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

• 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
• 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

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谓的中性粒细胞炎症的范式转移途径，与与IL-8和其他趋化因子相关的“经典”模式不同，中性粒细胞炎症可以在慢性炎症性疾病（如慢性阻塞性肺疾病（COPD））中自我传播。具体来说，IL-8启动中性粒细胞（PMN）内流，PMN反过来释放基质金属蛋白酶（MMPs）和脯氨酸内肽酶（PE），它们降解胶原并产生PMN特异性基质因子脯氨酸-甘氨酸-脯氨酸（PGP）。在IL-8消退后，PGP进一步传播PMN内流和中性粒细胞炎症。在更常见的急性炎症情况下，PGP途径被白三烯A4水解酶（LTA4H）的氨基肽酶活性终止，白三烯A4水解酶（LTA4H）裂解PGP并使其失活。吸烟（CS）可通过直接或间接抑制LTA4H的作用，使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），但不能水解酶活性和乙酰化PGP，使其对LTA4H降解免疫，并显着提高三肽的趋化活性。一旦慢性炎症环境建立，乙酰PGP （N- PGP）水平升高即使在戒烟后也会持续存在。我们认为这种持久性是由内源性产生的活性醛驱动的，如丙烯醛和乙醛，它们可以使PGP乙酰化，也可以使氨基肽酶失活，但不能使LTA4H的水解酶活性失活。在最近完成的COPD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水平明显较低，与安慰剂治疗组相比，其恶化频率较低。这导致了本项目的主要论点，即N- PGP水平升高可能与COPD加重有关，并可能定义COPD患者中频繁加重的亚群。COPD研究（SPIROMICS）的亚群和中间结果测量队列提供了一个前所未有的机会，将COPD患者痰、血浆和尿液中的PGP和LTA4H与许多疾病参数（特别是恶化、肺气肿程度和疾病进展）联系起来。该建议还将测试LTA4H TAP异常是否在戒烟后仍在COPD中继续存在，以及这种缺陷是否与PGP水平相关。最后，该研究将把痰中PGP的基线水平与血浆和尿液的PGP水平联系起来。在SPIROMICS队列中，血浆和尿液将用于纵向研究PGP水平，以评估可能与COPD亚群和/或疾病参数相关的PGP水平随时间的变化。