Acquired LTA4H Dysfunction in COPD

COPD 患者获得性 LTA4H 功能障碍

• 批准号: 8515516
• 负责人: J Edwin Blalock
• 金额: $ 47.63万
• 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: 2012-08-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8515516
• 关键词: Acetylation; Acute; Alveolar; Amino Acids; Aminopeptidase; Antioxidants; Biological Markers; Chronic; Chronic Obstructive Airway Disease; Clinical Research; Collagen; Data; Disease; Epithelial Cells; Functional disorder; Glycine; Human; Hydrolase; IL8 gene; Immune; Individual; Inflammation; Inflammatory; Leukotriene A4; Lung Inflammation; Matrix Metalloproteinases; Mediating; Messenger RNA; Mucolytics; Mus; Pathway interactions; Patients; Peptide Hydrolases; Peptides; Pharmaceutical Preparations; Proline; Reporting; Single Nucleotide Polymorphism; Smoke; Smoker; Smoking; base; chemokine; cigarette smoke-induced; cigarette smoking; design; expectation; inhibitor/antagonist; leukotriene A4 hydrolase; mouse model; neutrophil; never smoker; non-smoker; prevent; prolyl oligopeptidase; promoter; public health relevance; smoking cessation

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）：我们已经描述了一些人所称的中性粒细胞炎症的范式转变途径，与与IL-8相关的“经典”模式不同，该途径可以在慢性炎症性疾病（例如COPD）中自我传播。具体来说，IL-8 启动中性粒细胞 (PMN) 流入，PMN 进而释放蛋白水解级联，降解胶原蛋白并生成 PMN 特异性的基质碱、脯氨酸-甘氨酸-脯氨酸 (PGP)。 IL-8 消退后，PGP 会进一步传播 PMN 流入和中性粒细胞炎症。在更常见的急性炎症情况下，PGP 途径被白三烯 A4 水解酶 (LTA4H) 的氨肽酶活性终止，从而破坏 PGP。该项目的论文是，吸烟 (CS) 通过对 LTA4H 的抑制作用导致 PGP 通路自我传播，并且即使在戒烟后，这些作用在 COPD 中仍然存在。我们假设CS可以化学修饰和灭活LTA4H的氨肽酶，但不能水解酶活性，并且乙酰化PGP，使其免受LTA4H降解并显着增加三肽的趋化活性。这些观点得到了许多观察结果的支持：1) CS 在 COPD 小鼠模型中诱导 PGP、PMN 流入和肺泡增大； 2）PGP可引起小鼠PMN流入和肺泡肿大； 3) PGP 似乎是 COPD 的生物标志物； 4) LTA4H 启动子中已报道与 COPD 相关的单核苷酸多态性 (SNP)。该项目的结果将阐明 CS 烟雾如何以及在何处使 LTA4H 氨肽酶活性失活。该信息对于最终设计针对水解酶活性的 LTA4H 抑制剂（而不是目前可用的同时阻断水解酶和氨肽酶活性的抑制剂）非常有用。在临床研究中，我们将确定 LTA4H 在吸烟者和慢性阻塞性肺病患者中也有类似的修饰。在 COPD 小鼠模型中，我们将确定是否与预期相反，目前供人类最终使用的 LTA4 抑制剂可能通过阻断 LTA4H 氨肽酶活性并提高 PGP 来加剧 COPD。最后，我们将评估粘液溶解/抗氧化剂羧甲司坦是否可以通过影响 PGP 炎症途径来改善吸烟小鼠 COPD 模型，该物质可以阻止 CS 介导的 LTA4H 氨肽酶抑制并阻断 PGP 乙酰化。