The role of IL-3 in myocardial infarction

心肌梗死(MI)是世界范围内主要的死亡原因，当冠状动脉血栓形成或栓塞性闭塞导致血液供应中断时，最常发生心肌梗死。我们认识到，冠状动脉闭塞的后果不是全部或没有，而是可以根据临床结果的不同而有所不同。例如，左心室的扩张性重塑预示着不良的长期结果，因为左心室的泵血通常效率低下，这会导致功能性二尖瓣反流和心力衰竭综合征，这是生活质量的主要障碍，并耗尽医疗资源。因此，人们越来越多地关注最初的缺血性损伤后发生的愈合反应。结果表明，在最初的2天内，大量来源于骨髓和脾的炎性Ly-6鸡单核细胞聚集在心肌中。5天后，炎性Ly-6Chigh单核细胞阶段让位于Ly-6Clow修复性巨噬细胞，从而诱导心肌愈合。有趣的是，Swirski等人。提示白介素3(IL-3)是炎性单核细胞产生的有效诱导剂，导致Ly-6 Chigh单核细胞在梗塞心肌中积聚增加。这一观察结果似乎令人惊讶，因为IL-3可能是最著名的嗜碱性粒细胞和肥大细胞的诱导者，也是接触性超敏反应的贡献者。在这种方法中，我们将研究IL-3在心肌梗塞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抗体治疗的小鼠。左前降支(LAD)结扎诱导MI。此外，我们的目标是确定在心肌梗死背景下负责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，在骨髓、血液和脾中进行详细的细胞和分子分析，通过无创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。这些实验可能确定IL-3是治疗心肌梗死患者的一种新的治疗方法。

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.