PGP, A Possible Biomarker for COPD Exacerbations and or Progression

描述（由申请人提供）：我们已经描述了一些人所称的嗜酸性炎症的范式转换途径，其不同于与IL-8和其他趋化因子相关的“经典”模式，可以在慢性炎症性疾病如慢性阻塞性肺病（COPD）中自我传播。具体地，IL-8启动中性粒细胞（PMN）内流，PMN继而释放基质金属蛋白酶（MMP）和脯氨酰内肽酶（PE），其降解胶原并产生PMN特异性基质因子脯氨酸-甘氨酸-脯氨酸（PGP）。PGP然后在IL-8消退后进一步传播PMN内流和嗜中性粒细胞炎症。在更常见的急性炎症情况下，PGP途径被白三烯A4水解酶（LTA 4 H）的氨肽酶活性终止，该酶切割并灭活PGP。 吸烟（CS）可通过对LTA 4 H的直接和间接抑制作用导致PGP途径自我传播和引发疾病。CS可以化学修饰和抑制LTA 4 H的三氨基肽酶（TAP），但不能修饰水解酶活性，并且可以乙酰化PGP，使其对LTA 4 H降解免疫，并显著增加三肽的趋化活性。一旦慢性炎症环境建立，乙酰基PGP（N-PGP）水平升高，然后持续在COPD，即使戒烟后。我们认为这种持久性是由内源性产生的反应性醛，如丙烯醛和乙醛驱动的，它们可以乙酰化PGP以及抑制LTA 4 H的氨肽酶活性，但不抑制其水解酶活性。 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，阿奇霉素治疗组的病情加重频率较低。这导致了该项目的主要论点，即升高的N-PGP水平可能与COPD急性加重相关，并可能定义COPD患者的一个亚群，这些患者是频繁的急性加重者。COPD研究（SPIROMICS）队列中的亚群和中间结局指标代表了将COPD患者痰液、血浆和尿液中的PGP和LTA 4 H与许多疾病参数（特别是急性加重、肺气肿程度和疾病进展）相关联的前所未有的机会。该提案还将测试异常的LTA 4 H TAP活性是否在COPD中即使在戒烟后仍继续存在，以及这种缺陷是否与PGP水平相关。最后，研究将基线痰液PGP水平与血浆和尿液的PGP水平相关联。然后将使用血浆和尿液纵向研究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。

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.