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: 9055553
• 负责人: Michelle N Hernandez
• 金额: $ 1.84万
• 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 2017-01-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9055553
• 关键词: Air; Air Pollution; Apolipoprotein E; Area; Axonal Transport; Biological; Biological Markers; Blood; Blood-Air Barrier; Brain; C57BL/6 Mouse; 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-1 beta; 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; TNF gene; Time; Tissues; Toxic effect; Transcription Factor AP-1; Triton X100; Up-Regulation; Work; base; cytokine; emergency service responder; improved; inflammatory marker; irritation; mouse model; nervous system disorder; neuroinflammation; neuron loss; 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）的影响的科学数据，更具体地说是世贸中心（WTC）灰尘暴露及其神经炎症潜力。研究发现，PM 可以跨过膜屏障（空气-血液、血脑），从而与大脑和中枢神经系统直接相互作用。由于普遍采用口呼吸的独特暴露场景，急救人员暴露于极高浓度的超粗碱性腐蚀性 PM（>20μm；pH 9.2-11.5）。正是由于这种性质，WTC 颗粒可能会对嗅球的嗅觉神经元产生重大影响，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在世贸中心倒塌事件两天后在纽约曼哈顿零地附近收集的鼻内施用世贸中心 PM 对鼻神经界面的任何潜在炎症影响。在这项研究中，我们建议使用 C57Bl/6 和 ApoE-/- 小鼠模型来帮助识别氧化应激结果以及通过炎症影响鼻上皮完整性 鼻神经界面以及神经组织的反应。我们假设，通过鼻内施用 WTC PM 诱导的炎症将导致活性氧物质 (ROS) 的形成，可能会引发与 ApoE-/- 模型中神经元死亡相关的促炎症级联反应。这些潜在的结果将通过比较两种菌株的氧化应激炎症标志物和基因表达来评估。使用 ApoE-/- 小鼠将有助于了解小胶质细胞调节和潜在的多巴胺能神经毒性的机制。在此过程中，WTC PM 可能会引发小胶质细胞激活，从而导致各种促炎标记物的产生，例如 TNFa、IL-1ß、IL-6，以及活性氧 (ROS) 的形成，如之前在其他 PM 暴露研究中所见。诸如此类的机械级联反应已在 ApoE-/- 小鼠的神经元死亡中得到证实。 PM 暴露引起的细胞内氧化应激在系统和神经学上与不良健康结果有关，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，该系统以及系统内的生物级联也可以与其他暴露相结合而被高度利用和增强，从而导致共同暴露场景，从而进一步加剧因环境污染物的重复侵害而造成的环境伤害。上皮损伤后 由于随后的颗粒物暴露和侮辱循环而导致屏障突破，受试者有可能变得更脆弱或更容易患上神经系统疾病。