Testing Fish Oil Derivatives in Healing of Chronic Venous Leg Ulcers

测试鱼油衍生物治疗慢性腿部静脉溃疡的效果

• 批准号: 8240219
• 负责人: Jodi Christine McDaniel
• 金额: $ 15.25万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8240219
• 关键词: Affect; Age; Albumins; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Beds; CD59 Antigen; Caring; Cell Culture Techniques; Cells; Chronic; Clinical; Clinical Trials; Control Groups; Diet; Dietary intake; Disease; Double-Blind Method; Economic Burden; Emotional; Epidemiologic Studies; Experimental Designs; Extracellular Matrix; Fish Oils; Growth Factor Receptors; Healed; Healthcare; High Prevalence; Human; Inflammation; Inflammation Mediators; Inflammatory; Intake; Interleukin-12; Interleukin-6; Intervention; Lead; Leg Ulcer; Leukocyte Elastase; Liquid substance; Metabolism; Mineral Oil; Molecular; Neutrophil Collagenase; Nutrient; Omega-3 Fatty Acids; Oral; Pathogenesis; Patient Care; Patients; Peptide Hydrolases; Persons; Polyunsaturated Fatty Acids; Population; Randomized; Recruitment Activity; Recurrence; Reporting; Resources; Science; Site; Supplementation; Testing; Time; Tissues; Treatment Cost; Venous; Vitamin A; White Blood Cell Count procedure; Wound Healing; Zinc; base; cytokine; efficacy testing; fatty acid metabolism; healing; health economics; improved; innovation; lipid mediator; migration; neutrophil; prevent; research study; wound

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.

描述（由申请人提供）：慢性静脉腿溃疡（CVLU）由于高患病率和复发率而造成了巨大的健康和经济负担。需要创新的方法来改善CVLU的治疗方法，因为当前涉及局部疗法的策略通常无效。 CVLU的发病机理涉及大量活化的多形核白细胞（PMN），这些白细胞（PMN）分泌过多的蛋白酶，这些蛋白酶在伤口床上造成组织损伤和持续的炎症。 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.在炎症性疾病的动物模型中，这些脂质介质抑制了PMN迁移到发炎的部位，并减少与募集和激活PMN有关的促炎细胞因子的细胞合成和分泌。但是，尚无研究研究EPA+DHA衍生的脂质介质对与CVLU持续性炎症相关的PMN的影响。此外，在美国，N-3 EPA/DHA饮食摄入量大大低于建议，并且大多数EPA/DHA体内商店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EPA+DHA摄入量将改善CVLU的愈合。该R21的目的是在CVLU患者的双盲，随机，实验性设计中测试该组织假设的三个基本推论，随机分为两组：（i）56天的口服补充剂，用2.5 g/d的EPA + 0.5 g/d的DHA和（II）56天的DHA和（II）56天（II）56天（II）补充了车辆（矿物油））。组织假设的基础是：1）与对照组相比，在28和56天，在28和56天，EPA+DHA补充组将具有更高水平的EPA+EPA+DHA组水平的较高水平的EPA+DHA组的CVLU伤口流体，将具有更高水平的EPA+DHA衍生的脂质介质和较低水平的促炎细胞因子（IL-11，IL-6和TNF1）； 2）与对照组相比，CVLU伤口液在CVLU伤口液中，EPA+DHA补充组的PMN计数较低，PMN衍生的蛋白酶（基质金属蛋白酶8和中性粒细胞弹性酶）的计数较低； 3）EPA+DHA补充组将在28和56天的重新上皮化增加，这将与伤口床中的PMN活性成反比。提出的实验的发现将通过增加对EPA+DHA衍生的脂质介质的理解来影响CVLU患者的护理，从而影响伤口愈合和PMN功能，并可能导致一种创新的，系统性的方法来增强对非治疗或复发性CVLU的治疗。如果支持我们组织假设的三个推论，则将提出一项全尺度临床试验，以评估EPA+DHA补充对CVLU患者伤口愈合的细胞和分子机制的影响。 公共卫生相关性：拟议的R21研究将研究鱼油的生物活性成分EPA+DHA如何影响人类慢性静脉腿溃疡（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过度，长时间的炎症，从而阻止伤口愈合。结果将提供有关使用EPA+DHA作为CVLU患者使用EPA+DHA作为辅助治疗的新科学信息。