FISH OIL ON LUNG AND SYSTEMIC INFLAMMATION IN PATIENTS WITH ACUTE LUNG INJURY

鱼油对急性肺损伤患者肺部和全身炎症的影响

• 批准号: 7720879
• 负责人: Renee D Stapleton
• 金额: $ 23.57万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7720879
• 关键词: Acids; Acute Lung Injury; Adhesions; Adult Respiratory Distress Syndrome; Alveolar; Animals; Antioxidants; Arachidonate 5-Lipoxygenase; Arachidonic Acids; Attenuated; Biochemical; Bronchoconstriction; Capillary Permeability; Carbohydrates; Carotene; Cell membrane; Chronic; Clinical; Computer Retrieval of Information on Scientific Projects Database; Control Groups; Corn Oil; Count; County; Critical Illness; Data; Diet; Dinoprostone; Eicosanoids; Eicosapentaenoic Acid; Endopeptidases; Endotoxins; Enteral; Enteral Feeding; Environmental air flow; Family suidae; Fatty acid glycerol esters; Fever; Fish Oils; Funding; Grant; Human; Hypoxemia; IL8 gene; Immune; Incidence; Individual; Industry; Inflammation; Inflammatory; Injury; Institution; Interleukin-1; Interleukin-10; Interleukin-6; Intravenous; Length of Stay; Leukocytes; Leukotriene B4; Leukotrienes; Levocarnitine; Linoleic Acids; Lipids; Literature; Lung; Mechanical ventilation; Mediator of activation protein; Membrane; Metabolism; Modeling; Morbidity - disease rate; Nutrient; Organ failure; Outcome; Oxidants; Patients; Peptide Hydrolases; Persons; Phase; Phase II Clinical Trials; Phospholipids; Physiological; Placebos; Platelet aggregation; Play; Production; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Publishing; Pulmonary Edema; Rattus; Research; Research Personnel; Resources; Respiratory Failure; Rodent Model; Role; Sepsis; Series; Source; Supplementation; Sus scrofa; Taurine; Therapeutic; Thinking; Thromboxanes; United States National Institutes of Health; Vascular Permeabilities; Vasodilation; Vasodilation disorder; Vitamin E; borage oil; concept; cyclooxygenase 1; cyclooxygenase 2; cytokine; feeding; improved; lung injury; macrophage; mortality; neutrophil; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. ALI and the acute respiratory distress syndrome (ARDS) are common and severe complications of pulmonary or systemic injury, resulting in hypoxemic respiratory failure. The recent King County Lung Injury Project found the incidence to be 79 cases/100,000 person-years, exceeding most previous estimates.1 ALI is a major cause of morbidity and mortality and further research aimed at reducing these consequences is needed. The devastating clinical manifestations of ALI are thought to result from massive activation of the proinflammatory response.2, 3 Activated macrophages release cytokines such as IL-1, IL-6, IL-8, IL-10, and TNF-¿, which in turn activate neutrophils locally. The activated neutrophils then produce proteases, oxidants, and lipid-derived mediators including eicosanoids, which perpetuate the lung injury cycle.4 The eicosanoid inflammatory mediators are derived from arachidonic acid (AA), a common membrane phospholipids in the usual Western diet.5, 6 When the inflammatory cascade is activated, AA is metabolized by cyclooxygenase (COX) to the 2-series prostaglandins (PGs) and thromboxanes (TXs) and by 5-lipoxygenase (LOX) to the 4-series leukotrienes (LTs). These pro-inflammatory eicosanoids play a prominent role in fever, vascular permeability, vasodilatation, platelet aggregation, leukocyte adhesion, bronchoconstriction, and production of other cytokines.7-11 Eicosapentaenoic acid (EPA) and docosahexanoic acid (DHA) are two essential n-3 FAs found in fish oil. When consumed, n-3 FAs are incorporated into immune cell membranes,12, 13 replacing AA.6 By restricting