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）：支气管肺发育不良（BPD）是早产儿中一种严重的慢性炎症性肺部疾病，与肺部持续存在活化的中性粒细胞有关。 BPD 的独特病理学表明，这些婴儿的中性粒细胞在信号通路中表现出发育缺陷，从而下调其活性并通过细胞凋亡上调其清除率。最近的证据表明，炎症反应的消退是通过花生四烯酸通过环氧合酶-2 和脂氧合酶产生的类二十烷酸的产生的连续变化来调节的。这种“类二十烷酸类别转换”导致组织损伤部位的前列腺素和脂氧素从炎症向抗炎转变。我们推测，新生儿肺部中性粒细胞的持续存在和 BPD 的发生是由于抗炎类二十烷酸活性的成熟缺陷造成的。此外，新生儿重症监护病房中的早产儿接触有毒物质可能会加剧这些缺陷，从而导致病理过程。住院新生儿会接触大量含有增塑剂邻苯二甲酸二(2-乙基己基)酯 (DEHP) 的富含 PVC 的设备。早产儿的 DEHP 及其生物活性代谢物 MEHP 水平显着高于任何其他人群。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，它介导抗炎类二十烷酸的作用。我们推测邻苯二甲酸盐通过干扰 PPAR-( 介导的类二十烷酸信号传导而导致 BPD。为了检验我们的假设，计划进行研究：1) 确定足月和早产新生儿中性粒细胞相对于成人的抗炎类二十烷酸生成和活性是否发生改变；2) 分析中性粒细胞反应性受损的机制新生儿中性粒细胞对抗炎类二十烷酸的反应，并评估邻苯二甲酸盐是否会改变这些反应。美国儿科学会、美国 FDA 和人类生殖风险评估中心最近都指出，公共卫生部门迫切需要更多有关邻苯二甲酸盐对人类新生儿的毒性的数据，包括 PPAR 信号传导的作用在这些影响中。我们的研究结果将提出预防或治疗新生儿 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) 是早产儿慢性肺损伤的一种形式，与肺部活化中性粒细胞的异常持续存在有关。我们将研究这样的假设：新生儿中这些细胞的下调和去除受损是由于类花生酸（一类生物活性脂质介质）炎症调节的成熟缺陷造成的。此外，住院新生儿广泛接触邻苯二甲酸酯增塑剂可能会进一步损害抗炎类二十烷酸信号。美国儿科学会和美国食品和药物管理局表示迫切需要进一步研究邻苯二甲酸盐对人类新生儿的毒性，包括它们在 BPD 中的作用。拟议的研究将满足这一需求，提出减少新生儿炎症引起的 BPD 和其他不良后果的发生率的方法。