PGP, A Possible Biomarker for COPD Exacerbations and or Progression

PGP，COPD 恶化和/或进展的可能生物标志物

基本信息

批准号：
8334299
负责人：
J Edwin Blalock
金额：
$ 36.63万
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：
2012
资助国家：
美国
起止时间：
2012-09-12 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8334299
关键词：
Acetaldehyde Acrolein Acute Aldehydes Alveolar Aminopeptidase Ancillary Study Azithromycin Biological Assay Biological Markers Chronic Chronic Obstructive Airway Disease Cleaved cell Clinical Clinical Research Cohort Studies Collagen Defect Disease Disease Progression Environment Frequencies Glycine Hydrolase IL8 gene Immune Impairment Individual Inflammation Inflammatory Lead Lung Inflammation Lung diseases Macrolides Mediating Mus N-acetyl-proline-glycine-proline Outcome Measure Pathway interactions Patients Peptide Hydrolases Peptides Placebos Plasma Proline Pulmonary Emphysema Relative (related person)Reporting Single Nucleotide Polymorphism Smoking Sputum System Testing Time Urine chemokine cigarette smoke-induced cigarette smoking cohort leukotriene A4 hydrolase mouse model neutrophil prevent prolyl oligopeptidase promoter smoking cessation trend

项目摘要

DESCRIPTION (provided by applicant): We have described what some have called a paradigm shifting pathway of neutrophilic inflammation which, unlike the "classic" mode associated with IL-8 and other chemokines, can become self propagating in chronic inflammatory diseases such as chronic obstructive pulmonary disease (COPD). Specifically, IL-8 initiates neutrophil (PMN) influx, the PMNs in turn release matrix metallo-proteases (MMPs) and prolyl endopeptidase (PE) which degrade collagen and generate the PMN-specific matrikine, proline-glycine-proline (PGP). PGP then propagates further PMN influx and neutrophilic inflammation after IL-8 has subsided. In more common acute inflammatory circumstances, the PGP pathway is terminated by the aminopeptidase activity of leukotriene A4 hydrolase (LTA4H) which cleaves and inactivates PGP. Cigarette smoking (CS) can cause the PGP pathway to become self propagating and disease provoking by direct and indirect inhibitory effects on LTA4H. CS can chemically modify and inactivate LTA4H's triaminopeptidase (TAP) but not hydrolase activity as well as acetylate PGP which renders it immune to LTA4H degradation and markedly increases the chemotactic activity of the tri-peptide. Once a chronic inflammatory environment is established, elevated acetyl PGP (N--PGP) levels then persist in COPD even after smoking cessation. We believe this persistence is driven by endogenously produced reactive aldehydes, such as acrolein and acetaldehyde, which can acetylate PGP as well as inactivate the aminopeptidase but not hydrolase activity of LTA4H. In a recently completed ancillary study to the COPD Clinical Research Network (CCRN) Macrolide trial, we have observed substantially lower levels of N--PGP in the azithromycin-treated group, which had a lower exacerbation frequency, as compared to placebo-treated individuals. This has led to the main thesis of this project that elevated N--PGP levels may be associated with COPD exacerbations and may define a subpopulation of COPD patients that are frequent exacerbators. The Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort represents an unprecedented opportunity to correlate PGP and LTA4H in sputum, plasma, and urine of COPD patients with numerous disease parameters, in particular exacerbations, degree of emphysema and disease progression. This proposal will also test whether aberrant LTA4H TAP activity continues in COPD even after smoking cessation and whether this defect is associated with PGP levels. Lastly, the study will correlate baseline sputum PGP levels with those of plasma and urine. Plasma and urine will then be used to study PGP levels longitudinally in the SPIROMICS cohort to assess changes with time that may associate with COPD subpopulations and/or with parameters of disease. PUBLIC HEALTH RELEVANCE: We have discovered a means by which smoking and COPD can prevent a natural mechanism that controls lung inflammation by degrading the neutrophil chemokine, PGP. In doing so, chronic PGP-mediated inflammation occurs and contributes to COPD. We are evaluating whether perturbations of this system and increased PGP levels are biomarkers for COPD exacerbations and disease progression.

描述（由申请人提供）：我们描述了一些人所说的中性粒细胞炎症的范式转换途径，与与 IL-8 和其他趋化因子相关的“经典”模式不同，该途径可以在慢性炎症性疾病（例如慢性阻塞性肺病）中自我传播。肺部疾病（慢性阻塞性肺病）。具体而言，IL-8 启动中性粒细胞 (PMN) 流入，PMN 进而释放基质金属蛋白酶 (MMP) 和脯氨酰内肽酶 (PE)，降解胶原蛋白并生成 PMN 特异性基质碱、脯氨酸-甘氨酸-脯氨酸 (PGP)。 IL-8 消退后，PGP 会进一步传播 PMN 流入和中性粒细胞炎症。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，该酶会裂解并灭活 PGP。吸烟 (CS) 可通过对 LTA4H 的直接和间接抑制作用，导致 PGP 通路自我繁殖并引发疾病。 CS 可以化学修饰和灭活 LTA4H 的三氨基肽酶 (TAP)，但不能水解酶活性，并且乙酰化 PGP，使其免受 LTA4H 降解的影响，并显着增加三肽的趋化活性。一旦建立了慢性炎症环境，即使在戒烟后，COPD 中乙酰 PGP (N--PGP) 水平也会持续升高。我们认为这种持久性是由内源性产生的活性醛（例如丙烯醛和乙醛）驱动的，它们可以乙酰化 PGP 并灭活氨肽酶，但不能灭活 LTA4H 的水解酶活性。在最近完成的一项慢性阻塞性肺病临床研究网络 (CCRN) 大环内酯试验的辅助研究中，我们观察到阿奇霉素治疗组的 N--PGP 水平显着降低，与安慰剂治疗组相比，该组的病情恶化频率较低。这导致了该项目的主要论点：N--PGP 水平升高可能与 COPD 恶化有关，并可能定义 COPD 患者的一个亚群，该亚群是常见的恶化者。 COPD 研究中的亚群和中间结果测量 (SPIROMICS) 队列提供了一个前所未有的机会，可以将 COPD 患者痰液、血浆和尿液中的 PGP 和 LTA4H 与众多疾病参数（特别是病情加重、肺气肿程度和疾病进展）相关联。该提案还将测试即使在戒烟后，COPD 中异常的 LTA4H TAP 活性是否仍持续，以及这种缺陷是否与 PGP 水平相关。最后，该研究将基线痰 PGP 水平与血浆和尿液的水平相关联。然后，血浆和尿液将用于纵向研究 SPIROMICS 队列中的 PGP 水平，以评估可能与 COPD 亚群和/或疾病参数相关的随时间的变化。公共健康相关性：我们发现了一种方法，吸烟和慢性阻塞性肺病可以通过降解中性粒细胞趋化因子 PGP 来阻止控制肺部炎症的自然机制。在此过程中，会发生 PGP 介导的慢性炎症并导致 COPD。我们正在评估该系统的扰动和 PGP 水平的升高是否是 COPD 恶化和疾病进展的生物标志物。