Role of MIF and CD74 in the pathogenesis of emphysema

项目总结 肺气肿是慢性阻塞性肺疾病(COPD)的一种常见病理表现， 美国第四大死因。肺气肿最重要的可改变的危险因素是 长期接触香烟烟雾(CS)。然而，并不是所有的吸烟者都会患上肺气肿，因此，细胞 对CS的反应是疾病进展的重要机制。我们的长期目标是定义 细胞对CS的反应和保护肺免受肺气肿影响的氧化应激。我们已经确定了一个 天然免疫细胞因子巨噬细胞迁移抑制(MIF)的细胞保护作用MIF减少 氧化应激与肺组织氧化应激的后果(如细胞衰老和细胞凋亡) 内皮细胞和Mif基因缺失的小鼠容易患肺气肿。MIF在体内分泌 但矛盾的是，重度COPD患者的MIF却降低了。目标是MIF或ITS 下游通路，可能具有治疗作用。然而，MIF是一种具有广泛调节作用的多效性分子。 要将MIF生物学转化为治疗，必须剖析其细胞保护途径。我们的目标是 这项建议是为了确定MIF拮抗肺气肿发展的机制。 我们的初步数据表明，MIF通过其受体CD74介导其保护作用。我们的假设是 MIF通过减轻CS介导的内皮细胞衰老来预防肺气肿的发展 CD74依赖方式。在目标1中，我们将定义MIF-CD74相互作用的机制 延缓血管内皮细胞衰老。在目标2中，我们将确定内皮细胞CD74在调节中的作用 易患肺气肿。在目标3中，我们将确定靶向mif-CD74的治疗潜力。 肺气肿的相互作用。这些目标的实现将极大地促进我们对 肺气肿的发病机制，并可能确定基于MIF生物学的精确治疗方法 肺气肿患者。

PROJECT SUMMARY Emphysema is a common pathologic manifestation of Chronic Obstructive Pulmonary Disease (COPD), the fourth leading cause of death in the United States. The most important modifiable risk factor for emphysema is chronic exposure to cigarette smoke (CS). Yet, not all smokers develop emphysema and, therefore, cellular responses to CS are important mechanisms underlying disease progression. Our long-term goal is to define the cellular responses to CS and oxidative stress that protect the lung from emphysema. We have identified a cytoprotective role for the innate immune cytokine Macrophage Migration Inhibitory (MIF). MIF decreases oxidative stress and consequences of oxidative stress (e.g. cellular senescence and apoptosis) in lung endothelial cells, and mice with a genetic deletion of Mif are susceptible to emphysema. MIF is secreted in response to CS, but, paradoxically, MIF is decreased in patients with severe COPD. Targeting MIF, or its downstream pathways, may be therapeutic. However, MIF is a pleiotropic molecule with broad regulatory effects. To translate MIF biology into therapy, it will be essential to dissect out its cytoprotective pathways. Our goal for this proposal is to determine the mechanisms through which MIF antagonizes the development of emphysema. Our preliminary data suggests MIF mediates its protective effects through its receptor CD74. Our hypothesis is MIF protects against the development of emphysema by mitigating CS-mediated endothelial senescence in a CD74 dependent manner. In Aim 1, we will define the mechanism through which the MIF-CD74 interaction reduces endothelial senescence. In Aim 2, we will determine the role of endothelial CD74 in regulating susceptibility to emphysema. In Aim 3, we will determine the therapeutic potential of targeting MIF-CD74 interactions in emphysema. Completion of these aims will significantly advance our understanding of the pathogenesis of emphysema and may identify precision-based approaches based on MIF biology for treating patients with emphysema.