Mechanisms of Inflammatory Lung Disease in Neonates

新生儿炎症性肺病的机制

• 批准号: 7739034
• 负责人: BARRY I. WEINBERGER
• 金额: $ 23.4万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-17 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7739034
• 关键词: Academy; Address; Adult; American; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Arachidonic Acids; Binding; Bronchopulmonary Dysplasia; Cells; Chronic; Data; Defect; Development; Devices; Diethylhexyl Phthalate; Disease; Down-Regulation; Eicosanoid Production; Eicosanoids; Evaluation; Excision; Exhibits; Human; Immunoglobulin Class Switching; Incidence; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Lipoxins; Lipoxygenase; Lipoxygenase 2; Lung; Lung diseases; Mediating; Mediator of activation protein; Modeling; Mono-S; Neonatal; Newborn Infant; Outcome; Pathologic Processes; Pathology; Pathway interactions; Pediatrics; Peroxisome Proliferator-Activated Receptors; Phase; Plasticizers; Population; Predisposition; Premature Infant; Process; Production; Prostaglandins; Public Health; Regulation; Relative (related person); Reproduction; Resolution; Risk; Role; Signal Pathway; Signal Transduction; Site; Testing; Tissues; Toxic effect; United States Food and Drug Administration; cyclooxygenase 2; lipid mediator; mono-(2-ethylhexyl)phthalate; neonate; neutrophil; novel; novel strategies; phthalates; prevent; public health relevance; response; toxicant; transcription factor

DESCRIPTION (provided by applicant): Bronchopulmonary Dysplasia (BPD), a severe form of chronic inflammatory lung disease in preterm infants, is associated with the persistence of activated neutrophils in the lungs. The unique pathology of BPD suggests that neutrophils from these babies exhibit developmental defects in signaling pathways that down regulate their activity and up regulate their clearance via apoptosis. Recent evidence suggests that resolution of the inflammatory response is regulated by sequential changes in the production of eicosanoids generated from arachidonic acid via cyclooxygenase-2 and lipoxygenase. This "eicosanoid class-switch" results in the transition from inflammatory to anti-inflammatory prostaglandins and lipoxins at sites of tissue injury. We hypothesize that persistence of neutrophils in the lungs of neonates and the development of BPD are due to maturational defects in anti-inflammatory eicosanoid activity. Moreover, exposure of preterm infants in the NICU to toxicants that exacerbate these defects may contribute to the pathologic process. Hospitalized neonates are exposed to numerous PVC-rich devices containing the plasticizer di-(2-ethylhexyl) phthalate (DEHP). Levels of DEHP and its bioactive metabolite, MEHP, are significantly higher in preterm neonates than in any other population. Recent studies have shown that phthalates may be antagonists of the transcription factor PPAR-(, which mediates the actions of anti-inflammatory eicosanoids. We speculate that phthalates contribute to BPD by interfering with PPAR-(-mediated eicosanoid signaling. To test our hypothesis, studies are planned to: 1) determine if anti-inflammatory eicosanoid production and activity are altered in term and preterm neonatal neutrophils relative to adults and 2) analyze mechanisms underlying impaired responsiveness of neonatal neutrophils to anti-inflammatory eicosanoids and assess whether phthalates alter these responses. The American Academy of Pediatrics, U.S. FDA, and the Center for the Evaluation of Risks to Human Reproduction have all recently noted that there is an urgent public health need for more data on the toxicity of phthalates in human neonates, including the role of PPAR signaling in these effects. Results from our studies will suggest novel approaches to preventing or treating BPD and other inflammatory diseases in newborns. PUBLIC HEALTH RELEVANCE: Bronchopulmonary Dysplasia (BPD), a form of chronic pulmonary injury in premature infants, is associated with abnormal persistence of activated neutrophils in the lungs. We will investigate the hypothesis that impaired down regulation and removal of these cells in newborns are due to maturational defects in the regulation of inflammation by eicosanoids, a class of bioactive lipid mediators. Moreover, widespread exposure of hospitalized newborns to phthalate plasticizers may further impair anti- inflammatory eicosanoid signaling. The American Academy of Pediatrics and U.S. Food and Drug Administration have expressed the urgent need for further study examining the toxicity of phthalates in human neonates, including their role in BPD. The proposed studies will address this need, suggesting ways to decrease the incidence of BPD and other adverse outcomes that result from inflammation in newborns.

描述（由申请人提供）：早产儿的一种严重的慢性炎性肺部疾病形式支气管肺发育异常（BPD）与肺中激活的嗜中性粒细胞的持续性有关。 BPD的独特病理表明，来自这些婴儿的中性粒细胞在信号通路中表现出发育缺陷，从而降低其活性并通过凋亡来调节清除率。最近的证据表明，通过环氧酶-2和脂氧酶从蛛网膜化产生的类花生四烯酸产生的eicosanoids产生的顺序变化来调节炎症反应的分辨率。这种“类类切换”导致组织损伤部位从炎症到抗炎的前列腺素和脂蛋白的过渡。我们假设中性粒细胞在新生儿肺中的持久性和BPD的发展是由于抗炎类花生酸活性的成熟缺陷所致。此外，NICU中早产儿的暴露于加剧这些缺陷的毒物可能有助于病理过程。住院的新生儿暴露于含增塑剂Di-（2-乙基己基）邻苯二甲酸酯（DEHP）的众多富PVC的设备。早产新生儿的DEHP及其生物活性代谢产物MEHP的水平明显高于任何其他人群。最近的研究表明，邻苯二甲酸盐可能是转录因子pPAR-的拮抗剂（，它介导抗炎类花生酸酯的作用。我们推测，邻苯二甲酸酯通过干扰PPAR的 - （ - 介导的eicosanoid信号传导。测试我们的假设，是否有抗性的静脉植物，是：1）是否有抗性，是否有抗性，是否有抗性，是否有抗性，是否有抗性，是否是抗毒药，是否是抗抗性的。新生儿中性粒细胞相对于成年人，2）分析新生儿中性粒细胞对抗炎类花生酸的反应性受损的机制，并评估邻苯二甲酸盐是否改变了这些反应。美国儿科学会，美国FDA和人类繁殖风险评估中心最近都指出，紧急公共卫生需要更多关于邻苯二甲酸盐在人类新生儿中的毒性的数据，包括PPAR信号在这些作用中的作用。我们研究的结果将提出预防或治疗新生儿中BPD和其他炎症性疾病的新方法。公共卫生相关性：支气管肺发育不良（BPD）是早产婴儿的慢性肺损伤形式，与肺中激活的嗜中性粒细胞异常持久性有关。我们将调查以下假设：新生儿中这些细胞的减少和去除损害是由于类eicosanoids（一类生物活性脂质介体）调节炎症的成熟缺陷。此外，住院的新生儿对邻苯二甲酸酯增塑剂的广泛暴露可能会进一步损害抗炎性类类固醇信号传导。美国儿科和美国食品和药物管理局表示迫切需要进一步研究检查人类新生儿（包括其在BPD中的作用）邻苯二甲酸盐的毒性。拟议的研究将满足这一需求，提出减少BPD发病率和其他因新生儿炎症而导致的不良结果的方法。