DHA attenuates Inflammatory Responses Through Altering RAGE Signaling

DHA 通过改变 RAGE 信号传导减弱炎症反应

• 批准号: 8332279
• 负责人: Lynette Kay Rogers
• 金额: $ 35.64万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8332279
• 关键词: Acids; Advanced Glycosylation End Products; Affect; Affinity; Alveolar Macrophages; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; Binding; Blood specimen; Bronchopulmonary Dysplasia; Chemotaxis; Clinical Trials; Development; Diagnosis; Disease; Docosahexaenoic Acids; Dose; Endothelial Cells; Epithelial; Epithelial Cells; Event; Exhibits; Extracellular Domain; Fetus; Genetic Transcription; Goals; Growth; Health; Human; Human Milk; Hyperoxia; Infant; Inflammation; Inflammatory; Inflammatory Response; Injury; Knockout Mice; Leukocyte Chemotaxis; Leukocytes; Ligands; Link; Lung; Measures; Mediating; Medical; Membrane; Milk; Milk Banks; Molecular; Mothers; Mus; Neurologic; Newborn Infant; Oxygen; Parenteral Nutrition; Pattern; Phospholipids; Plasma; Play; Premature Birth; Premature Infant; Production; Property; Receptor Signaling; Risk; Role; Severities; Signal Pathway; Signal Transduction; Specificity; Structure; Supplementation; Testing; Third Pregnancy Trimester; Time; Tissues; Type I Epithelial Receptor Cell; Vitamins; Woman; cell type; chemokine; cytokine; improved; life-sustaining therapy; long chain fatty acid; lung development; lung injury; monocyte; mouse model; premature; prenatal; protein expression; receptor; receptor binding; receptor-mediated signaling; respiratory

DESCRIPTION (provided by applicant): Docosahexaenoic acid (DHA) is a long chain fatty acid that exhibits anti-inflammatory and immuno-modulating properties. Although the mechanisms involved are not completely understood, the anti-inflammatory properties of long chain fatty acids are thought to include effects on signaling pathways resulting in modified gene transcription. To date, a specific high affinity receptor for DHA has not been identified however DHA-mediated decreases in cytokine and chemokine production are likely due to receptor related mechanisms. Receptor for Advanced Glycation End Products (RAGE) is a "Damage Associated Molecular Pattern" receptor and, as such, is able to engage classes of unrelated molecules using tertiary structure for ligand recognition. RAGE is highly expressed in lung; specifically epithelial type I cells, endothelial cells, and alveolar macrophages. RAGE protein expression is increased in the lungs of mice exposed to hyperoxia, and the increase is related to the severity of injury. Furthermore, RAGE knockout mice are protected from hyperoxic lung injury, indicating that RAGE-mediated events play a role in the development of lung injury. DHA is preferentially accreted by the third trimester human fetus to aid the maturation of neurological tissues. Extremely preterm infants are born prior to this accretion and are often not provided "pre-formed" DHA in parenteral nutrition or receive low levels in milk from human milk banks. In addition, prematurely born infants often require life-sustaining therapies, including ventilatory support and high concentrations of oxygen and are at risk for inflammation associated with hyperoxic lung injury. Bronchopulmonary Dysplasia (BPD) is one of the most common diseases of prematurity and is closely linked to both maternal and infant inflammatory responses. Infants diagnosed with BPD have decreased lung alveolarization and often require respiratory support for a prolonged period of time. Furthermore, infants with BPD often exhibit delayed neurological development and are at risk for other medical problems that further impair their overall health. The central hypothesis is that DHA attenuates hyperoxia- induced lung injury by decreasing leukocyte chemotaxis, through altering RAGE expression and signaling pathways. Aim 1 will test the hypothesis that DHA supplementation decreases inflammation through the modulation of soluble RAGE (sRAGE) levels and activity. sRAGE is generated by proteolytic cleavage of the extracellular domain of membrane-bound RAGE (mRAGE). sRAGE can enhance chemotaxis and promote maturation and differentiation of monocytes. This aim will investigate the mechanisms by which DHA decreases sRAGE levels in the context of hyperoxia exposure. Aim 2 will test the hypothesis that DHA supplementation alters RAGE-mediated signaling pathways. DHA can propagate or antagonize receptor- mediated signaling by either directly binding to the ligand domain or influencing the ability of ligand to bind or activate the receptor. This aim will investigate the mechanisms by which DHA diminishes intracellular pro- inflammatory signaling. Aim 3 will test the hypothesis that DHA supplementation to lactating women will provide DHA to preterm infants and result in decreased sRAGE expression and inflammatory responses in both the mother and the infant. These studies will investigate the influence of DHA on sRAGE levels in the context of preterm birth. The studies outlined in this proposal will combine an established newborn mouse model of hyperoxia exposure and arrested lung development with clinical investigations in preterm human infants to investigate the mechanisms by which DHA decreases inflammation and improves lung growth.

