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

 描述(由申请人提供)：目前，关于颗粒物(PM)的影响，更具体地说是世界贸易中心(WTC)粉尘暴露及其神经炎症潜力，总体上缺乏科学数据。已发现PM可跨膜屏障(空气-血液、血-脑)转运，从而允许与大脑和中枢神经系统直接相互作用。由于嘴呼吸普遍存在的独特暴露情景，急救人员暴露在极高浓度的超粗碱性腐蚀性PM(&gt；20微米；pH 9.2-11.5)中。根据这种性质，WTC颗粒可能会对嗅球的嗅觉神经元产生重大影响，导致口咽腔受损，并有可能使受试者更容易受到随后PM的影响，更容易患上神经疾病。这项研究的目的是评估在世贸中心坍塌事件发生两天后，在纽约曼哈顿世贸中心遗址附近收集的鼻腔内给药的WTC 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-/-小鼠模型来帮助确定氧化应激结果以及通过炎症反应来确定鼻黏膜上皮完整性。 在鼻-神经界面以及神经组织中的反应。我们假设，通过鼻腔给药WTC PM引起的炎症将导致活性氧物种(ROS)的形成，在ApoE-/-模型中潜在地激发与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氧化应激的炎性标记物和两个菌株的基因表达来评估。使用ApoE-/-小鼠将有助于理解涉及小胶质细胞调节和潜在的多巴胺能神经毒性的机制。在这样做的过程中，WTC PM可能会诱导小胶质细胞的激活，从而导致各种促炎标志物的产生，如以前在其他PM暴露研究中看到的那样，以及活性氧物种(ROS)的形成。在载脂蛋白E-/-小鼠的神经元死亡中，已经证实了类似这样的机械性级联反应。PM暴露引起的细胞内氧化应激在系统和神经学上与不良的健康后果有关，包括组织病理学的变化、DNA损伤和由此导致的神经疾病。更重要的是，这一系统以及系统内的生物级联也可以被高度利用，并与其他暴露相结合，导致共同暴露的情况，从而进一步加强环境污染物反复侮辱带来的环境伤害。上皮损伤后的AS 此外，由于随后的PM暴露和侮辱循环导致屏障被打破，受试者有可能变得更脆弱或更容易患上神经疾病。

 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.