Anti-inflammatory lipids in acute mucosal inflammation

描述(由申请人提供) 炎症性肠病(IBD)与急剧增加有关 在世界各地发生的结直肠癌每年的发病率为 大约每10万人中有12人。中性粒细胞的异常激活和 脂质和多肽介质的显著增加是这些疾病的主要迹象 炎症性疾病以及缺血再灌注损伤，一种已知的 外科手术的并发症。急性炎症反应是如何转换的 从重要的宿主防御到异常炎症和中性粒细胞介导的组织 损伤仍有待完全阐明。因此，内生机制 这会扰乱促炎环路，这是有意义的。阿司匹林和omega-3 多不饱和脂肪酸(PUFA)是一种治疗剂，可以证明 有益于炎症性疾病以及预防结肠癌。 然而，它们的作用机制仍然需要明确界定，但 目标是形成脂类介体，即二十烷类化合物。两者都有治疗作用 药物会触发新型抗炎脂类的形成， 即15R-脂氧素和omega-3多不饱和脂肪酸衍生的15R-和18R-系列二十烷类化合物。 这项研究将检验这样一种假设，即急性炎症导致 调节和暂时产生抗炎脂质信号，以及 Omega-3脂肪酸和阿司匹林增强这些保护性脂质介质 电路。 本应用程序的具体目标将采用以下组合方法 结构鉴定、分子生物学和转基因技术描绘三个 脂质信号在中性粒细胞介导的肠道中的主要作用 损伤：i)建立促炎和抗炎的时间关系 二十烷类化合物。二)确定阿司匹林和omega-3多不饱和脂肪酸对二十烷类化合物的影响 简介和阐明新的保护性脂质介体。三)确定是否 新型阿司匹林和omega-3多不饱和脂肪酸触发的脂质介质对 中性粒细胞异常激活与脂质受体表达的变化 介质是异常肠炎的标志物。博大精深 这一应用的长期目标是阐明内源性途径 阻断PMN介导的损伤，促进炎症的消退。结果 从这个项目可能提供新的抗炎工具来控制 炎症性疾病，如溃疡性结肠炎和慢性疾病。

DESCRIPTION (provided by applicant) Inflammatory bowel diseases (IBD) that are associate with a dramatic increase in colorectal cancer occur throughout the world with an annual incidence of approximately 12/100,000 people. Aberrant activation of neutrophils and a profound increase in lipid and peptide mediators are cardinal signs of these inflammatory diseases as well as for ischemia reperfusion injury, a known complication of surgical procedures. How acute inflammatory responses switch from vital host defense to aberrant inflammation and neutrophil mediated tissue injury remains to be completely elucidated. Therefore, endogenous mechanisms that disrupt pro-inflammatory circuits are of interest. Aspirin and omega-3 polyunsaturated fatty acids (PUFA) are therapeutic agents that demonstrate benefits in inflammatory diseases as well as prevention of colon cancer. However, their mechanisms of action still needs to be clearly defined but targets the formation of lipid mediators namely eicosanoids. Both therapeutic agents trigger the formation of novel classes of anti-inflammatory lipids, namely 15R-lipoxins and omega-3 PUFA derived 15R-and 18R-series eicosanoids. This study shall test the hypothesis that acute inflammation induces a regulated and temporal generation of anti-inflammatory lipid signals and that omega-3 fatty acid and aspirin augment these protective lipid mediator circuits. The specific aims of this application will employ a combined approach of structural elucidation, molecular biology and transgenics to delineate three main aspect of the role of lipid signals in neutrophil mediated intestinal injury: i) Establish the temporal relationship of pro- and anti-inflammatory eicosanoids. ii) Determine the impact of aspirin and omega-3 PUFA on eicosanoid profiles and elucidate novel protective lipid mediators. iii) Determine if novel aspirin and omega-3 PUFA triggered lipid mediators are protective against aberrant PMN activation and if changes in expression of receptors for lipid mediators are markers for aberrant intestinal inflammation. The broad and long-term objectives of this application are to elucidate endogenous pathways that block PMN mediated injury to promote resolution of inflammation. Results from this project may provide novel anti-inflammatory tools for controlling inflammatory diseases such as Ulcerative Colitis and Chron's Disease.