Protective Effects of Fatty Acids in Phthalate-Induced Inflammation in Neonates

脂肪酸对邻苯二甲酸盐引起的新生儿炎症的保护作用

基本信息

批准号：
8711719
负责人：
Anna Marie Vetrano
金额：
$ 23.36万
依托单位：
RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-06 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8711719
关键词：
Academy Address Adult Affinity Agonist American Apoptosis Apoptotic Attenuated Binding Biological Assay Blood Circulation Bronchopulmonary Dysplasia Caring Catheters Cells Chemicals Chemotaxis Chronic Chronic Disease Data Development Diet Dietary Fats Dietary Fatty Acid Dietary Intervention Dietary Supplementation Disease Down-Regulation Environmental Exposure Evaluation Exposure to Fatty Acids Fluorescence Resonance Energy Transfer Gene Expression Gene Targeting Human Impairment Incidence Infant Inflammation Inflammatory Inflammatory Response Injury Intervention Intravenous Leeches Ligand Binding Domain Ligands Lipids Measures Mediating Medical Device MicroRNAs Molecular Profiling Necrotizing Enterocolitis Neonatal Newborn Infant Nitrates Northern Blotting Nutritional Pathway interactions Pediatrics Peroxisome Proliferator-Activated Receptors Phagocytosis Plasticizers Plastics Polyunsaturated Fatty Acids Population Post-Transcriptional Regulation Predisposition Production Public Health Regulation Relative (related person)Reproduction Resolution Respiratory Burst Risk Role Signal Pathway Signal Transduction Testing Thiazolidinediones Time Toxic effect cytokine mono-(2-ethylhexyl)phthalate neonate neutrophil novel phthalates prevent protective effect response time use toxicant transcription factor troglitazone

项目摘要

DESCRIPTION (provided by applicant): Phthalate plasticizers are ubiquitous toxicants in the neonatal ICU. These compounds leech into the circulation of neonates in high concentrations from PVC-containing medical devices. They increase and prolong inflammatory responses in neonates, who are already susceptible to chronic inflammation because of immaturity of signaling pathways controlling the resolution of inflammation. Therefore, phthalate exposure likely contributes to the high incidence of severe complications associated with persistent inflammation, such as bronchopulmonary dysplasia. Since phthalate-containing medical devices are essential for neonatal survival, the use of dietary supplementation to counteract phthalate toxicity may offer a practical alternative to limiting their use. It has been shown that phthalate-mediated activation of neonatal neutrophils is reduced by synthetic agonists of peroxisome proliferator activated receptor-(PPAR-?), suggesting that phthalates act by competitively inhibiting activity of this transcription factor, which is a key pathway mediating the down regulation of inflammatory activity in neutrophils. Endogenous PPAR-? ligands, such as ?-3 polyunsaturated fatty acids (PUFA) and nitrated fatty acids, are known to attenuate neutrophil activity. Taken together, these findings suggest that dietary PPAR-? agonists may attenuate the inflammatory toxicity of phthalates. It is hypothesized that PPAR-? activity is developmentally impaired in neonatal neutrophils and that exposure to phthalates further delays the resolution of inflammatory responses in these cells. Activation of PPAR-? via its natural ligands, ?-3 fatty acids and nitrated fatty acids, may ameliorate these effects. In these studies, the effects of phthalates and fatty acids on PPAR-? signaling will be characterized in neonatal neutrophils, and with adult cells. The potential roles of these dietary PPAR-? agonists in ameliorating the inflammatory effects of phthalates will be quantified. Finally, specific mechanisms underlying differential susceptibility of adults and neonates to PPAR ligands will be identified. The American Academy of Pediatrics, U.S. FDA, and the Center for the Evaluation of Risks to Human Reproduction have noted an urgent public health need for data on the toxicity of phthalates in human neonates, and on the role of PPAR signaling in these effects. These findings will address this need, and may suggest novel nutritional interventions to prevent chronic inflammatory conditions associated with exposure to phthalates in neonates.

描述（由申请人提供）：邻苯二甲酸酯增塑剂是新生儿ICU中普遍存在的毒物。这些化合物从含PVC的医疗设备高浓度的新生儿循环中。它们增加并延长了新生儿的炎症反应，由于控制炎症分辨率的信号通路的不成熟，他们已经容易受到慢性炎症的影响。因此，邻苯二甲酸盐暴露可能导致与持续炎症有关的严重并发症的高发病率，例如支气管肺发育不良。由于含邻苯二甲酸酯的医疗设备对于新生儿生存至关重要，因此使用补充饮食来抵消邻苯二甲酸酯毒性可能提供了一种实际替代方案，可以替代其使用。已经表明，邻苯二甲酸酯介导的新生儿嗜中性粒细胞的激活减少了过氧化物酶体增殖物的合成激动剂激活受体（PPAR-？），这表明phthalate phthalation通过竞争性抑制这种转录因子的活性来起作用，从而介导了下降的炎症途径，从而介导了下降的炎症性活性。内源性PPAR-？众所周知，配体，例如？-3多不饱和脂肪酸（PUFA）和硝化脂肪酸，可以减弱中性粒细胞活性。综上所述，这些发现表明饮食ppar-？激动剂可能会衰减邻苯二甲酸酯的炎症毒性。假设PPAR-？活性在新生儿中性粒细胞中受到发育障碍，暴露于邻苯二甲酸盐进一步延迟了这些细胞中炎症反应的分辨率。 PPAR-激活？通过其天然配体？-3脂肪酸和硝化脂肪酸，可以改善这些作用。在这些研究中，邻苯二甲酸盐和脂肪酸对PPAR-的影响？信号传导将在新生儿中性粒细胞和成年细胞中进行表征。这些饮食中的潜在作用？缓解邻苯二甲酸酯的炎症作用方面的激动剂将被定量。最后，将确定成人和新生儿对PPAR配体的差异敏感性的特定机制。美国儿科学会，美国FDA和人类繁殖风险评估中心已经指出，公共卫生对人类新生儿中邻苯二甲酸盐毒性的数据需要紧迫，以及PPAR信号在这些作用中的作用。这些发现将满足这一需求，并可能提出新的营养干预措施，以防止与新生儿暴露于邻苯二甲酸盐有关的慢性炎症状况。