Oxidative Stress and Anti-Inflammatory Lipids in Airway Disease

描述(由申请人提供)： 拟议的实验将检验这样一个假设，即哮喘和慢性阻塞性肺病患者存在脂质介质生成的失调。在对感染的反应中，白细胞和组织驻留细胞相互作用，产生脂质介质，增强呼吸道的免疫反应，并参与抗微生物宿主防御机制。微生物杀死和恢复呼吸道内稳态是一个由特定的介质和细胞事件协调的活跃过程。白细胞的激活导致脂质介质的产生，这些介质具有强大的生物学作用，有助于增强呼吸道的免疫反应，并参与抗微生物宿主防御机制。白三烯(LTS)和前列腺素(PGs)迅速产生，以增强白细胞的反应。脂氧素(LX)的形成是暂时延迟的，但最终对粘膜宿主防御和控制感染和病原体介导的炎症至关重要。与主要由单个细胞内的花生四烯酸产生并随后释放的PG和LT不同，LX的生物合成发生在细胞与细胞的相互作用期间。细胞间LX生物合成中间体的细胞外交换为这些易受氧化应激影响的途径提供了便利，氧化应激将扰乱LX的形成，并有利于替代产物的产生，如F2-异前列腺素，这些产物表现出炎症而不是LX的反调节特性。最近在几种呼吸道炎症疾病中发现LX生成减少，包括严重哮喘，与COPD加重一样，与氧化应激增加有关。因此，呼吸道中氧化应激的增加可能会减少宿主保护性、逆调节的脂质介质的形成，从而增加呼吸道感染或炎症的易感性。为了验证我们的假设，我们提出了三个具体的目标来确定：分析脂肪酸底物的酶和非酶氧化之间的关系，确定哮喘慢性呼吸道感染过程中脂氧素和相关逆调节脂质介质的产生，测量急性COPD加重和缓解期间脂氧素和相关逆调节脂质介质生物合成的时间进程。这项建议的具体目标是揭示呼吸道感染和炎症的易感性基础，识别新的生物标记物，并开发治疗哮喘和慢性阻塞性肺病的新策略。病情恶化是哮喘和慢性阻塞性肺病最严重的表现，这两种常见的呼吸道疾病影响着数百万美国人的生活。即使正确使用了支气管扩张剂、皮质类固醇和其他目前可用的药物，临床反应也是不同的。因此，对新见解的临床需求仍然很大，尚未得到满足。一些哮喘或慢性阻塞性肺病患者表现出天生对呼吸道感染的易感性，这种易感性只能通过抗生素短暂地解决。在这项建议中，我们试图更好地了解在呼吸道感染和炎症过程中调用的自然生物过程，这些过程破坏了自然的体内平衡机制。(摘要结束)

DESCRIPTION (provided by applicant): The proposed experiments will test the hypothesis that dysregulation of lipid mediator generation occurs in asthma and COPD. In response to infection, leukocytes and tissue-resident cells interact to generate lipid mediators that enhance the airway's immune responses and engage anti-microbial host defense mechanisms. Microbial killing and restoration of airway homeostasis is an active process coordinated by specific mediators and cellular events. Leukocyte activation leads to the generation of lipid mediators with potent biological actions that serve to enhance the airway's immune responses and engage anti-microbial host defense mechanisms. Leukotrienes (LTs) and prostaglandins (PGs) are rapidly generated to enhance leukocyte responses. Lipoxin (LX) formation is temporally delayed, yet ultimately critical for mucosal host defense and control of infection and pathogen- mediated inflammation. Unlike PGs and LTs that are principally generated from arachidonate within single cells for subsequent release, LX biosynthesis occurs during cell-cell interactions. The extracellular exchange of LX biosynthetic intermediates between cells lends these pathways vulnerable to oxidative stress that would disrupt LX formation and favor the generation of alternate products, such as F2-isoprostanes, that display pro-phlogistic rather than LXs' counter-regulatory properties. Decreased LX generation has recently been identified in several diseases of airway inflammation, including severe asthma, which like COPD exacerbations, is associated with increased oxidative stress. Thus, increased oxidative stress in the airway may predispose to diminished formation of host protective, counter-regulatory lipid mediators and thereby an increased susceptibility for airway infection or inflammation. To test our hypothesis, we propose three specific aims to determine: To profile relationships between enzymatic and non-enzymatic oxygenation of fatty acid substrates, To determine the generation of lipoxins and related counter-regulatory lipid mediators during chronic airway infection in asthma, To measure the time course for lipoxin and related counter-regulatory lipid mediator biosynthesis during acute COPD exacerbation and resolution. This proposal's specific aims are directed towards uncovering the basis for susceptibility to airway infection and inflammation, identifying novel biomarkers and developing new therapeutic strategies for asthma and COPD. Exacerbations are the most serious expression of asthma and COPD, common respiratory ailments that affect the lives of millions of Americans. Even with the proper use of bronchodilators, corticosteroids and other currently available medications, clinical responses are variable. Consequently, there remains a significant unmet clinical need for new insights. Some individuals with asthma or COPD display an inherently increased susceptibility for airway infection that is only transiently addressed with antibiotics. In this proposal, we seek to develop a better understanding of the natural biological processes invoked during airway infection and inflammation that dysregulate the natural homeostatic mechanisms. (End of Abstract)