Acquired LTA4H Dysfunction in COPD

COPD 患者获得性 LTA4H 功能障碍

基本信息

批准号：
8680355
负责人：
J Edwin Blalock
金额：
$ 49.03万
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：
2012-08-01 至 2016-05-31
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：我们已经描述了有些人称为中性粒细胞炎症的范式转移途径，与IL-8相关的“经典”模式不同，它可以在慢性炎症性疾病（例如COPD）中自我传播。具体而言，IL-8启动嗜中性粒细胞（PMN）涌入，PMN又释放了一种蛋白水解级联反应，该蛋白水解级联反应会降解胶原蛋白并产生PMN特异性的基质氨基氨基氨基氨基氨基氨基氨基氨基氨基氨基酯，脯氨酸 - 甘氨酸 - 丙啉（PGP）。然后，PGP在IL-8后进一步传播PMN涌入和中性粒细胞炎症。在更常见的急性炎症情况下，PGP途径被白细胞A4水解酶（LTA4H）的氨基肽酶活性终止，该酶破坏了PGP。该项目的论点是，吸烟（CS）会导致PGP途径通过对LTA4H的抑制作用而自我传播，即使在戒烟后，这些影响仍然存在于COPD中。我们假设CS可以化学修改LTA4H的氨基肽酶，而不是水解酶活性，而不是水解酶活性以及乙酰化PGP，从而使其免疫对LTA4H的降解，并显着增加了三肽的趋化活性。这些想法得到了许多观察的支持：1）CS在COPD的小鼠模型中诱导PGP，PMN涌入和肺泡增大； 2）PGP会导致小鼠的PMN涌入和肺泡扩大； 3）PGP似乎是COPD的生物标志物； 4）与COPD相关的LTA4H启动子中已经报道了单核苷酸多态性（SNP）。该项目的结果将阐明CS烟雾如何和何处使LTA4H的氨基肽酶活性灭活。该信息将在最终设计的LTA4H抑制剂的设计中非常有用，该抑制剂特定于水解酶活性，而不是当前可用的抑制剂，该抑制剂可阻止水解酶和氨基肽酶活性。在临床研究中，我们将在吸烟者和COPD的个体中类似地建立LTA4H。在COPD的小鼠模型中，我们将确定与期望相反的是，目前旨在最终使用人类使用的LTA4抑制剂，可能通过阻止LTA4H的氨基肽酶活性和升高PGP来加剧COPD。最后，我们将评估粘液溶剂/抗氧化剂，甲状腺素半胱氨酸是否可以防止CS介导的LTA4H氨基肽酶抑制以及阻断PGP乙酰化可以通过对PGP炎性途径的影响来改善COPD吸烟小鼠模型的PGP乙酰化模型。