A Novel Exosomal Inflammatory Pathway

一种新的外泌体炎症途径

基本信息

批准号：
10540601
负责人：
J Edwin Blalock
金额：
$ 18.21万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-18 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10540601
关键词：
Acute Acute Lung Injury Acute Respiratory Distress Syndrome Aminopeptidase Animals Anti-Inflammatory Agents Biological Markers Blood Vessels Brain Chemicals Chronic Chronic Obstructive Pulmonary Disease Collagen Disease Enzymes Evolution Extracellular Matrix Degradation Functional disorder Generations Glycine Human Human Pathology IL8 gene Immune In Vitro Inflammation Inflammatory Inflammatory Bowel Diseases Lead Link Lung infections Mediator of activation protein Metalloproteases Mus Organ Pathogenicity Pathologic Pathway interactions Patients Peptide Hydrolases Phenotype Process Prognostic Marker Proline Role Smoke Smoking Stroke System Tissues chronic inflammatory disease cigarette smoking exosome leukotriene A4 hydrolase mouse model neutrophil novel novel diagnostics novel therapeutics programs prolyl oligopeptidase

项目摘要

PROJECT SUMMARY This Program has defined what some have called a paradigm shifting pathway of neutrophilic inflammation which, unlike the “classic” mode associated with IL-8, can become self-propagating in chronic inflammatory diseases such as COPD. Specifically, IL-8 initiates neutrophil (PMN) influx, the PMNs in turn release matrix metalloproteases (MMPs) and prolyl endopeptidase (PE) which degrade collagen and generate the PMN-specific matrikine, proline-glycine-proline (PGP). In more common acute inflammatory circumstances, the PGP pathway is terminated by the aminopeptidase activity of leukotriene A4 hydrolase (LTA4H) which destroys PGP. Cigarette smoking (CS) can chemically modify and inactivate LTA4H’s aminopeptidase but not hydrolase activity as well as acetylate PGP rendering it immune to LTA4H. This drives persistently elevated PGP levels and chronic neutrophilic inflammation in COPD. In the Program’s journey to understand the PGP system, we have identified a novel potential prognostic biomarker for COPD, CF, and ARDS, linked matrix degradation to vascular leak, and discovered an anti-inflammatory role for a pro-inflammatory enzyme, LTA4H. PGP has also recently been shown to link extracellular matrix degradation to: acute lung injury, inflammatory bowel disease, ischemic brain stroke, and modulation of acute pulmonary infection. Consequently, the discovery of the PGP system has particular significance as a fundamental mediator of pathophysiology in a number of disorders and organs. One enigmatic aspect of our studies has been an inability to generate PGP in vitro with collagen and the appropriate proteases in solution. The thesis of this R35 application is that this enigma is due to the requirement that PGP generating enzymes, such as PE, be exosome associated. This idea is supported by many observations, most notably, that airway exosomes from COPD patients, but not controls, are PMN-derived and cause a COPD-like phenotype when transferred to mice. Collectively, the findings led to our hypothesis that proteolytic exosomes constitute a new aspect of the inflammatory process and may participate in chronic inflammatory disorders such as COPD via the PGP pathway. If successful, the results of this project will define a novel entity, i.e. proteolytic exosome, which drives neutrophilic inflammation via PGP generation which is regulated by LTA4H and can cause a COPD-like disease in mice. In human studies, we will phenotype proteolytic exosomes and delineate whether they are biomarkers of COPD that correlate with disease parameters and can transfer pathology from humans to mice. In a smoking mouse model of COPD we will characterize the evolution of such exosomes and whether they can transfer disease from smoked to naïve animals. Although, the definition of a new pathogenic entity is daunting, the track record of this Program and the expertise of the PI and team suggest a successful endeavor. If so, a complete understanding of the proteolytic exosome may lead to new diagnostics and therapeutics for chronic inflammatory diseases such as COPD.

项目概要该计划定义了一些人所说的中性粒细胞炎症的范式转变途径与 IL-8 相关的“经典”模式不同，它可以在慢性炎症中自我传播具体而言，IL-8 会引发中性粒细胞 (PMN) 流入，PMN 进而释放基质。金属蛋白酶 (MMP) 和脯氨酰内肽酶 (PE) 可降解胶原蛋白并产生 PMN 特异性苦参碱、脯氨酸-甘氨酸-脯氨酸 (PGP) 在更常见的急性炎症情况下，PGP 途径。被白三烯 A4 水解酶 (LTA4H) 的氨肽酶活性终止，该酶会破坏香烟中的 PGP。吸烟 (CS) 可以化学修饰和灭活 LTA4H 的氨肽酶，但也不能抑制水解酶活性因为乙酰化 PGP 使其对 LTA4H 免疫，这会导致 PGP 水平持续升高并导致慢性。在该计划了解 PGP 系统的过程中，我们已经确定了 COPD 中的中性粒细胞炎症。一种用于 COPD、CF 和 ARDS 的新型潜在预后生物标志物，将基质降解与血管渗漏联系起来，最近还发现了促炎酶 LTA4H 的抗炎作用。研究显示细胞外基质降解与以下疾病有关：急性肺损伤、炎症性肠病、缺血性脑 PGP 系统的发现已对中风和急性肺部感染的调节进行了测试。作为许多疾病和器官的病理生理学的基本介质具有特别重要的意义。我们研究的一个神秘之处是无法在体外用胶原蛋白和适当的方法生成 PGP。该 R35 应用的论点是，这个谜团是由于 PGP 的要求造成的。产生酶，如 PE，与外泌体相关，这一想法得到了许多观察的支持，大多数观察都支持这一观点。值得注意的是，来自 COPD 患者（而非对照者）的气道外泌体是 PMN 衍生的，会引起类似 COPD 的症状。总的来说，这些发现导致了我们的假设：蛋白水解外泌体。构成炎症过程的一个新方面，可能参与慢性炎症性疾病，例如如果成功，该项目的结果将定义一个新的实体，即蛋白水解物。外泌体，通过 PGP 生成驱动中性粒细胞炎症，PGP 受 LTA4H 调节，可以在人类研究中，我们将对蛋白水解外泌体进行表型分析并描述。它们是否是慢性阻塞性肺病的生物标志物，与疾病参数相关并且可以从在吸烟的慢性阻塞性肺病小鼠模型中，我们将描述这种外泌体的进化和它们是否可以将疾病从熏制的动物身上转移到新的致病菌的定义上。实体令人望而生畏，该计划的跟踪记录以及 PI 和团队的专业知识表明该计划是成功的如果是这样，对蛋白水解外泌体的完整了解可能会带来新的诊断和治疗方法。慢性炎症性疾病（例如慢性阻塞性肺病）的治疗方法。