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.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 ALI和急性呼吸窘迫综合征(ARDS)是常见的严重的肺部或全身损伤并发症，可导致低氧性呼吸衰竭。金县最近的肺损伤项目发现，发病率为79例/10万人年，超过了以前的大多数估计。1 ALI是发病率和死亡率的主要原因，需要进一步研究以减少这些后果。 ALI的破坏性临床表现被认为是由于促炎反应的大量激活所致。2、激活的巨噬细胞释放细胞因子，如IL-1、IL-6、IL-8、IL-10和TNF-β，这些细胞因子反过来又在局部激活中性粒细胞。被激活的中性粒细胞然后产生蛋白酶、氧化剂和脂类介质，包括二十烷基类化合物，使肺损伤循环永久化。4二十烷基类炎症介质来自花生四烯酸(AA)，这是通常西方饮食中常见的一种膜磷脂。5、6当炎症级联被激活时，AA被环氧合酶(COX)代谢成2系列前列腺素(PGs)和血栓烷(TXs)，并被5-脂氧合酶(LOX)代谢成4系列白三烯(LTs)。这些促炎二十烷类化合物在发热、血管通透性、血管扩张、血小板聚集、白细胞黏附、支气管收缩和其他细胞因子的产生方面发挥着突出的作用。 二十碳五烯酸(EPA)和二十二碳六烯酸(DHA)是鱼油中两种必需的n-3脂肪酸。当摄入时，n-3FA被结合到免疫细胞膜上，12，13取代AA.6通过限制底物AA的数量，类二十烷的形成受到限制。9 EPA还通过COX抑制AA的代谢。14此外，EPA是COX和5-LOX的底物，被代谢成3系列PGs和TXs以及5系列LT，它们的活性明显低于AA.15，16 EPA和DHA已经在动物研究中被证明可以减少AA衍生的二十烷类化合物的产生。17，18 EPA和DHA提高了接受感染性攻击的大鼠的存活率19以及内毒素诱导的休克和慢性脓毒症的啮齿动物模型20。21 EPA减轻猪ALI模型的肺水肿。 EPA和DHA与亚油酸(GLA)和抗氧化剂(维生素E和C、胡萝卜素、牛磺酸和L肉碱)结合在一起，形成了一种商业高脂肪低碳水化合物肠内配方，称为Oxepa？(Ross Products)。GLA是一种n-6脂肪酸，它存在于琉球藻油中，它被代谢成双高-亚油酸，然后再转化为AA。Oxepa已经在几项由行业赞助的动物研究中进行了评估。已证实能降低炎性细胞膜AA浓度；23-28降低肺泡LTB4、PGE2和TXB2浓度；24、25降低肺毛细血管通透性；24减少内毒素血症大鼠肺泡中性粒细胞聚集。 仅有的对危重病人中n-3脂肪酸的研究使用了Oxepa。已经在ALI和脓毒症患者中进行了三个小型II期试验。29-31在所有三个试验中的对照组服用Pulmocare？(Ross Products)，这是一种高脂肪低碳水化合物的肠内配方奶粉，与Oxepa等氮，但不含鱼油。每项研究都发现Oxepa组的生理、生化和临床结果是积极的，包括改善氧合，降低BALF中性粒细胞计数，降低BALF IL-8和LTB4，缩短机械通气时间，减少ICU住院时间，减少新的器官衰竭。一项研究发现服用Oxepa可降低死亡率。 这些数据的解释受到两个重要限制的限制：1)对照组喂食了含有大量玉米油的配方，玉米油主要由亚油酸(n-6 FA)组成，可能是促炎的，因为它可以增加AA的浓度；2)n-3 FA对ALI患者炎症、生理和临床结局的独立影响是无法评估的。此外，将几种营养素组合到危重患者的商业肠内配方中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，没有关于个别药物的I期和II期人体试验发表；2)患者可能得不到足够量的营养素，因为输送依赖于肠内喂养(ICU患者通常获得他们处方热量需求的60%)。 即使有这些局限性，我相信Oxepa的治疗益处很可能来自EPA+DHA，而不是GLA或抗氧化剂，尽管不能排除营养物质之间的积极相互作用。抗氧化剂可能只有很少的贡献，如果有的话，因为现有的文献不支持抗氧化剂补充的大的临床益处。33此外，ALI患者静脉注射PGE1的两大RCT，由GLA，34，35增加，没有发现在生存期，机械通气期，或住院时间方面有改善。 为了回答EPA和DHA是否对ALI患者有独立的治疗益处的问题，我们正在进行肠内鱼油与安慰剂的II期随机对照试验。