the amount of substrate AA, the formation of eicosanoids is limited.9 EPA also acts to inhibit metabolism of AA by COX.14 Additionally, EPA is a substrate for COX and 5-LOX and is metabolized to the 3-series PGs and TXs and the 5-series LTs, which are significantly less active than those derived from AA.15, 16 EPA and DHA have been shown in animal studies to decrease production of AA-derived eicosanoids.17, 18 EPA and DHA improved survival in rats receiving an infectious challenge19 and in rodent models of endotoxin-induced shock20 and chronic sepsis.21 EPA attenuated pulmonary edema in a pig ALI model.22 EPA and DHA have been combined with ¿-linoleic acid (GLA) and antioxidants (vitamins E and C, ¿-carotene, taurine, and L-carnitine) into a commercial high-fat low-carbohydrate enteral formula called Oxepa¿ (Ross Products). GLA is an n-6 FA found in borage oil that is metabolized to dihomo-¿-linoleic acid that is then converted to AA. Oxepa¿ has been evaluated in several industry-sponsored animal studies. It has been shown to decrease AA concentration in inflammatory cell membranes;23-28 reduce alveolar concentrations of LTB4, PGE2, and TXB2;24, 25 decrease pulmonary capillary permeability;24 and reduce alveolar neutrophil accumulation25 in endotoxemic rats. The only studies of n-3 FAs in critically ill humans have used Oxepa¿. Three small phase II trials have been performed in patients with ALI and sepsis.29-31 The control groups in all 3 trials were given Pulmocare¿ (Ross Products), a high-fat low-carbohydrate enteral formula that is isonitrogenous with Oxepa¿ but does not contain fish oil. Each study found positive physiological, biochemical, and clinical outcomes in the Oxepa¿ group, including improved oxygenation, decreased BALF neutrophil count, reduced BALF IL-8 and LTB4, decreased duration of mechanical ventilation, decreased ICU length of stay, and fewer new organ failures. One study found a mortality benefit with Oxepa¿.31 Interpretation of these data is restricted by two important limitations: 1) the control groups were fed a formula containing high amounts of corn oil, which is largely composed of linoleic acid (n-6 FA) and may be proinflammatory since it could increase concentrations of AA and 2) the independent effects of n-3 FAs on inflammatory, physiologic, and clinical outcomes in ALI patients are impossible to assess. Furthermore, the investigational approach of combining several nutrients into a commercial enteral formula for critically ill patients leads to two important problems: 1) the scientific "proof of concept" for each nutrient is poor, with no phase I and II human trials being published on the individual agents and 2) patients may not receive adequate amounts of the nutrient since delivery is dependent upon enteral feeding (ICU patients commonly receive 60% of their prescribed caloric need).32 Even with these limitations, I believe the therapeutic benefits of Oxepa¿ most likely result from EPA+DHA rather than GLA or antioxidants, although a positive interaction between the nutrients cannot be ruled out. Antioxidants likely have only minimal, if any, contribution because the existing literature does not support a large clinical benefit with antioxidant supplementation.33 Additionally, two large RCTs of intravenous PGE1, which is increased by GLA,34, 35 in ALI patients have found no improvement in survival, duration of ventilation, or length of stay.36, 37 To answer the question of whether or not EPA and DHA have an independent therapeutic benefit in patients with ALI, we are conducting a phase II RCT of enteral fish oil versus placebo.

