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: 7959625
• 负责人: Renee D Stapleton
• 金额: $ 24.47万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7959625
• 关键词: Acids; Acute Lung Injury; Adhesions; Adult Respiratory Distress Syndrome; Alveolar; Animals; Antioxidants; Arachidonate 5-Lipoxygenase; Arachidonic Acids; Attenuated; Biochemical; Biology; Bronchoconstriction; Capillary Permeability; Carbohydrates; Carotene; Cell membrane; Chronic; Clinical; Computer Retrieval of Information on Scientific Projects Database; Control Groups; Corn Oil; County; Critical Illness; Data; Diet; Dinoprostone; Eicosanoids; Eicosapentaenoic Acid; 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; Inflammation Mediators; 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; Taurine; Therapeutic; Thromboxanes; Translational Research; United States National Institutes of Health; Vascular Permeabilities; Vasodilation; Vitamin E; borage oil; 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的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 ALI和急性呼吸窘迫综合征（ARDS）是肺或全身损伤的常见和严重并发症，导致低氧血症性呼吸衰竭。 最近的King County肺损伤项目发现发病率为79例/100，000人年，超过了大多数以前的估计。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促炎反应的大量激活引起的。2，3活化的巨噬细胞释放细胞因子，如IL-1，IL-6，IL-8，IL-10和TNF-α，这些细胞因子反过来局部激活中性粒细胞。 然后，活化的中性粒细胞产生蛋白酶、氧化剂和脂质衍生的介质，包括类二十烷酸，其使肺损伤周期持续。4类二十烷酸炎症介质来源于花生四烯酸（AA），一种常见的西方饮食中的膜磷脂。5，6当炎症级联被激活时，AA通过环氧合酶（考克斯）代谢为2-系列前列腺素（PG）和血栓烷（TX），并通过5-脂氧合酶（LOX）代谢为4-系列白三烯（LT）。 这些促炎性类二十烷酸在发热、血管通透性、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发挥重要作用。7 -11 二十碳五烯酸（EPA）和二十二碳六烯酸（DHA）是鱼油中发现的两种必需n-3脂肪酸。 当消耗时，n-3 FA被掺入免疫细胞膜中，12，13取代AA。6通过限制底物AA的量，类二十烷酸的形成受到限制。9 EPA还可以抑制AA通过COX的代谢。14此外，EPA是考克斯和5-LOX的底物，并代谢为3系列PG和TX以及5系列LT，其活性明显低于AA.15、16衍生的那些 动物研究表明，EPA和DHA可减少AA衍生类二十烷酸的产生。17，18 EPA和DHA可提高接受感染性挑战的大鼠19以及内毒素诱导的休克20和慢性脓毒症啮齿动物模型的存活率。21 EPA可减轻猪ALI模型的肺水肿。22 EPA和DHA已与<$-亚油酸（GLA）和抗氧化剂（维生素E和C，<$-胡萝卜素，牛磺酸和L-肉毒碱）结合成一种商业高脂肪低碳水化合物肠内配方称为Oxepa <$（罗斯产品）。 GLA是琉璃苣油中发现的一种n-6 FA，其代谢为二高亚油酸，然后转化为AA。 Oxepa已在几项行业赞助的动物研究中进行了评估。 已显示其降低炎症细胞膜中的AA浓度;23-28降低肺泡中LTB 4、PGE 2和TXB 2的浓度;24，25降低肺毛细血管通透性;24并减少内毒素血症大鼠中肺泡中性粒细胞的积聚25。 在重症患者中进行的n-3 FA的唯一研究使用了Oxepa？。 在ALI和败血症患者中进行了三项小型II期试验。29 -31所有三项试验的对照组均给予Pulmocare <$（Ross Products），这是一种高脂肪低碳水化合物肠内配方，与Oxepa <$等氮，但不含鱼油。 每项研究都发现Oxepa组的生理、生化和临床结局积极，包括氧合改善、BALF中性粒细胞计数降低、BALF IL-8和LTB 4降低、机械通气持续时间缩短、ICU住院时间缩短和新发器官衰竭减少。 一项研究发现，Oxepa对死亡率有好处。 这些数据的解释受到两个重要限制的限制：1）对照组喂食含有大量玉米油的配方食品，玉米油主要由亚油酸（n-6 FA）组成，可能是促炎性的，因为它可以增加AA的浓度; 2）n-3 FA对ALI患者的炎症、生理和临床结局的独立影响无法评估。 此外，将几种营养素组合到用于危重患者的商业肠内配方中的研究方法导致两个重要问题：1）每种营养素的科学“概念证明”都很差，没有关于单独药剂的I期和II期人体试验发表，2）由于输送依赖于肠内喂养，（ICU患者通常获得60%的处方热量需求）。 即使有这些限制，我相信Oxepa的治疗益处最有可能来自EPA+DHA，而不是GLA或抗氧化剂，尽管不能排除营养素之间的积极相互作用。 抗氧化剂可能只有很小的贡献，如果有的话，因为现有的文献不支持抗氧化剂治疗的大的临床益处。33此外，两项关于静脉注射PGE 1的大型RCT，GLA增加了ALI患者的PGE 1，34，35，发现生存率，通气持续时间或住院时间没有改善。36，37 为了回答EPA和DHA是否对ALI患者有独立的治疗益处的问题，我们正在进行一项肠内鱼油与安慰剂的II期RCT。