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无法解决的机制。氧化低密度脂蛋白（oxLDL）被广泛认为是泡沫细胞形成和血管内皮细胞和巨噬细胞诱导促炎细胞因子产生的关键成分。然而，维持这种炎症状态的分子基础尚未确定。有趣的是，在oxLDL中产生的脂质衍生醛保留了oxLDL的生物活性。在外周组织中，急性炎症的消退是由反调节的抗炎介质完成的，包括脂质介质，如最近发现的促溶解脂毒素和新的溶解物（溶解期相互作用产物）。尽管对宿主防御入侵的病原体至关重要，但未解决的炎症可引起慢性炎症表型，在许多疾病状态中都可以观察到，如哮喘和动脉粥样硬化。事实上，脂肪素的生物合成在许多慢性炎症疾病中减少，通过合成脂肪素和溶解素恢复促溶解回路可以减少体内炎症。本研究的中心假设是，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，局部抗炎脂质介质可以促进oxLDL的清除，促进炎症的消退，减少动脉粥样硬化的发生。为了验证这一点，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溶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的产生（目的1）和巨噬细胞产生的促炎细胞因子和脂质介质（目的2）来评估，通过脂素和溶解素恢复这些途径是否会增强oxLDL的非炎症摄取（即在不产生促炎介质的情况下增加清除）。目的3将测试脂毒素和溶解素是否会减少血管炎症和动脉病变，将在apoe缺失小鼠中进行评估。我们将评估病变大小、形态、炎症脂质介质和细胞因子产生的变化。总的来说，这些研究的结果旨在更好地理解动脉粥样硬化中炎症不解决的机制。阐明内源性抗炎和促溶解脂质介质的作用和功能可以为开发治疗动脉粥样硬化的新治疗干预措施和方法奠定基础。

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.