Testing Fish Oil Derivatives in Healing of Chronic Venous Leg Ulcers

描述（由申请人提供）：慢性静脉性腿部溃疡（CVLU）由于其高患病率和复发率造成了重大的健康和经济负担。需要创新的方法来改善CVLU的治疗，因为目前涉及局部治疗的策略往往无效。CVLU的发病机制涉及大量活化的多形核白细胞（PMN）分泌过量的蛋白酶，导致组织损伤和伤口床的持续炎症。新出现的证据表明，鱼油的生物活性成分长链omega-3 （n-3）二十碳五烯（EPA）和二十二碳六烯（DHA）多不饱和脂肪酸（PUFA）的代谢会产生脂质介质，如溶解蛋白和保护蛋白，它们对PMN的招募和活性具有反调节作用。在炎性疾病的动物模型中，这些脂质介质抑制PMN向炎症部位的迁移，并减少参与招募和激活PMN的促炎细胞因子的细胞合成和分泌。然而，目前还没有研究检查EPA+ dha衍生的脂质介质对与CVLU持续炎症相关的PMN的影响。此外，在美国，n-3 EPA/DHA的膳食摄入量远低于推荐水平，大部分EPA/DHA的人体储存都来自饮食。基于这些发现，我们的组织假设是口服补充EPA+DHA摄入将促进CVLU的愈合。本R21的目的是通过对CVLU患者的双盲随机实验设计来检验这一组织假设的三个基本推论，随机分为两组：(I) 56天口服补充2.5 g/d的EPA + 0.5 g/d的DHA， （II） 56天补充载体（矿物油）。组织假说的推论是：1)与对照组相比，EPA+DHA补充组在28和56 d时CVLU创面液中EPA+DHA衍生的脂质介质水平较高，促炎细胞因子（IL-12、IL-6和TNF1）水平较低；2)与对照组相比，EPA+DHA添加组在28和56 d时CVLU创面液中PMN计数和PMN衍生蛋白酶（基质金属蛋白酶-8和中性粒细胞弹性酶）水平较低；3) EPA+DHA添加组在28和56 d的再上皮化增加更大，且与伤口床PMN活性呈负相关。该实验的发现将通过增加我们对影响伤口愈合和PMN功能的EPA+ dha衍生的脂质介质的理解，影响CVLU患者的护理，并可能导致一种创新的、系统性的方法来增加对不愈合或复发性CVLU的治疗。如果我们组织假设的三个推论得到支持，将提出一项全面的临床试验，评估EPA+DHA补充对CVLU患者伤口愈合的细胞和分子机制的影响。

DESCRIPTION (provided by applicant): Chronic venous leg ulcers (CVLU) pose significant health and economic burdens due to their high prevalence and recurrence rates. Innovative approaches to improve the treatment of CVLU are needed because current strategies involving topical therapies are often ineffective. The pathogenesis of CVLU involves high numbers of activated polymorphonuclear leukocytes (PMN) that secrete excessive amounts of proteases that cause tissue damage and persistent inflammation in the wound bed. Emergent evidence indicates that metabolism of long- chain omega-3 (n-3) eicosapentaenoic (EPA) and docosahexaenoic (DHA) polyunsaturated fatty acids (PUFA), the bioactive components of fish oil, produce lipid mediators, such as resolvins and protectins, which have counter-regulatory effects on PMN recruitment and activity. In animal models of inflammatory disease, these lipid mediators inhibit PMN migration to inflamed sites and reduce cell synthesis and secretion of proinflammatory cytokines that are involved in recruiting and activating PMN. However, there have been no studies examining the effects of EPA+DHA-derived lipid mediators on PMN associated with the persistent inflammation in CVLU. Furthermore, n-3 EPA/DHA dietary intake in the U.S. is considerably lower than recommended and the majority of EPA/DHA body stores are obtained from the diet. Based on these findings, our organizing hypothesis is that oral supplementation of EPA+DHA intake will improve healing of CVLU. The purpose of this R21 is to test three fundamental corollaries of this organizing hypothesis in a double-blind, randomized, experimental design on CVLU patients, randomized to two groups: (I) 56 days of oral supplementation with 2.5 g/d of EPA + 0.5 g/d of DHA and (II) 56 days of supplementation with vehicle (mineral oil). The corollaries of the organizing hypothesis are that: 1) the EPA+DHA supplemented group will have higher levels of EPA+DHA-derived lipid mediators and lower levels of proinflammatory cytokines (IL-12, IL-6 and TNF1) in CVLU wound fluid at 28 and 56 days compared to the Control Group; 2) the EPA+DHA supplemented group will have lower counts of PMN and lower levels of PMN-derived proteases (matrix metalloproteinase-8 and neutrophil elastase) in CVLU wound fluid at 28 and 56 days compared to the Control Group; and 3) the EPA+DHA supplemented group will have greater increases in re-epithelialization at 28 and 56 days, which will be inversely related to PMN activity in the wound bed. The findings from the proposed experiments will impact the care of persons with CVLU by increasing our understanding of EPA+DHA-derived lipid mediators that influence wound healing and PMN function, and may lead to an innovative, systemic approach to augment the treatment of nonhealing or recurrent CVLU. If the three corollaries of our organizing hypothesis are supported, a full scale clinical trial evaluating the effects of EPA+DHA supplementation on cellular and molecular mechanisms of wound healing in CVLU patients will be proposed.