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

这项拟议的研究针对的是国家老龄研究所的一项使命-发展理解和 改善老化过程中慢性伤口的健康状况。拟议项目的目标是增强 了解慢性静脉性小腿溃疡(CVLU)，并提供循证指导治疗 CVLU，在老年人中造成大量发病率、残疾、住院甚至死亡的伤口 成年人。CVLU需要新的治疗方法，因为标准的局部治疗往往无效或有效 只能在短期内治愈。与PA-16-230一致，老化中的不可愈合溃烂伤口，该项目的 跨学科团队计划测试一种含有鱼油生物活性成分的口服营养疗法，以 促进愈合，防止CVLU复发。CVLU的病理生物学涉及静脉高压和高 静脉循环中活化的中性粒细胞数量与溃疡 微环境，在那里它们分泌过多的蛋白酶，使溃疡长期发炎。 来自该团队以前工作的收集数据支持组织假设，增加摄入 二十碳五烯酸(EPA)和二十二碳六烯酸(DHA)口服补充可加速CVLU 通过提高EPA+DHA衍生的脂质介质水平和降低血浆中的 促炎症细胞因子，从而在系统和溃疡微环境中减少PMN的激活。这个 集体结果也有望缓解CVLU相关的疼痛并提高生活质量(QOL)。这个 随机、双盲研究建议纳入248名连续符合条件的60岁≥CVLU成年人 他们继续在两所大学的创伤门诊接受标准护理。参与者将被随机分配 2组：每日口服EPA+DHA(2.5g/d EPA+0.5g/d DHA)12周或每日口服 用安慰剂。在0、4、8和12周，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； 苏巴伊姆1a。比较血液中性粒细胞炎性细胞因子基因的表达；目的2.比较中性粒细胞 血液和CVLU液中的活化以及CVLU液中PMN衍生的蛋白水解酶水平；目的3.比较还原 在伤口区域，控制已知的影响愈合的因素，并确定与脂质介质的关系， 细胞因子与中性粒细胞活化。苏巴伊姆3a。比较CVLU复发频率和研究变量水平 在EPA+DHA组中治愈的CVLU的两个亚型之间的血液中(在额外的3个月后 超过12周的EPA+DHA治疗与安慰剂治疗相比)。苏巴伊姆3b。比较一下疼痛的症状 两组和两个亚组在第一个和最后一个时间点的时间点和生活质量。调查结果在意料之中 目的：引导一种新的低风险辅助口服疗法，以靶向和减少CVLU患者中性粒细胞的过度激活。 因此，这种疗法有望促进老年CVLU的愈合，阻止复发，改善生活质量。

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.