该副本是使用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这是调查员的机构。 ALI和急性呼吸窘迫综合征（ARDS）是常见和严重的肺部或全身性损伤并发症，导致缺氧性呼吸衰竭。最近的金县肺损伤项目发现，这一事件为79例/100,000例，超过了以前的大多数估计。1ALI是发病率和死亡率的主要原因，需要进一步的研究旨在减少这些后果。 ALI的毁灭性临床表现被认为是由于促炎反应的大量激活而引起的。2，3活化的巨噬细胞释放了诸如IL-1，IL-6，IL-8，IL-8，IL-10和TNF-¿等细胞因子，而tnf-¿然后，活化的嗜中性粒细胞产生蛋白酶，氧化物和脂质衍生的介质，包括eicosanoids，这些介质会使肺损伤循环永存。4类eicosanoid炎症介质介质源自芳族酸（AA），源自弧菌磷酸化的（AA），一种常见的西部饮食中的普通膜磷脂。环氧合酶（COX）到2系列前列腺素（PGS）和血栓烷（TXS）以及5-脂氧合酶（LOX）到4系列白细胞（LTS）。这些促炎性类花生酸在发烧，血管渗透性，血管舒张，血小板聚集，白细胞粘附，支气管收缩和其他细胞因子的产生中起着重要作用。7-11 eicosapentaenoic酸（EPA）和二十二烷酰己酸（DHA）是鱼油中发现的两个必不可少的N-3 Fas。 When consumed, n-3 FAs are incorporated into immunocell membranes,12, 13 replacing AA.6 By restricting the amount of substrate AA, the formation of eicosanoids is limited.9 EPA also acts to inhibit metabolism of AA by COX.14 Additionally, EPA is a substrate for COX and 5-LOX and is metabolized to the 3-series PGs and TXs和5系LT，其活性明显低于AA.15，16 EPA和DHA在动物研究中已显示以减少AA衍生的eicosanoid的产生。17、18 EPA和DHA改善了接受感染性挑战的大鼠的生存率19，以及内毒素诱导的休克20和慢性SEPSIS的啮齿动物模型。21 EPA和DHA已与 - 氯酸（GLA）和抗氧化剂（维生素E和C， - 氯烷，牛磺酸和L-肉碱）结合使用，称为商业高脂低脂肠道肠源性，称为OXEPA。（ROSS产品）。 GLA是在泻湖油中发现的N-6 FA，被代谢为二二烯酸 - 然后转化为AA。 Oxepa¿在几项行业赞助的动物研究中已经评估过它。已显示它可以降低炎症细胞膜中的AA浓度； 23-28降低了LTB4，PGE2和TXB2; 24，24，25降低肺毛细血管通透性； 24; 24并降低肺泡嗜中性粒细胞在内毒素大鼠中25 在重病人类中，N-3 FAS的唯一研究使用了Oxepa¿。在患有ALI和败血症患者的患者中，已经进行了三项小型II期试验。29-31所有3个试验中的对照组均给对照组（ROSS产品）（ROSS产品），这是一种高脂肪的低脂肠内配方，该配方属于oxepa®，但不含鱼油。每项研究都发现Oxepa¿组的生理，生化和临床结果呈阳性，包括改善氧合，改善BALF中性粒细胞计数，减少BALF IL-8和LTB4，改善机械通气的持续时间，改善ICU住院时间，以及更少的新器官失败。一项研究发现OXEPA¿.31具有死亡率。 Interpretation of these data is restricted by two important limitations: 1) the control groups were fed a formula containing high amounts of corn oil, which is largely composed of linoleic acid (n-6 FA) and may be proinflammatory since it could increase concentrations of AA and 2) the independent effects of n-3 FAs on inflammatory, physiological, and clinical outcomes in ALI patients are impossible to assess.此外，将几种营养物相结合到危重患者的商业肠道室内公式的研究方法导致了两个重要问题：1）每种营养素的科学“概念证明”很差，没有I和II期的人类试验在单个药物上发表，并且患者可能无法获得依赖性的患者的适当需求（cal cal）（ICU）（ICU）（ICU）。 即使有这些局限性，我认为Oxepa¿的治疗益处很可能是由EPA+DHA而不是GLA或抗氧化剂引起的，尽管不能排除营养素之间的积极相互作用。抗氧化剂的贡献可能很小，因为现有文献不支持补充抗氧化剂的临床益处。33此外，两个大的静脉内PGE1大型RCT被GLA，GLA，34，35在Ali患者中没有发现，在Ali的患者中没有发现任何改善，或者没有改善。 为了回答EPA和DHA是否对ALI患者具有独立的治疗益处的问题，我们正在进行II期肠道鱼油与安慰剂的II期RCT。