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

描述(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，但新发现的证据表明，最近发现的内源性抗炎分子可能对适当的控制和保护免受伤害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(MEFAs)的单环氧化物对于减少损伤引起的炎症反应至关重要，包括在心脏中。虽然在动物疾病模型中有很有希望的证据，但MEFAs在人类中的新陈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在人类急性损伤/炎症模型(即心脏手术)中评估血浆MEFAs与循环和尿促炎症介质的关系。这项工作代表了对离散和适时组织损伤的人体模型的高度创新的使用，以阐明MEFAs在人类中的生物学作用和相关性。这是通过将我们的拟议研究嵌套在Omega-3脂肪酸预防术后心房颤动(OPERA)试验中实现的，该试验是一项针对1516名心脏手术患者的随机、双盲、安慰剂对照试验，旨在测试围手术期口服鱼油对包括促炎生物标志物在内的生物终点和包括术后心房颤动(POAF)在内的临床终点的影响。这项研究现有资金用于受试者登记、样本收集/存储以及这些终点的确定/测量。虽然MEFAs是鱼油衍生的脂肪酸的代谢物，但饮食中的鱼油对MEFAs在人类急性损伤/炎症反应中的影响尚不清楚。通过将这项生物学研究嵌套在OPERA(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对MEFAs损伤/炎症反应的无偏见影响。这些结果将对了解膳食脂肪酸如何影响MEFAs的反应具有巨大的意义，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，我们将能够免费评估MEFAs的反应与这一临床相关结果的潜在相关性，这是心脏手术的常见和严重并发症。我们将通过测量OPERA中随机选择的一组患者(n=800)的血浆MEFAs及其代谢物水平，然后评估MEFAs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MEFAs反应的影响；以及MEFAs水平与POAF的关系，来执行这项新颖的工作。

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.