COUNTERACT Supplement--ASPIRE: Air Pollution: Strategies for Personalized Intervention to Reduce Exposure

摘要 氯是一种反应性气体，由于大量生产和使用， 工业应用中故意和意外释放。目前的行政补充， 母案申请涉及开发下一代治疗剂， 一旦释放这种化学品威胁，死亡率和发病率将大大降低。我们的研究小组发表在 从我们的母公司赠款共同铺平了道路的概念，PM2.5暴露导致系统性 炎症（包括神经元炎症）通过TLR 4和氧化应激途径。最近我们 证明Nrf 2-Keap 2系统可能代表了一个关键途径，通过该途径，屏障功能可能被 树立政治意识Nrf 2的激活可能代表消除屏障功能障碍的治疗方式， 减轻氯损伤。在这个补充申请中，我们将测试2个目标，除了提供机械 对氯暴露心肺损伤的深入了解也将测试2种策略，TLR 4抑制和Nrf 2 活化，以减轻全身炎症反应氯暴露。在目标1中，我们将研究 不同剂量的氯暴露对TLR 4激活剂如氧化磷脂产生的影响， 肺表面活性物质液体和这些对肺和全身炎症的影响，在野生型，TLR 4-/-和 Keap 1-/-小鼠。我们将研究TLR 4抑制剂的鼻内和全身给药在保护TNM细胞中的作用。 防止氯气伤害。在目标2中，我们将测试氯的血脑屏障渗透性是一个概念， 系统毒性的重要组成部分，并将测试几种新型小分子Nrf 2激活剂的影响 减少中枢神经系统和肺部炎症。为了实现这些目标，并为了扩大调查结果， 原始研究（基于我们的初步研究），我们要求一个具体的补充，使我们能够测试 这些概念。我们认为，这一补充裁决是高度响应特别要求， 美国国立卫生研究院化学威胁对策（CounterACT）计划。

ABSTRACT Chlorine is a reactive gas that is a continuing chemical threat given the large amounts produced and used for industrial application from both intentional and accidental release. The current administrative supplement to the parent application is directed towards development of next generation therapeutics that can significantly reduce mortality and morbidity in the event of release of this chemical threat. The studies published by our group in from our parent grant have collectively paved the way for the concept that PM2.5 exposure results in systemic inflammation (including neuronal inflammation) through TLR4 and oxidative stress pathways. Recently we have demonstrated that the Nrf2-Keap2 system could represent a key pathway through which barrier function may be maintained. Activation of Nrf2 may represent a therapeutic modality to abrogate barrier dysfunction and attenuate chlorine injury. In this supplemental application we will test 2 aims that besides providing mechanistic insights into cardiopulmonary injury with chlorine exposure will also test 2 strategies, TLR4 inhibition and Nrf2 activation in mitigating systemic inflammation in response to chlorine exposure. In Aim 1 we will examine the effect of different doses of chlorine exposure on generation of TLR4 activators such as oxidized phospholipids in the lung surfactant fluid and the impact of these on lung and systemic inflammation in wildtype, TLR4-/- and Keap1-/-mice. We will investigate the impact of intranasal and systemic delivery of TLR4 inhibitors in protecting against chlorine injury. In Aim 2 we will test the concept that blood brain barrier permeability with chlorine is an important component of systemic toxicity and will test the impact of several novel small molecular Nrf2 activators in reducing CNS and lung inflammation. To achieve these objectives and in order to extend the findings from the original study (based on our preliminary studies) we request a specific supplement that will enable us to test these concepts. We believe that this supplemental award is highly responsive to the special request for supplements to the NIH Countermeasures Against Chemical Threats (CounterACT) program.