A Novel Exosomal Inflammatory Pathway

一种新的外泌体炎症途径

• 批准号: 10320741
• 负责人: J Edwin Blalock
• 金额: $ 87.76万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-18 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320741
• 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

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.

项目摘要 该程序定义了有些人所说的中性粒细胞造成途径的范式移动途径 与与IL-8相关的“经典”模式不同，它可以在慢性炎症中自我传播 诸如COPD之类的疾病。 金属蛋白酶（MMP）和Prolel内肽酶（PE）降解胶原蛋白并生成PMN特异性 基金，脯氨酸 - 甘氨酸 - 丙啉（PGP）。 由白细胞A4水解酶（LTA4H）的氨基肽酶活性终止 吸烟（CS）可以化学修改和灭活LTA4H的氨基肽酶，而不是水解酶活性 由于乙酰酸PGP使其免疫LTA4H。 copd中的嗜中性炎症。 COPD，CF和ARDS的一种新型潜在程序的预后生物标志物，将基质降解与Vascal泄漏联系起来， 并发现了促炎酶LTA4H的抗炎作用。 显示以将细胞外基质降解与：急性肺损伤，炎症肠疾病，缺血性脑部 中风和急性肺部感染的调节。 作为疾病和器官源自病理生理学的基本介体的特殊意义。 我们研究的神秘方面是无法在体外与胶原蛋白和适当的应用产生PGP 溶液中的蛋白酶。 与PE这样的酶产生的酶是与许多观察相关的外外的。 值得注意的是，COPD患者而非对照的气道外泌体是PMN衍生的，并引起类似COPD的样子 表型转移到小鼠时，发现导致了我们的假设totemolytyticomes 征集炎症过程的新方面，并可能参与此类慢性炎症疾病 作为通过PGP途径的COPD，如果成功的结果将定义一个新的实体，即蛋白质 外泌体，通过PGP产生驱动中性粒细胞炎症，该炎症由LTA4H调节，可以 在人类研究中引起小鼠的COPD样疾病，我们将表型蛋白质外泌体并描绘 它们是否是与疾病参数相关的COPD的生物标志物，并且可以从 人类在copd的吸烟小鼠模型中，我们将表征此类外泌体的演变 尽管可以将疾病从烟熏到幼稚的动物。 实体令人生畏，PI和团队的专业知识的往绩提出了成功 努力。 长期炎症疾病（例如COPD）的治疗剂。