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The role of IL-3 in myocardial infarction

IL-3在心肌梗死中的作用

基本信息

批准号：
331536185
负责人：
Dr. Florian Kahles
金额：
--
依托单位：
Klinik für Kardiologie, Angiologie und Internistische Intensivmedizin (Med. Klinik I)
依托单位国家：
德国
项目类别：
Research Fellowships
财政年份：
2016
资助国家：
德国
起止时间：
2015-12-31 至 2018-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/331536185?language=en
关键词：
role IL myocardial infarction

项目摘要

Myocardial infarction (MI) is a leading cause of death worldwide and occurs most often when thrombotic or embolic occlusion of coronary arteries interrupts blood supply. We recognize that the consequence of a coronary occlusion is not all or nothing, but can vary in ways that correlate with clinical outcomes. Expansive remodeling of the left ventricle, for example, predicts poor long-term outcomes because the ventricles often pump ineffectively, which leads to functional mitral regurgitation and to the syndrome of heart failure, a major impediment to quality of life and drain on healthcare resources. As a result, there has been increased focus on the healing response that occurs after the initial ischemic insult. It has been shown that a large number of inflammatory Ly-6Chigh monocytes, which originate the bone marrow and spleen, accumulate in the myocardium over the first 2 days. Five days later, the inflammatory Ly-6Chigh monocyte phase gives way to Ly-6Clow reparative macrophages, thereby inducing myocardial healing. Interestingly, Swirski et al. could show that Interleukin 3 (IL-3) is a potent inducer of inflammatory monocyte production leading to increased accumulation of Ly-6Chigh monocytes in the infarcted myocardium. This observation seems surprising, since IL-3 is perhaps best known as an inducer of basophils and mast cells and contributor to contact hypersensitivity. In this approach, we will study the role of IL-3 in post MI inflammation and repair. We will therefore utilize IL-3-deficient mice and mice treated with an IL-3 antibody. MI will be induced by LAD (left anterior descending artery) ligation. Furthermore we are aiming to identify the cell type/tissue responsible for IL-3 secretion in the context of MI. To answer these questions detailed histologic analysis of the heart in experimental groups, detailed cellular and molecular profiling in the bone marrow, blood, and spleen, detailed analysis of leukocyte function by non-invasive functional imaging and analysis of heart function will be performed. These experiments might identify IL-3 as a novel therapeutic approach for the treatment of patients with myocardial infarction.

心肌梗死（MI）是全球范围内的主要死亡原因，最常发生在冠状动脉血栓性或栓塞性闭塞中断血液供应时。我们认识到，冠状动脉闭塞的后果不是全有或全无，而是可以以与临床结果相关的方式变化。例如，左心室的扩张性重塑预测了不良的长期结果，因为心室通常泵送无效，这导致功能性二尖瓣返流和心力衰竭综合征，这是生活质量和医疗资源消耗的主要障碍。因此，人们越来越关注在初始缺血性损伤后发生的愈合反应。已经表明，在最初2天内，大量源自骨髓和脾的炎性Ly-6Chigh单核细胞在心肌中积聚。5天后，炎症性Ly-6C高单核细胞阶段让位于Ly-6C低修复性巨噬细胞，从而诱导心肌愈合。有趣的是，Swirski等人可以显示白细胞介素3（IL-3）是炎性单核细胞产生的有效诱导剂，导致Ly-6Chigh单核细胞在梗塞心肌中的积累增加。这一观察结果似乎令人惊讶，因为IL-3可能最为人所知的是作为嗜碱性粒细胞和肥大细胞的诱导剂，并促进接触性超敏反应。在这种方法中，我们将研究IL-3在MI后炎症和修复中的作用。因此，我们将利用IL-3缺陷小鼠和用IL-3抗体处理的小鼠。结扎左前降支（LAD）诱发心肌梗死。此外，我们的目标是确定在MI的情况下负责IL-3分泌的细胞类型/组织。为了回答这些问题，将对实验组的心脏进行详细的组织学分析，对骨髓、血液和脾脏进行详细的细胞和分子分析，通过非侵入性功能成像对白细胞功能进行详细分析，并对心脏功能进行分析。这些实验可能将IL-3确定为治疗心肌梗死患者的新治疗方法。