Impact of Omega-3 Fatty Acid Oral Therapy on Healing of Chronic Venous Leg Ulcers in Older Adults

这项拟议中的研究提出了国家老龄化研究所的一项使命--加深对老龄化的理解， 改善衰老中慢性伤口的健康结果。拟议项目的目标是加强 慢性下肢静脉溃疡（CVLU）的知识，并提供循证治疗指南， CVLU是导致老年人大量发病、残疾、住院甚至死亡的伤口。 成年人了CVLU需要新的治疗方法，因为标准的局部治疗通常无效或产生 只是短期的治愈。与PA-16-230一致，老化中的不愈合溃疡伤口，该项目的 一个跨学科小组计划测试一种含有鱼油生物活性成分的口服营养疗法， 刺激愈合并防止CVLU复发。CVLU病理学涉及静脉高血压和高血压。 静脉循环和溃疡中活化的多形核白细胞（PMN）数量 微环境，在那里它们分泌过量的蛋白酶，使溃疡慢性发炎。 来自该团队先前工作的集体数据支持组织假设，即增加摄入量 口服补充二十碳五烯酸（EPA）和二十二碳六烯酸（DHA）将加速CVLU 通过提高EPA+ DHA衍生的脂质介质的水平和降低 促炎细胞因子，从而减少全身和溃疡微环境中的PMN活化。的 预期集体结局也可缓解CVLU相关疼痛并改善生活质量（QoL）。的 一项随机、双盲研究拟纳入248例连续合格的≥ 60岁CVLU成人 他们继续在两间大学伤口门诊诊所接受标准护理。受试者将被随机分配 分为2组：12周的每日口服EPA+DHA治疗（2.5 g/d EPA + 0.5 g/d DHA）或每日口服治疗 安慰剂。在0、4、8和12周时，在两组中，团队将追求三个具体目标：目标1。 比较血液和CVLU液中EPA+ DHA衍生的脂质介质和炎性细胞因子的水平; Subaim 1a.目的2.比较血液中中性粒细胞炎症因子基因的表达。比较PMN 血液和CVLU流体中的活化，以及CVLU流体中的PMN衍生的蛋白酶水平;目的3.比较约简 在伤口区域，控制已知影响愈合的因素，并确定与脂质介质的关系， 细胞因子和PMN活化。Subaim 3a.比较CVLU复发频率和研究变量水平 在EPA+DHA组中具有治愈CVLU的2个亚组之间的血液中（在另外3个月的治疗后）， EPA+DHA治疗与安慰剂治疗超过12周）。Subaim 3b.比较疼痛的症状 2组和2个亚组的第一个和最后一个时间点的QoL。调查结果预计 导致一种新的低风险辅助口服治疗，以靶向和减少CVLU患者的过度PMN激活。 因此，预期该疗法可刺激CVLU在衰老中的愈合，阻止复发并改善QoL。

The proposed research addresses a mission of the National Institute on Aging – to develop understanding and improve health outcomes of chronic wounds in aging. The goals of the proposed project are to enhance knowledge of chronic venous leg ulcers (CVLUs) and provide evidence-based guidance in the treatment of CVLUs, wounds that cause substantial morbidity, disability, hospitalization, and even mortality among older adults. New therapies for CVLUs are needed because standard topical therapies are often ineffective or yield only short-term healing. Congruent with PA-16-230, Non-healing Ulcerative Wounds in Aging, the project’s interdisciplinary team plans to test an oral nutrient therapy containing the bioactive elements of fish oil to stimulate healing and prevent recurrence of CVLUs. CVLU pathobiology involves venous hypertension and high numbers of activated polymorphonuclear leukocytes (PMNs) in venous circulation and the ulcer microenvironment, where they secrete excessive amounts of proteases that keep ulcers chronically inflamed. Collective data from the team’s previous work support the organizing hypothesis that increasing intake of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) with oral supplementation will expedite CVLU healing and prevent recurrence by raising levels of EPA+DHA-derived lipid mediators and lowering levels of proinflammatory cytokines, thereby reducing PMN activation systemically and in ulcer microenvironments. The collective outcomes are also expected to relieve CVLU-related pain and improve quality of life (QoL). The randomized, double-blind study proposes to include 248 successive eligible adults ≥ 60 years of age with CVLUs who continue to receive standard care at two university out-patient wound clinics. Participants will be randomized to 2 groups: 12 weeks of daily oral therapy with EPA+DHA (2.5 g/d of EPA + 0.5 g/d of DHA) or daily oral therapy with placebo. At 0, 4, 8 and 12 weeks, across the 2 groups, the team will pursue three specific aims: Aim 1. Compare levels of EPA+DHA-derived lipid mediators, and inflammatory cytokines in blood and CVLU fluid; Subaim 1a. Compare inflammatory cytokine gene expression by PMNs in blood; Aim 2. Compare PMN activation in blood and CVLU fluid, and PMN-derived protease levels in CVLU fluid; Aim 3. Compare reduction in wound area, controlling for factors known to affect healing, and determine relationships with lipid mediators, cytokines and PMN activation. Subaim 3a. Compare frequency of CVLU recurrence and levels of study variables in blood between 2 subgroups within the EPA+DHA group with healed CVLUs (after 3 additional months of EPA+DHA therapy versus placebo therapy beyond Week 12). Subaim 3b. Compare the symptom of pain at all time points and QoL at first and last time points across the 2 groups and 2 subgroups. The findings are expected to lead to a new low-risk adjunct oral therapy to target and reduce excessive PMN activation in CVLU patients. As such, the therapy is expected to stimulate healing of CVLUs in aging, deter recurrence and improve QoL.