Targeting the Active Resolution of Inflammation for Cardiovascular Disease Prevention

项目摘要 炎症对于宿主防御反应至关重要，但不受调节的炎症是宿主防御反应的关键因素。 动脉粥样硬化血栓形成，并将斑块起始与随后的生长和急性破裂联系起来，导致临床 心血管（CVD）事件。炎症抑制的临床试验显着减少了心血管疾病事件， 证实了炎症-CVD假说，并刺激了对炎症的兴趣， CVD预防这种疗法可能具有广泛的影响，因为临床上的残余炎症风险 这种做法很普遍，而且治疗不足。重要的是，最近的证据表明， 炎症不是一个被动的过程，而是发生在一个涉及化学物质的主动协调过程中。 称为特化促消退介质（SPMs）的介质，包括消退素、maresins、脂氧素， 保护素（神经保护素）和阿司匹林触发的促消退介质，每一种都具有特征性的生物学特性， 行动然而，知识上的一个主要差距是哪些特定的SPM或SPM组可能具有心脏保护作用， 人类种群。受我们令人兴奋的初步发现的启发，某些SPM的血浆水平是 与CVD风险和炎症特征相关，并响应NHLBI NOT-ES-20-018：促进 炎症消退的基础和应用研究为了确定SPM在CVD中的作用，我们 我建议检验这一假设，即特定的SPM是CVD保护的早期指标， 炎症并随着时间的推移与其消退相关。这一具有成本效益的提案利用了 来自三个良好的表型和基因型前瞻性研究的资源。我们将调查一个广泛的小组 使用高通量质谱分析法测定循环血浆SPM和促炎介质 与CVD事件（共2339例病例）相关，包括在一个子集中随时间重复测量。我们的首要 目的是：1）在初级和二级预防中评估SPM与未来CVD事件的关联 慢性炎症人群，并评估随机阿司匹林治疗的效果调整 与安慰剂相比，因为阿司匹林对SPM生物合成具有重要的促消退作用; 具有CVD风险因子和下游生物标志物以及全身炎症的细胞因子的循环SPM; 并对循环SPM进行全基因组关联研究，以更好地了解 对SPM功能的机械见解;以及3）评估SPM随时间的时间变化， 下游促炎生物标志物和细胞因子水平的伴随变化，并检查 用随机低剂量甲氨蝶呤与安慰剂调节SPM。我们将检查的功能动作 使用离体白细胞试验检测炎症基因表达的相关CVD相关SPM， 巨噬细胞促分解功能。本提案的结果将确定和验证解决调解人 以及可能在心脏保护中发挥关键作用的途径， 因为残余的炎症风险是常见的，并且用当前的治疗方法仍然治疗不足。

PROJECT SUMMARY Inflammation is crucial for the host defense response, but unregulated inflammation is a key element of atherothrombosis and links plaque initiation to subsequent growth and acute rupture, leading to clinical cardiovascular (CVD) events. Clinical trials of inflammation inhibition have significantly reduced CVD events, confirmed the inflammation-CVD hypothesis, and stimulated interest in targeting inflammation specifically for CVD prevention. Such therapies could have widespread impact, since residual inflammatory risk in clinical practice is common and undertreated. Importantly, recent evidence demonstrates that the resolution of inflammation is not a passive process but occurs in an active coordinated process involving chemical mediators called specialized pro-resolving mediators (SPMs) that include resolvins, maresins, lipoxins, protectins (neuroprotectins), and aspirin-triggered pro-resolving mediators, each with characteristic biological actions. Yet a major gap in knowledge is which specific SPMs or sets of SPMs may be cardioprotective in human populations. Motivated by our exciting preliminary findings that plasma levels of certain SPMs are related to CVD risk and inflammatory traits, and in response to NHLBI NOT-ES-20-018: Promoting Fundamental and Applied Research in Inflammation Resolution to identify the role of SPMs in CVD, we propose to test the hypothesis that specific SPMs are early indicators of CVD protection from inflammation and are associated with its resolution over time. This cost-efficient proposal leverages resources from three well-phenotyped and genotyped prospective studies. We will examine an extensive panel of circulating plasma SPMs and proinflammatory mediators using a high-throughput mass spectrometry assay in relation to incident CVD (total 2339 cases) including repeated measures over time in a subset. Our primary aims are to: 1) Evaluate associations of SPMs with future CVD events in primary and secondary prevention populations enriched with chronic inflammation, and assess effect modification by randomized aspirin therapy vs placebo since aspirin has important pro-resolving effects on SPM biosynthesis; 2) Examine associations of circulating SPMs with CVD risk factors and downstream biomarkers and cytokines of systemic inflammation; and perform genome-wide association study of circulating SPMs, to better understand biological pathways for mechanistic insights into SPM functions; and 3) Assess temporal changes in SPMs over time in relation to concomitant changes in levels of downstream proinflammatory biomarkers and cytokines, and examine modulation of SPMs with randomized low-dose methotrexate vs placebo. We will examine functional actions of the relevant CVD-associated SPMs using ex vivo leukocyte assays for inflammatory gene expression and macrophage pro-resolving function. Results from this proposal will identify and validate resolution mediators and pathways that may play a pivotal role in cardioprotection and could have important public health significance since residual inflammatory risk is common and remains undertreated with current therapeutics.