The role of anti-inflammatory lipid mediators in atherogenesis

描述(由申请人提供)：长期目标是描述动脉粥样硬化的发病机制及其未能解决的问题。人们普遍认为，氧化低密度脂蛋白(OxLDL)是泡沫细胞形成和血管内皮细胞和巨噬细胞产生促炎细胞因子的关键成分。然而，维持这种炎症状态的分子基础尚未建立。有趣的是，oxLDL中脂质衍生的醛的生成保留了oxLDL的生物活性。在外周组织中，急性炎症的消退是通过反调节的抗炎介质来完成的，包括脂介质，如最近表征的前分解脂蛋白和新的分解相相互作用产物(Resolvins)。虽然对宿主适当防御入侵病原体至关重要，但未解决的炎症可导致在许多疾病状态下观察到的慢性炎症表型，如哮喘和动脉粥样硬化。事实上，在许多慢性炎症性疾病中，脂氧素的生物合成减少，用合成的脂氧素和分解素恢复前分解回路可以减少体内的炎症。将在这项提议中检验的中心假设是，oxLDL通过阻止局部抗炎脂质介质的形成来抑制促分解回路。由此可见，局部抗炎脂质介质应促进oxLDL的清除，促进炎症消退，减少动脉粥样硬化的发生。为了测试这一点，第一个目标将确定oxLDL或其生物活性醛成分是否通过抑制脂素和分解素的生物合成来促进血管炎症。其他实验将通过超氧化物生产(目标1)和巨噬细胞产生促炎细胞因子和脂质介质(目标2)来评估，用脂氧素和解毒剂恢复这些途径是否能增强oxLDL的非炎症性摄取(即，增加清除而不产生促炎介质)。目的3将测试脂氧素和解析剂是否能减少血管炎症和动脉损伤，这将在apoE基因缺失的小鼠中进行评估。我们将评估病变大小、形态以及炎性脂质介质和细胞因子产生的变化。总体而言，这些研究的结果旨在更好地理解动脉粥样硬化中炎症未被解决的机制。阐明内源性抗炎和促分解脂质介质的作用和功能可以为开发新的治疗干预措施和治疗动脉粥样硬化的方法奠定基础。

DESCRIPTION (provided by applicant): The long-term goal is to delineate the mechanisms of the pathogenesis of atherosclerosis and its failure to resolve. It is widely accepted that oxidized low-density lipoprotein (oxLDL) is a critical component in foam cell formation and in the induction of pro-inflammatory cytokine production by vascular endothelial cells and macrophages. However, the molecular basis for maintaining this inflammatory status has not been established. Of interest, the generation of lipid-derived aldehydes in oxLDL retains the bioactivity of oxLDL. In peripheral tissues, the resolution of acute inflammation is accomplished by counter regulatory anti- inflammatory mediators including lipid mediators, such as the recently characterized pro-resolving lipoxins and the novel resolvins (resolution phase interaction products). Although vital for proper host defense against invading pathogens, unresolved inflammation can give rise to a chronic inflammatory phenotype that is observed in many disease states, such as asthma and atherosclerosis. Indeed, lipoxin biosynthesis is decreased in many chronic inflammatory diseases and restoration of pro-resolving circuits with synthetic lipoxins and resolvins reduces inflammation in vivo. The central hypothesis, to be tested in this proposal, is that oxLDL suppresses pro-resolving circuits by preventing the formation of local anti- inflammatory lipid mediators. It follows that local anti-inflammatory lipid mediators should facilitate the clearance of oxLDL, promote the resolution of inflammation and decrease atherogenesis. To test this, the first aim will establish whether oxLDL or its bioactive aldehyde components promote vascular inflammation by inhibiting lipoxin and resolvin biosynthesis. Additional experiments will examine whether restoration of these pathways with lipoxins and resolvins enhances non-phlogistic uptake of oxLDL (i.e., increased clearance without the generation of pro-inflammatory mediators), as assessed by superoxide production (Aim 1) and pro-inflammatory cytokine and lipid mediator generation by macrophages (Aim 2). Aim 3 will test whether lipoxins and resolvins decrease vascular inflammation and arterial lesions that will be evaluated in apoE-null mice. We will evaluate changes in lesion size, morphology and inflammatory lipid mediator and cytokine production. Overall, results from these studies are aimed to develop a better understanding of the mechanisms by which inflammation is not resolved in atherosclerosis. Elucidation of the role and function of endogenous anti-inflammatory and pro-resolving lipid mediators could form the basis for the development of novel therapeutic interventions and approaches for treating atherosclerosis.