Oxidative Stress and Anti-Inflammatory Lipids in Airway Disease

气道疾病中的氧化应激和抗炎脂质

• 批准号: 7354732
• 负责人: Bruce D Levy
• 金额: $ 43.75万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7354732
• 关键词: Acids; Acute; Address; Adrenal Cortex Hormones; Affect; American; Anabolism; Ancillary Study; Anti-Inflammatory Agents; Anti-inflammatory; Antibiotics; Appendix; Arachidonate 5-Lipoxygenase; Asthma; Biochemical Markers; Biochemical Reaction; Biological; Biological Markers; Biological Process; Bronchodilator Agents; CD59 Antigen; Cell Communication; Cells; Chlamydophila pneumoniae; Chronic; Chronic Obstructive Airway Disease; Clinical; Data; Disease; Enzyme Gene; Enzyme-Linked Immunosorbent Assay; Essential Fatty Acids; Event; F2-Isoprostanes; Fatty Acids; Generations; High Pressure Liquid Chromatography; Homeostasis; Host Defense; Host Defense Mechanism; Immune response; Individual; Infection; Infection Control; Inflammation; Isoprostanes; Kinetics; Leukocytes; Leukotriene B4; Leukotrienes; Life; Link; Lipids; Lipoxins; Mass Spectrum Analysis; Measurement; Measures; Mediating; Mediator of activation protein; Monitor; Mono-S; Mycoplasma pneumoniae; Oxidative Stress; Pathway interactions; Pharmaceutical Preparations; Plasma; Polymerase Chain Reaction; Predisposition; Process; Property; Prostaglandins; Relative (related person); Resolution; Sampling; Series; Signal Transduction; System; Testing; Time; Tissues; Translating; Whole Blood; abstracting; airway inflammation; antimicrobial; arachidonate; base; cysteinyl-leukotriene; extracellular; in vivo; insight; killings; leukocyte activation; lipid mediator; lipoxin A4; microbial; microbial host; novel; novel therapeutics; pathogen; research study; respiratory; response; restoration

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)

描述（由申请人提供）： 拟议的实验将检验哮喘和慢性阻塞性肺病中脂质介质生成失调的假设。为了应对感染，白细胞和组织驻留细胞相互作用产生脂质介质，增强气道的免疫反应并参与抗微生物宿主防御机制。微生物的杀灭和气道稳态的恢复是一个由特定介质和细胞事件协调的主动过程。白细胞活化导致产生具有有效生物作用的脂质介质，可增强气道的免疫反应并参与抗微生物宿主防御机制。白三烯 (LT) 和前列腺素 (PG) 快速生成，可增强白细胞反应。脂氧素（LX）的形成虽然暂时延迟，但最终对于粘膜宿主防御以及感染和病原体介导的炎症的控制至关重要。与主要由单细胞内的花生四烯酸产生并随后释放的 PG 和 LT 不同，LX 生物合成发生在细胞与细胞相互作用期间。细胞之间 LX 生物合成中间体的细胞外交换使这些途径容易受到氧化应激的影响，氧化应激会破坏 LX 的形成，并有利于替代产物的产生，例如 F2-异前列烷，这些产物显示出促炎特性，而不是 LX 的反调节特性。最近在多种气道炎症疾病中发现了 LX 生成的减少，包括严重哮喘，与慢性阻塞性肺病 (COPD) 恶化一样，与氧化应激增加有关。因此，气道中氧化应激的增加可能导致宿主保护性、反调节脂质介质的形成减少，从而增加气道感染或炎症的易感性。为了检验我们的假设，我们提出了三个具体目标来确定： 分析脂肪酸底物酶促和非酶促氧化之间的关系， 确定哮喘慢性气道感染期间脂氧素和相关反调节脂质介质的产生， 测量慢性阻塞性肺病急性加重和缓解期间脂氧素和相关反调节脂质介质生物合成的时间过程。该提案的具体目标是揭示气道感染和炎症易感性的基础，识别新的生物标志物并开发哮喘和慢性阻塞性肺病的新治疗策略。哮喘和慢性阻塞性肺病是影响数百万美国人生活的常见呼吸系统疾病，哮喘和慢性阻塞性肺病最严重的表现是病情加重。即使正确使用支气管扩张剂、皮质类固醇和其他现有药物，临床反应也是可变的。因此，对于新见解的临床需求仍然存在重大未满足的情况。一些患有哮喘或慢性阻塞性肺病的人表现出天生的气道感染易感性，只能用抗生素暂时解决。在本提案中，我们寻求更好地理解气道感染和炎症期间引起的自然稳态机制失调的自然生物过程。 （摘要完）