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，以在计算机、离体和急性心力衰竭（天）中进行扩展。 5) 慢性心力衰竭（第 28 天）的结果，这是转化的关键并表明心力衰竭患者的生存获益。 非免疫抑制促缓解疗法是一项未满足的医疗需求，有可能成为第一个 这些研究是通过心脾方式控制慢性炎症和延迟心力衰竭的有效疗法。 将在配体-受体特异性途径中识别脂质介质的免疫细胞特异性新靶标，而不是 比抗体或细胞因子特异性抑制更有效，这可能会增强对患有以下疾病的患者的治疗应用： 未来5-6年内将出现HF。