Endogenous Anti-Inflammatory Lipid Mediators, Fish Oil and Post-Operative Atrial

描述（由申请人提供）：尽管炎症与包括心血管系统在内的几种慢性疾病的发展有关，但新出现的证据表明，最近发现的内源性抗炎分子可能对适当控制和保护免受损伤和过度炎症至关重要。体外和动物研究表明，来自长链多不饱和脂肪酸（MEFA）的单环氧化合物对于减少对损伤的炎症反应至关重要，包括心脏。虽然在动物疾病模型中有很有希望的证据，但MEFA在人类中的代谢和抗炎功能在很大程度上仍未被探索。这项拟议的工作将首次评估血浆MEFA与急性损伤/炎症（即心脏手术）人体模型中循环和尿液促炎介质的关系。这项工作代表了离散和适时组织损伤的人类模型的高度创新性使用，以阐明MEFA在人类中的生物学作用和相关性。这是通过将我们提出的研究嵌套在用于预防术后房颤（OPERA）试验中而实现的，OPERA试验是一项在1516名心脏手术患者中进行的随机、双盲、安慰剂对照试验，以测试围手术期口服鱼油对生物终点（包括促炎生物标志物）和临床终点（包括术后房颤（POAF））的影响。本研究现有资金用于受试者入组、样本采集/储存和这些终点的确定/测量。虽然MEFA是鱼油衍生脂肪酸的代谢产物，但膳食鱼油对MEFA对人类急性损伤/炎症反应的影响尚不清楚。通过将这项生物学研究嵌套在OPERA（一项现有的鱼油随机对照试验）中，我们将能够直接评估口服鱼油摄入对MEFA对损伤/炎症反应的无偏影响。这些结果将对理解膳食脂肪酸如何影响MEFAs反应具有巨大意义，并代表了这项工作的第二个高度创新的方面。最后，考虑到OPERA对POAF的关注，我们将能够在不增加成本的情况下评估MEFA对这种临床相关结局（心脏手术的常见和严重并发症）的反应的潜在相关性。我们将通过测量OPERA中随机选择的患者亚组（n=800）的MEFA及其代谢物的血浆水平，然后评估MEFA水平与炎症生物标志物的相互关系;口服鱼油治疗与安慰剂对这些MEFA反应的影响;以及MEFA水平与POAF的关系来进行这项新工作。 公共卫生相关性：这项研究将提高我们对人类抗炎MEFA和促炎介质之间可能的相互关系的理解;评估口服鱼油摄入对MEFAs对损伤/炎症反应的无偏影响，以及MEFAs对术后房颤反应的潜在相关性，房颤是心脏手术的常见和严重并发症。因此，这些结果可能有助于为MEFAs在人类健康中的可能作用提供初步的新见解，并可能指导未来针对MEFAs途径的治疗策略。

DESCRIPTION (provided by applicant): Although inflammation has been linked to development of several chronic diseases, including of the cardiovascular system, emerging evidence suggests that recently identified endogenous anti-inflammatory molecules may be critical for appropriate control and protection against injury and excessive inflammation. In vitro and animal studies suggest that Mono-Epoxides derived from long-chain polyunsaturated Fatty Acids (MEFAs) are crucial for reducing inflammatory responses to injury, including in the heart. While there is promising evidence in animal disease models, the metabolism and anti-inflammatory function of MEFAs in humans remain largely unexplored. This proposed work will evaluate for the first time the relationships of plasma MEFAs with circulating and urine pro-inflammatory mediators in a human model of acute injury/inflammation, i.e. cardiac surgery. This work represents a highly innovative use of a human model of discrete and well-timed tissue injury to elucidate the biologic roles and relevance of MEFAs in humans. This is made possible by nesting our proposed study in the Omega-3 Fatty Acids for Prevention of Post-Operative Atrial Fibrillation (OPERA) Trial, a randomized, double-blind, placebo controlled trial among 1516 cardiac surgery patients to test the effects of peri-operative oral fish oil on both biologic endpoints, including pro- inflammatory biomarkers, and clinical endpoints including post-operative atrial fibrillation (POAF). The study has existing funding for subject enrollment, sample collection/storage, and ascertainment/measurement of these endpoints. Although MEFAs are metabolites of fish-oil-derived fatty acids, the impact of dietary fish oil on MEFAs response to acute injury/inflammation in humans is unknown. By nesting this biologic research within OPERA, an existing randomized controlled trial of fish oil, we will be able to directly evaluate the unbiased effects of oral fish oil intake on MEFAs response to injury/inflammation. These results will have tremendous significance for understanding how dietary fatty acids affect MEFAs response, and represent a second highly innovative aspect of this work. Finally, given the focus of OPERA on POAF, we will be able to evaluate at no additional cost the potential relevance of MEFAs response to this clinically relevant outcome, a common and serious complication of cardiac surgery. We will perform this novel work by measuring plasma levels of MEFAs and their metabolites in a randomly selected subset of patients (n=800) in OPERA, and then assessing the interrelationships of MEFAs level with biomarkers of inflammation; the effects of oral fish oil treatment, vs. placebo, on these MEFAs response; and the relationship of MEFAs levels with POAF. PUBLIC HEALTH RELEVANCE: This study will improve our understanding in humans of the possible inter-relation between anti- inflammatory MEFAs and pro-inflammatory mediators; evaluate the unbiased effects of oral fish oil intake on MEFAs response to injury/inflammation, and the potential relevance of MEFAs response to post-operative atrial fibrillation, a common and serious complication of cardiac surgery Thus, the results may help to provide initial novel insights into MEFAs possible role in human health and potentially guide future therapeutic strategies targeting the MEFAs pathway.