描述（由申请人提供）：二十二碳六烯酸（DHA）是一种长链脂肪酸，具有抗炎和免疫调节特性。虽然所涉及的机制尚未完全了解，但长链脂肪酸的抗炎特性被认为包括对导致基因转录修饰的信号传导途径的影响。迄今为止，尚未鉴定出DHA的特异性高亲和力受体，然而DHA介导的细胞因子和趋化因子产生的减少可能是由于受体相关机制。晚期糖基化终产物受体（RAGE）是一种“损伤相关分子模式”受体，因此能够利用三级结构与不相关的分子结合以进行配体识别。在肺中高度表达;特别是上皮I型细胞、内皮细胞和肺泡巨噬细胞。在高氧暴露的小鼠肺组织中，HSP 70蛋白表达增加，并且这种增加与损伤的严重程度有关。此外，RAGE基因敲除小鼠受到保护，免受高氧肺损伤，表明RAGE介导的事件在肺损伤的发展中发挥作用。DHA优先被妊娠晚期的人类胎儿吸收，以帮助神经组织的成熟。极早产儿在这种增长之前出生，并且通常没有在肠外营养中提供“预形成”的DHA，或者从母乳库中获得低水平的母乳。此外，早产儿通常需要维持生命的治疗，包括呼吸支持和高浓度氧气，并有患高氧肺损伤相关炎症的风险。支气管肺发育不良（BPD）是早产儿最常见的疾病之一，与母婴炎症反应密切相关。诊断为BPD的婴儿肺泡化减少，通常需要长时间的呼吸支持。此外，患有BPD的婴儿通常表现出神经发育延迟，并有可能出现其他医学问题，进一步损害他们的整体健康。中心假设是DHA通过改变IL-2的表达和信号通路，降低白细胞趋化性，从而减轻高氧诱导的肺损伤。目的1将检验补充DHA通过调节可溶性脂肪酸（sodium）水平和活性来减少炎症的假设。通过蛋白水解切割膜结合的β-淀粉样蛋白（β-淀粉样蛋白）的细胞外结构域产生β-淀粉样蛋白。saccharide可增强单核细胞的趋化性并促进单核细胞的成熟和分化。这一目标将研究DHA在高氧暴露的情况下降低sodium水平的机制。目的2将检验补充DHA改变RAGE介导的信号通路的假设。DHA可以通过直接结合配体结构域或影响配体结合或激活受体的能力来传播或拮抗受体介导的信号传导。这一目标将研究DHA减少细胞内促炎信号传导的机制。目的3将检验以下假设：向哺乳期妇女补充DHA将为早产儿提供DHA，并导致母亲和婴儿的sliptin表达和炎症反应降低。这些研究将调查DHA对早产背景下的sodium水平的影响。本提案中概述的研究将联合收割机结合已建立的高氧暴露和肺发育停滞的新生小鼠模型与早产人类婴儿的临床研究，以研究DHA减少炎症和改善肺发育的机制。