Acquired LTA4H Dysfunction in COPD

COPD 患者获得性 LTA4H 功能障碍

• 批准号: 8857226
• 负责人: J Edwin Blalock
• 金额: $ 49.28万
• 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 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8857226
• 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; Health; 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; 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）：我们描述了一些被称为中性粒细胞炎症的范式转移途径，与与IL-8相关的“经典”模式不同，中性粒细胞炎症可以在慢性炎症性疾病（如COPD）中自我传播。具体来说，IL-8启动中性粒细胞（PMN）内流，PMN反过来释放蛋白水解级联，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）。在IL-8消退后，PGP进一步传播PMN内流和中性粒细胞炎症。在更常见的急性炎症情况下，PGP途径被白三烯A4水解酶（LTA4H）的氨基肽酶活性终止，从而破坏PGP。本项目的论点是吸烟（CS）通过抑制LTA4H导致PGP通路自我传播，并且这些影响在戒烟后仍持续存在于COPD中。我们假设CS可以化学修饰和灭活LTA4H的氨基肽酶，但不能使水解酶活性和乙酰化PGP，从而使其免疫LTA4H降解并显着增加三肽的趋化活性。这些观点得到了一系列观察结果的支持：1)在COPD小鼠模型中，CS诱导PGP、PMN内流和肺泡增大；2) PGP可引起小鼠PMN内流和肺泡增大；3) PGP可能是COPD的生物标志物；4) LTA4H启动子中的单核苷酸多态性（SNP）已被报道与COPD相关。该项目的结果将阐明CS烟雾如何以及在何处使LTA4H的氨基肽酶活性失活。这些信息将对最终设计针对水解酶活性的LTA4H抑制剂非常有用，而不是目前可用的既阻断水解酶活性又阻断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患者中也有类似的改变。在COPD小鼠模型中，我们将确定是否与预期相反，目前拟最终用于人类的LTA4抑制剂可能通过阻断LTA4H的氨基肽酶活性和升高PGP而加剧COPD。最后，我们将评估粘解/抗氧化剂，碳半胱氨酸，是否可以阻止cs介导的LTA4H的氨基肽酶抑制以及阻断PGP乙酰化，通过对PGP炎症途径的影响来改善吸烟小鼠COPD模型。