Acquired LTA4H Dysfunction in COPD

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相关的“经典”模式，可以在慢性炎症性疾病如COPD中自我传播。具体地，IL-8启动中性粒细胞（PMN）内流，PMN继而释放降解胶原蛋白并产生PMN特异性基质因子脯氨酸-甘氨酸-脯氨酸（PGP）的蛋白水解级联。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途径被破坏PGP的白三烯A4水解酶（LTA 4 H）的氨肽酶活性终止。该项目的论点是，吸烟（CS）导致PGP途径通过对LTA 4 H的抑制作用而自我传播，并且即使在戒烟后，这些作用在COPD中仍然存在。我们假设CS可以化学修饰和抑制LTA 4 H的氨肽酶，但不能修饰水解酶活性，也可以乙酰化PGP，使其对LTA 4 H降解具有免疫力，并显著增加三肽的趋化活性。这些观点得到了大量观察结果的支持：1）CS在COPD小鼠模型中诱导PGP、PMN内流和肺泡扩大; 2）PGP可导致小鼠中PMN内流和肺泡扩大; 3）PGP似乎是COPD的生物标志物; 4）已报道LTA 4 H启动子中的单核苷酸多态性（SNP）与COPD相关。这个项目的结果将阐明如何和CS烟雾灭活LTA 4 H的氨肽酶活性。该信息将在最终设计对水解酶活性特异的LTA 4 H抑制剂而不是目前可获得的阻断水解酶和氨肽酶活性的抑制剂中非常有用。在临床研究中，我们将确定LTA 4 H在吸烟者和COPD患者中的变化类似。在小鼠COPD模型中，我们将确定是否与预期相反，目前用于最终人类使用的LTA 4抑制剂可能通过阻断LTA 4 H的氨肽酶活性和升高PGP而加重COPD。最后，我们将评估粘液溶解剂/抗氧化剂羧半胱氨酸是否可以通过对PGP炎症通路的影响来改善吸烟小鼠COPD模型，羧半胱氨酸可以防止CS介导的对LTA 4 H氨基肽酶的抑制以及阻断PGP乙酰化。 公共卫生相关性：我们已经发现了一种方法，通过这种方法，吸烟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。在这样做的过程中，吸烟会导致慢性PGP介导的炎症，并导致COPD。我们正在评估可能通过增强PGP的破坏来治疗COPD的新药。

DESCRIPTION (provided by applicant): We have described what some have termed 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 a proteolytic cascade that degrades collagen and generates 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 destroys PGP. The thesis of this project is that cigarette smoking (CS) causes the PGP pathway to become self propagating by inhibitory effects on LTA4H and that these effects persist in COPD even after smoking cessation. We hypothesize that CS can chemically modify and inactivate LTA4H's aminopeptidase 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. These ideas are supported by a number of observations: 1) CS induces PGP, PMN influx, and alveolar enlargement in a mouse model of COPD; 2) PGP can cause PMN influx and alveolar enlargement in mice; 3) PGP appears to be a biomarker for COPD; 4) single nucleotide polymorphisms (SNP) have been reported in the LTA4H promoter that are associated with COPD. The results of this project will elucidate how and where CS smoke inactivates LTA4H's aminopeptidase activity. This information will be extremely useful in the eventual design of LTA4H inhibitors that are specific for hydrolase activity rather than currently available inhibitor that block both hydrolase and aminopeptidase activities. In clinical studies, we will establish tha LTA4H is similarly modified in smokers and individuals with COPD. In a mouse model of COPD, we will determine whether contrary to expectations, current LTA4 inhibitors intended for eventual human use, may exacerbate COPD by blocking LTA4H's aminopeptidase activity and elevating PGP. Lastly, we will evaluate whether the mucolytic/antioxidant, carbocysteine, which prevents CS-mediated inhibition of LTA4H's aminopeptidase as well as blocks PGP acetylation can ameliorate the smoking mouse model of COPD via effects on the PGP inflammatory pathway. PUBLIC HEALTH RELEVANCE: We have discovered a means by which smoking can prevent a natural mechanism that controls lung inflammation by degrading the neutrophil chemokine, PGP. In doing so, smoke causes chronic PGP-mediated inflammation and contributes to COPD. We are evaluating new drugs that may treat COPD by enhancing the destruction of PGP.