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: 8491756
• 负责人: Lynette Kay Rogers
• 金额: $ 34.57万
• 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/8491756
• 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。尽管所涉及的机制尚不完全清楚，但长链脂肪酸的抗炎特性被认为包括对信号通路的影响，从而导致基因转录的改变。迄今为止，尚未确定 DHA 的特定高亲和力受体，但 DHA 介导的细胞因子和趋化因子产生减少可能是由于受体相关机制所致。高级糖基化终产物受体 (RAGE) 是一种“损伤相关分子模式”受体，因此能够使用三级结构来接合一类不相关的分子以进行配体识别。 RAGE在肺中高表达；特别是I型上皮细胞、内皮细胞和肺泡巨噬细胞。暴露于高氧的小鼠肺部中RAGE蛋白表达增加，并且增加与损伤的严重程度相关。此外，RAGE 基因敲除小鼠免受高氧肺损伤，表明 RAGE 介导的事件在肺损伤的发展中发挥作用。 DHA 优先由妊娠晚期的人类胎儿吸收，以帮助神经组织的成熟。极早产儿在这种沉积之前出生，并且通常没有在肠外营养中提供“预先形成的”DHA，或者从母乳库中获得的乳汁含量较低。此外，早产儿通常需要维持生命的治疗，包括通气支持和高浓度氧气，并且有发生与高氧性肺损伤相关的炎症的风险。支气管肺发育不良（BPD）是最常见的早产儿疾病之一，与母婴炎症反应密切相关。被诊断患有 BPD 的婴儿肺泡化程度降低，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迟缓，并且面临其他健康问题的风险，从而进一步损害他们的整体健康。核心假设是，DHA 通过改变 RAGE 表达和信号通路，减少白细胞趋化性，从而减轻高氧诱导的肺损伤。目标 1 将检验以下假设：补充 DHA 通过调节可溶性 RAGE (sRAGE) 水平和活性来减少炎症。 sRAGE 是通过膜结合 RAGE (mRAGE) 的胞外结构域的蛋白水解裂解产生的。 sRAGE可以增强趋化性，促进单核细胞的成熟和分化。该目标将研究 DHA 在高氧环境下降低 sRAGE 水平的机制。目标 2 将检验 DHA 补充剂改变 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。该目标将研究 DHA 减少细胞内促炎信号传导的机制。目标 3 将检验以下假设：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 sRAGE 表达和炎症反应减少。这些研究将调查 DHA 对早产情况下 sRAGE 水平的影响。该提案中概述的研究将把已建立的高氧暴露和肺部发育停滞的新生小鼠模型与早产儿的临床研究相结合，以研究 DHA 减少炎症和改善肺部生长的机制。