World Trade Center Dust Derived Oxidative Stress at the Nasal-Neural Interface

世贸中心灰尘导致鼻神经界面氧化应激

• 批准号: 8909568
• 负责人: Michelle N Hernandez
• 金额: $ 3.51万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8909568
• 关键词: Air; Air Pollution; Apolipoprotein E; Area; Axonal Transport; Biological; Biological Markers; Blood; Blood-Air Barrier; Brain; C57BL/6 Mouse; Cessation of life; Cilia; Corrosives; Coughing; DNA Damage; Data; Deposition; Disease Outcome; Dose; Dust; Elderly; Elements; Enzyme-Linked Immunosorbent Assay; Epithelial; Event; Exposure to; Gene Expression; Generic Drugs; Goals; Health; Histopathology; Human; Inductively Coupled Plasma Mass Spectrometry; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-6; Irrigation; Knowledge; Lead; Link; Location; Measures; Membrane; Modeling; Mouth Breathing; Mucous Membrane; Mus; Nasal Lavage Fluid; Nature; Nerve Degeneration; Neuraxis; Neurologic; Neurons; New York; Nose; Olfactory Mucosa; Olfactory Receptor Neurons; Oropharyngeal; Outcome; Oxidative Stress; Particulate Matter; Pathway interactions; Predisposition; Production; Reactive Oxygen Species; Research; Source; System; Time; Tissues; Toxic effect; Transcription Factor AP-1; Triton X100; Tumor Necrosis Factor-alpha; Up-Regulation; Work; base; cytokine; emergency service responder; improved; inflammatory marker; irritation; mouse model; nervous system disorder; neuroinflammation; neurotoxicity; olfactory bulb; olfactory sensory neurons; particle; pollutant; public health relevance; relating to nervous system; response

 DESCRIPTION (provided by applicant): Currently, there is an overall lack of scientific data with regard to effects of particulate matter (PM), more specifically World Trade Center (WTC) dust exposure, and its neuro-inflammatory potential. PM has been found to translocate across membrane barriers (air-blood, blood-brain), allowing for direct interaction with the brain and central nervous system. Due to the unique exposure scenario in which mouth breathing was prevalent, first responders were exposed to extremely high concentration of supercoarse alkaline corrosive PM (>20µm; pH 9.2-11.5). By this very nature, WTC particles may have a significant impact on the olfactory neurons of the olfactory bulb, eliciting injury to the oropharyngeal cavity, and potentially making subjects more vulnerable to subsequent PM exposure and more susceptible to develop neurological disorders. The goal of this study is to assess any potential inflammatory effects at the nasal-neural interface from intra-nasally administered WTC PM, collected near ground zero in Manhattan, New York 2 days after the WTC collapse event. In this study, we propose the use of C57Bl/6 and ApoE-/- mouse models to aid in identifying oxidative stress outcomes as well nasal epithelial integrity via inflammatory responses at the nasal-neural interface, as well as in neural tissues. We hypothesize that inflammation induced via intra-nasally administered WTC PM will lead to reactive oxygen species formation (ROS), potentially inciting a proinflammatory cascade linked to neuronal death in ApoE-/- models. These potential outcomes will be assessed by comparing inflammatory markers of oxidative stress and gene expression in both strains. Usage of ApoE-/- mice will aid in understanding mechanisms involved in microglial modulation and potential dopaminergic neurotoxicity. In doing so, WTC PM may elicit microglial activation, thus leading to the production of various pro-inflammatory markers such as TNFa, IL-1ß, IL-6, and the formation of reactive oxygen species (ROS) as seen previously with other PM exposure studies. Mechanistic cascades such as these have been evidenced in neuronal death in ApoE-/- mice. Intracellular oxidative stress induced by PM exposure has been systemically and neurologically linked to adverse health outcomes, including changes in histopathology, DNA damage, and resultant neurological disorders. More importantly, this system, as well as biological cascades within the system, could also be highly exploited and augmented in combination with other exposures resulting in co-exposure scenarios, thus further potentiating environmentally induced injuries brought about by repetitive insult from ambient pollutants. Following epithelial injury as well as barrier breaching due to subsequent cycles of PM exposure and insults, subjects then have the potential to become more vulnerable or predisposed to neurological disorders.

 描述（由申请人提供）：目前，总体上缺乏关于颗粒物（PM）影响的科学数据，更具体地说，世界贸易中心（WTC）粉尘暴露及其神经炎症潜力。已经发现PM可以跨膜屏障（空气-血液，血液-脑）转移，从而与大脑和中枢神经系统直接相互作用。由于独特的暴露场景，其中口呼吸是普遍的，第一反应者暴露于极高浓度的超粗碱性腐蚀性PM（>20µm; pH 9.2-11.5）。由于这种性质，WTC颗粒可能对嗅球的嗅觉神经元产生显著影响，引起口咽腔损伤，并可能使受试者更容易受到后续PM暴露的影响，更容易患上神经系统疾病。本研究的目的是评估鼻内给药的WTC PM在鼻神经界面的任何潜在炎症效应，WTC PM在纽约曼哈顿的归零地附近收集，WTC倒塌事件后2天。在这项研究中，我们建议使用C57 Bl/6和ApoE-/-小鼠模型来帮助识别氧化应激结果以及通过炎症反应的鼻上皮完整性。 鼻神经界面以及神经组织的反应。我们假设通过鼻内给予WTC PM诱导的炎症将导致活性氧簇形成（ROS），可能引发与ApoE-/-模型中神经元死亡相关的促炎级联反应。这些潜在的结果将通过比较两种菌株中氧化应激和基因表达的炎症标志物来评估。ApoE-/-小鼠的使用将有助于理解参与小胶质细胞调节和潜在多巴胺能神经毒性的机制。在此过程中，WTC PM可能引起小胶质细胞活化，从而导致产生各种促炎标志物，如TNF α、IL-1 β、IL-6，以及形成活性氧（ROS），如先前在其他PM暴露研究中所见。在ApoE-/-小鼠的神经元死亡中已经证明了诸如此类的机制级联。由PM暴露诱导的细胞内氧化应激已在系统和神经学上与不良健康结果相关，包括组织病理学变化、DNA损伤和由此产生的神经系统疾病。更重要的是，这一系统以及该系统内的生物级联，还可以与其他暴露结合起来加以高度利用和扩大，从而导致共同暴露的情况，从而进一步加强环境污染物的反复侵害所造成的环境诱发伤害。上皮损伤后， 以及由于随后的PM暴露和损伤循环而导致的屏障破坏，则受试者有可能变得更脆弱或更易患神经障碍。