EMAP II, a molecular link of inflammation and apoptosis in pulmonary emphysema.

EMAP II，肺气肿炎症和细胞凋亡的分子联系。

基本信息

批准号：
7845078
负责人：
Matthias Clauss
金额：
$ 37.57万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-08 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7845078
关键词：
Abbreviations Accounting Adult Alveolar Alveolar wall Alveolus Apoptosis Apoptotic Biochemical Biological Biological Markers Blood capillaries Bronchoalveolar Lavage CXC Chemokines CXC chemokine receptor 3 CXCR3 gene Caspase Cells Cellular Stress Chemotaxis Chronic Obstructive Airway Disease Cigarette Cigarette smoke-induced emphysema Coupled Cytoskeleton Data Development Disease Elements Endothelial Cells Epithelial Cells Figs - dietary Gases Homing Human Hypoxia Immunohistochemistry Individual Inflammation Inflammatory Laboratories Leukocyte Elastase Link Liquid substance Lung Matrix Metalloproteinases Measurable Measures Mediating Mediator of activation protein Molecular Morbidity - disease rate Mus Patients Peptide Hydrolases Phenotype Positioning Attribute Production Proliferating Protease Inhibitor Proteins Proteolysis Pulmonary Emphysema RNA Splicing Reactive Oxygen Species Recruitment Activity Regulation Risk Factors Role Signal Transduction Smoke Smoker Stimulus Stromelysin 1 Testing Tetracyclines Trans-Activators Transgenes Transgenic Mice Transgenic Organisms Variant Vascular Endothelial Growth Factors Work alveolar destruction alveolar epithelium capillary cigarette smoke-induced cigarette smoking cigarette smoking cytokine endothelial monocyte-activating polypeptide II human EML2 protein improved macrophage monocyte mortality mouse model neutralizing antibody overexpression pressure promoter receptor research study response smoking cessation theories therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Cigarette smoke induces emphysema through mechanisms which cause a loss of both matrix and cellular elements of the lung. The two main paradigms to explain emphysema postulate a) an imbalance of protease/antiproteases triggered by inflammation and b) a state of excessive alveolar endothelial apoptosis causing capillary regression. These two mechanisms would explain the loss of alveolar wall characterizing emphysema. However, the coexistence of an excessive lung structural cell apoptosis with that of an activated inflammatory state in emphysema and the hierarchy of their interaction have not yet been explained. We propose the excess of endothelial-monocyte-activating protein (EMAP II) is a unifying molecular mechanism to link apoptosis and inflammation in emphysema. EMAP II is a cytokine induced by conditions present in emphysematous lungs, being released from cells upon proteolytic cleavage by caspases and matrix metalloproteinases, which are known to participate in COPD. We identified CXCR3 as a functional receptor for EMAP II which mediates EMAP II-induced endothelial cell apoptosis and monocyte activation. Given the potent pro-apoptotic effect of EMAP II on endothelial cells, coupled with its ability to activate and recruit pro-inflammatory monocytes, we hypothesize that excessive EMAP II release in response to cigarette smoking engages both lung endothelial cell apoptosis and monocyte inflammatory activation, and therefore is a key molecular mediator of emphysema. We postulate that smoke induces EMAP II, which causes CXCR3- dependent endothelial apoptosis and activates monocytes. Activated caspases and matrix metalloproteinases may further increase EMAP II in the lung, amplifying damage signals that culminate in emphysema. These studies are relevant to human emphysema, as we measured increased EMAP II in the lungs of emphysema patients. Indeed, our data indicate that smoke-induced emphysema is preceded by EMAP II production and apoptosis in mice and lung-specific EMAP II increases are sufficient to cause lung apoptosis and emphysema. We will test the function of the secreted EMAP II and its receptor by neutralizing antibodies in cigarette smoke-induced emphysema in mice and conditional EMAP II transgenic overexpression in the lung. We developed 3 specific aims: 1. To determine whether EMAP II is a biomarker and molecular mediator of cigarette smoke-induced emphysema. 2 To investigate whether excessive lung EMAP II induces emphysema by triggering lung endothelial cell apoptosis or by recruitment of monocytes/macrophages, and 3. To determine the mechanism of EMAP II-induced cell apoptosis in primary human endothelial lung cells. These aims, if achieved are expected to position EMAP II as a therapeutic target and/or biomarker of emphysema. PROJECT NARRATIVE: We propose that our experimental plan will allow us to identify a key player in emphysema; EMAP II, which may become a biomarker measurable in biological fluids, and may also prove to be an attractive pharmacological target in a disease with scarce therapeutical options, and a high morbidity and mortality. The excessive EMAP II release stimulated by cellular stresses and ongoing protease activation would account for a vicious and worth targeting cycle of alveolar destruction in the lung. Furthermore, our work will allow to refine mechanisms of endothelial cell apoptosis while unifying the two theories in the field, that of excessive inflammation with that of excessive apoptosis.

