Acquired LTA4H Dysfunction in COPD

描述(申请人提供)：我们已经描述了一些人所称的中性粒细胞炎症的范式转换途径，不同于与IL-8相关的“经典”模式，它可以在慢性阻塞性肺疾病等慢性炎症性疾病中自我传播。具体地说，IL-8启动中性粒细胞(PMN)的内流，PMN继而释放一个蛋白水解级联反应，降解胶原，并产生PMN特有的基质因子，脯氨酸-甘氨酸-脯氨酸(PGP)。在IL-8消退后，PGP会进一步促进PMN的流入和中性粒细胞的炎症。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，从而破坏PGP。本研究的主题是吸烟通过对LTA4H的抑制作用使PGP通路自我繁殖，并且即使戒烟后这些作用在COPD患者中仍然存在。我们推测，CS可以化学修饰和失活LTA4H的氨基肽酶，但不能使其水解酶活性和乙酰化Pgp失活，从而使其对LTA4H的降解具有免疫力，并显着提高三肽的趋化活性。这些观点得到了许多观察结果的支持：1)CS诱导COPD小鼠模型中PGP、PMN内流和肺泡扩大；2)PGP可以引起小鼠PMN内流和肺泡扩大；3)PGP似乎是COPD的生物标志物；4)已报道与COPD相关的LTA4H启动子中的单核苷酸多态(SNP)。该项目的结果将阐明CS烟雾如何以及在哪里灭活LTA4H的氨基肽酶活性。这些信息将在最终设计专门针对水解酶活性的LTA4H抑制剂，而不是目前可用的同时阻断水解酶和氨基肽酶活性的抑制剂。在临床研究中，我们将确定LTA4H在吸烟者和COPD患者中也有类似的修饰。在COPD小鼠模型中，我们将确定与预期相反，目前用于人类的LTA4抑制剂是否可能通过阻断LTA4H的氨基肽酶活性和升高PGP而加剧COPD。最后，我们将评估粘液溶解/抗氧化剂碳半胱氨酸是否可以通过影响PGP炎症途径来改善吸烟小鼠的COPD模型。

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.