Lipoxin-Mediated Inflammatory Resolution in Newborn Hyperoxic Lung Injury

脂氧素介导的新生儿高氧性肺损伤的炎症消退

• 批准号: 8133949
• 负责人: Rodney Britt
• 金额: $ 3万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8133949
• 关键词: Affect; Affinity; Age; Anti-Inflammatory Agents; Anti-inflammatory; Arachidonic Acids; Aspirin; Attenuated; Binding; Birth; Bronchopulmonary Dysplasia; Caring; Cells; Chronic lung disease; Clara cell; Complex; Complication; Development; Edema; Epithelial Cells; Genetic Transcription; Goals; Hyperoxia; Infant; Infant Mortality; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Leukocytes; Ligand Binding; Lipids; Lipoxin Receptors; Lipoxins; Lipoxygenase; Lung; Measures; Mediating; Modeling; Morbidity - disease rate; Mus; NF-kappa B; Neonatal; Newborn Infant; Oxygen; PTGS2 gene; Pathway interactions; Pharmaceutical Preparations; Pregnancy; Premature Infant; Process; Prostaglandin-Endoperoxide Synthase; Proteins; Resolution; Risk; Source; Structure; Structure of parenchyma of lung; Techniques; Testing; Tissues; United States; Vascularization; chemokine; cytokine; glycosylation; improved; in vitro Model; infant outcome; inflammatory marker; insight; lipoxin A4; lung development; lung injury; macrophage; mortality; neutrophil; premature; prevent; pup; respiratory; therapy development

DESCRIPTION (provided by applicant): Bronchopulmonary Dysplasia (BPD), a chronic lung disease that occurs in preterm infants, is characterized by inflammation, edema, and decreased alveolarization. Inflammation is a key contributing factor to the development of BPD and increases in leukocyte infiltration into the lung is the greatest source of inflammatory mediators. Lipoxins (LX) are arachidonic acid derived lipids that have been shown to mediate inflammatory resolution by decreasing neutrophil and macrophage infiltration. Aspirin, an anti-inflammatory drug that acetylates COX-2 and changes COX-2 function from a cyclooxygenases to a lipoxygenase, generates a more biologically stable and potent form of lipoxins, 15-epi lipoxins. Resolution pathways initiated by lipoxins or 15-epi lipoxins include binding to the high affinity lipoxin receptor, ALXR. Upon binding, these ligands decrease transcription of pro-inflammatory cytokines and chemokines. Our overall hypothesis is that administration of lipoxin-enhancing therapies during the course of newborn hyperoxic injury will attenuate the inflammatory responses and improve lung structure and function. In Specific Aim I, we will test the hypothesis that activation of ALXR by lipoxins or 15-epi-lipoxins In lung epithelial cells, specifically Clara cells, will decrease the transcription of chemokines and cytokines through pathways mediated by NF-kB and SOC-2. In Specific Aim II, we will test the hypothesis that administration of aspirin will decrease pulmonary inflammatory responses and leukocyte infiltration in newborn mouse pups exposed to hyperoxia. Newborn mouse pups will be treated with aspirin or vehicle and exposed to >95% 02. Markers of inflammation, specifically KC and MIP-2, will be measured in mouse lung tissues. Finally, we will test the hypothesis that administration of aspirin to newborn mouse pups exposed to hyperoxia will improve the lung structural deficits associated with hyperoxic injury using lung morphometric analyses. Our goal is to investigate the effects of enhanced inflammatory resolution during the course of hyperoxic injury in a newborn model. These studies will provide insight into the contribution of inflammation to the progression of hyperoxic injury and development of BPD. Bronchopulmonary Dysplasia (BPD) is a chronic lung disease that affects over 50,000 premature infants a year. Therapies to resolve inflammation and improve the lung development could greatly improve the morbidity and mortality of infants affected by BPD.

描述（由申请人提供）：支气管肺发育不良（BPD）是一种发生于早产儿的慢性肺部疾病，其特征是炎症、水肿和肺泡化减少。炎症是 BPD 发生的关键因素，肺部白细胞浸润的增加是炎症介质的最大来源。脂氧素 (LX) 是花生四烯酸衍生的脂质，已被证明可以通过减少中性粒细胞和巨噬细胞浸润来介导炎症消退。阿司匹林是一种抗炎药，可乙酰化 COX-2 并将 COX-2 功能从环氧合酶转变为脂氧合酶，产生一种生物稳定性更强、更有效的脂氧素，即 15-表脂氧素。由脂氧素或 15-表脂氧素启动的解析途径包括与高亲和力脂氧素受体 ALXR 的结合。结合后，这些配体减少促炎细胞因子和趋化因子的转录。我们的总体假设是，在新生儿高氧损伤过程中给予脂氧素增强疗法将减轻炎症反应并改善肺结构和功能。在特定目标 I 中，我们将测试这样的假设：肺上皮细胞（特别是 Clara 细胞）中的脂氧素或 15-表脂氧素激活 ALXR 将通过 NF-kB 和 SOC-2 介导的途径减少趋化因子和细胞因子的转录。在特定目标 II 中，我们将测试以下假设：给予阿司匹林会减少暴露于高氧的新生小鼠幼崽的肺部炎症反应和白细胞浸润。新生小鼠幼崽将接受阿司匹林或载体治疗，并暴露于>95% 02。将在小鼠肺组织中测量炎症标志物，特别是KC和MIP-2。最后，我们将使用肺形态测量分析来测试以下假设：给暴露于高氧的新生小鼠幼崽服用阿司匹林将改善与高氧损伤相关的肺结构缺陷。我们的目标是研究新生儿模型高氧损伤过程中增强炎症消退的效果。这些研究将深入了解炎症对高氧损伤进展和 BPD 发展的影响。支气管肺发育不良 (BPD) 是一种慢性肺部疾病，每年影响超过 50,000 名早产儿。解决炎症和改善肺部发育的疗法可以大大降低受 BPD 影响的婴儿的发病率和死亡率。