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A Novel Exosomal Inflammatory Pathway

一种新的外泌体炎症途径

基本信息

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
项目类别：
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

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.

项目总结