描述（由申请人提供）：香烟烟通过机制引起肺气肿，从而导致肺部基质和细胞元素的损失。解释肺气肿的两个主要范例提出a）炎症触发的蛋白酶/抗蛋白酶的不平衡和b）过度肺泡内皮细胞凋亡导致毛细血管回归的状态。这两种机制将解释肺泡壁的损失，表征了肺气肿。然而，尚未解释过多的肺结构细胞凋亡与肺气肿中激活的炎症状态和相互作用的层次结构的共存。我们提出过量的内皮 - 单细胞激活蛋白（EMAP II）是一种统一的分子机制，可将凋亡和肺气肿的炎症联系起来。 EMAP II是一种由质肺中存在的疾病诱导的细胞因子，在胱天蛋白酶蛋白水解裂解时从细胞中释放出来，胱天蛋白酶和基质金属蛋白酶酶，已知参与COPD。我们将CXCR3鉴定为EMAP II的功能受体，它介导EMAP II诱导的内皮细胞凋亡和单核细胞激活。鉴于EMAP II对内皮细胞的有效促凋亡作用，再加上其激活和募集促炎单核细胞的能力，我们假设响应香烟吸烟会释放过多的EMAP II释放，以响应肺部内皮细胞凋亡和单核细胞炎性激活和单核炎性激活，因此是一个蛋白质的分类器。我们假设烟雾会引起EMAP II，从而引起CXCR3依赖性内皮细胞凋亡并激活单核细胞。活化的胱天蛋白酶和基质金属蛋白酶可能会进一步增加肺中的EMAP II，从而扩增肺气肿中最终的损伤信号。这些研究与人类肺气肿有关，因为我们测量了肺气肿患者肺中EMAP II的增加。实际上，我们的数据表明，烟雾诱导的肺气肿先于小鼠EMAP II产生和凋亡，而肺特异性EMAP II的增加足以引起肺凋亡和肺气肿。我们将通过对小鼠烟雾诱导的肺气肿中和肺中有条件的EMAP II转基因过表达中和抗体中和抗体来测试分泌的EMAP II及其受体的功能。我们开发了3个具体目标：1。确定EMAP II是否是香烟烟雾诱导的肺气肿的生物标志物和分子介质。 2研究过度肺EMAP II通过触发肺内皮细胞凋亡或通过募集单核细胞/巨噬细胞诱导肺气肿，以及3。如果达到这些目标，则应将EMAP II定位为肺气肿的治疗靶标和/或生物标志物。项目叙述：我们建议我们的实验计划使我们能够确定肺气肿的关键参与者； EMAP II，它可能成为可在生物液中测量的生物标志物，并且可能被证明是具有稀缺治疗选择以及高发病率和死亡率的疾病中有吸引力的药理学靶标。由细胞应激和持续的蛋白酶激活刺激的过度EMAP II释放将解释肺部肺泡破坏的恶性且值得靶向的周期。此外，我们的工作将允许完善内皮细胞凋亡的机制，同时统一野外的两种理论，而过度炎症与过度凋亡。