Testing Fish Oil Derivatives in Healing of Chronic Venous Leg Ulcers

描述（由申请方提供）：慢性下肢静脉溃疡（CVLU）由于其高患病率和复发率而造成显著的健康和经济负担。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通常无效。CVLU的发病机制涉及大量活化的多形核白细胞（PMN），其分泌过量的蛋白酶，导致伤口床中的组织损伤和持续性炎症。新出现的证据表明，长链ω-3（n-3）二十碳五烯酸（EPA）和二十二碳六烯酸（DHA）多不饱和脂肪酸（PUFA）（鱼油的生物活性组分）的代谢产生脂质介质，例如消退素和保护素，其对PMN募集和活性具有反调节作用。在炎症性疾病的动物模型中，这些脂质介质抑制PMN迁移到发炎部位，并减少细胞合成和分泌参与招募和激活PMN的促炎细胞因子。然而，还没有研究检查EPA+ DHA衍生的脂质介质对与CVLU中持续性炎症相关的PMN的影响。此外，美国的n-3 EPA/DHA膳食摄入量大大低于推荐摄入量，并且大部分EPA/DHA身体储备都是从饮食中获得的。基于这些发现，我们的组织假设是，口服补充EPA+DHA摄入量将改善CVLU的愈合。本R21的目的是在双盲、随机、实验设计中对CVLU患者测试该组织假设的三个基本推论，CVLU患者被随机分为两组：（I）56天口服补充2.5 g/d EPA + 0.5 g/d DHA和（II）56天补充媒介物（矿物油）。组织假说的推论是：1）补充EPA+DHA的组将具有较高水平的EPA+ DHA衍生的脂质介质和较低水平的促炎细胞因子与对照组相比，在28和56天时CVLU伤口液中的IL-12、IL-6和TNF 1; 2）补充EPA+DHA的组将具有较低的PMN计数和较低水平的PMN衍生的蛋白酶（基质金属蛋白酶-8和中性粒细胞弹性蛋白酶）在28和56天时与对照组相比的CVLU伤口液中的含量;和3）补充EPA+DHA的组在28天和56天时将具有更大的上皮再形成增加，这将与伤口床中的PMN活性负相关。拟议实验的结果将通过增加我们对影响伤口愈合和PMN功能的EPA+ DHA衍生脂质介质的理解来影响CVLU患者的护理，并可能导致一种创新的系统性方法来加强对不愈合或复发性CVLU的治疗。如果我们的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补充剂对CVLU患者伤口愈合的细胞和分子机制的影响。 公共卫生相关性：拟议的R21研究将研究口服补充EPA+DHA（鱼油的生物活性成分）如何影响人类慢性下肢静脉溃疡（CVLU）的愈合。这项研究的发现将增加我们对慢性伤口愈合的理解，以及EPA+ DHA衍生的炎症介质如何减少阻止伤口愈合的过度，长期炎症。研究结果将提供关于使用EPA+DHA补充剂作为CVLU患者辅助治疗的实用性的新科学信息。

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. PUBLIC HEALTH RELEVANCE: The proposed R21 study will examine how oral supplementation with EPA+DHA, the bioactive components of fish oil, affects healing of chronic venous leg ulcers (CVLU) in humans. The findings from this research study will increase our understanding of chronic wound healing and how EPA+DHA-derived inflammatory mediators may reduce the excessive, prolonged inflammation that prevents wound healing. The results will provide new scientific information regarding the utility of using EPA+DHA supplementation as an adjunct treatment for patients with CVLU.