Mechanism of pathogenic macrophage activation in emphysema

肺气肿致病性巨噬细胞活化机制的研究 总结 慢性阻塞性肺疾病（COPD）是美国第三大死亡原因， 正在全球范围内增加。肺气肿是COPD的关键组成部分，最常与吸烟相关 吸烟的定义是肺表面积的不可逆损失和气体交换的减少， 牙槽壁的逐渐破坏虽然有助于启动和发病机制的因素 已经确定了肺气肿，包括复发性炎症、氧化应激、过量的蛋白酶活性， 细胞死亡和遗传学，我们仍然缺乏明确的机制，将提供新的目标，以减缓或停止疾病 戒烟期间或之后的进展。在这个建议中，我们已经确定了一个新的作用，病理 巨噬细胞导致肺气肿的进行性损害。初步数据显示，IL-33 在急性肺损伤后肺中的水平仍然升高，并与肺病原体的增加有关。 具有改变的M2表型的巨噬细胞（PLM）。此外，我们的数据还表明，IL-17 A是 这对于这种向PLM的过渡至关重要，其对M2巨噬细胞的正常愈合功能起作用。虽然 IL-17 A和IL-33都在COPD患者中发现，但关于它们如何影响COPD患者的免疫功能， 渐进性组织破坏的机制。实验将测试一种新的两步机制， 巨噬细胞活化，其中作为上皮细胞损伤的结果产生的IL-33和IL-13最初 导致常规的M2活化，随后是来自IL-17 A的第二信号，其修饰巨噬细胞， 介导肺泡破坏PLM。我们的提议旨在检验IL-33， IL-13和IL-17 A共同促进致病性肺巨噬细胞的产生， 在进行性肺气肿中的主要作用。一旦我们在前两个实验中更好地理解了基本机制， 目的，第三个目的将测试假设，即已知的可塑性巨噬细胞可以利用设计 减缓或阻止肺气肿进展的治疗策略。从这些中获得的见解 研究应该提供新的机制见解和新的潜在治疗靶点，以限制加速的 COPD患者的肺功能丧失。

Mechanism of pathogenic macrophage activation in emphysema Summary Chronic obstructive pulmonary disease (COPD) is the 3rd leading cause of death in the U.S. and its prevalence is increasing globally. Emphysema, a key component of COPD most commonly associated with cigarette smoking, is defined by an irreversible loss of lung surface area and decrements in gas exchange that arise from progressive alveolar wall destruction. While elements that contribute to the initiation and pathogenesis of emphysema have been identified, including recurrent inflammation, oxidative stress, excess protease activity, cell death and genetics, we still lack clear mechanisms that would provide novel targets to slow or stop disease progression during or after smoking cessation. In this proposal, we have identified a novel role for pathologic macrophages in causing the progressive damage in emphysema. Strong preliminary data shows that IL-33 remains elevated in the lung after acute lung damage and is associated with an increase in Pathogenic Lung Macrophages (PLM) that have an altered M2 phenotype. Furthermore, our data also suggest that IL-17A is critical for this transition into PLM that work against the normal healing function of M2 macrophages. Although both IL-17A and IL-33 have been found in patients with COPD, little is known about how they impact the mechanism of progressive tissue destruction. Experiments will test a novel 2-step mechanism for lung macrophage activation in which IL-33 and IL-13, generated as a consequence of epithelial cell damage, initially result in conventional M2 activation, followed by second signal from IL-17A that modifies the macrophages to the PLM that mediate alveolar destruction. Our proposal is designed to test the central hypothesis that IL-33, IL-13 and IL-17A work together to promote the generation of pathogenic lung macrophages that play a principal role in progressive emphysema. Once the basic mechanisms are better understood in our first two aims, the third aim will test the hypothesis that the known plasticity of macrophages can be exploited to devise a therapeutic strategy to blunt or stop the progression of emphysema. The insights obtained from these studies should provide novel mechanistic insights and new potential therapeutic targets to limit the accelerated loss of lung function in humans with COPD.