Contaminant Metal Content in Wildfire Smoke and Neuroinflammation

总结 近年来，美国西部地区的野火灾害不断发生，并呈上升趋势 这些事件的频率和严重性是由气候变化驱动的。这些事件产生的烟雾覆盖了 非洲大陆的大部分地区，超过1亿人受到影响。新墨西哥州地区的野火可以穿越 遗留的采矿污染或核开发地区。洛斯阿拉莫斯过去火灾的证据， 例如，在第一反应者的尿液中发现砷，镍和镉的显著升高。 我们进一步确定，在废弃的铀矿附近获得的木材铀含量很高， 铬、镍和钒。我们最近对自然发生的荒地火灾烟雾（WFS）的研究 来自加州2020年10月野火的暴露表明， 健康的老鼠。然而，有趣的是，暴露20天后，脑血管内皮细胞 表现出进化的表型，炎症减少的迹象，标志着适应相对 急性循环炎性刺激。关于环境如何影响的知识存在很大差距 像WFS这样的应激源会促进脑血管炎症， 控制神经炎症消退。在目前的更新建议中，我们将把我们所了解到的 从拉古纳普韦布洛和纳瓦霍民族铀矿现场的广泛实地工作，并返回更多 精确的，基于实验室的暴露系统，以解决木材的肺部和神经炎症风险 从这些地区获得的受金属污染的生物质产生的烟雾。因此，在目标1中，我们将确定 生物质燃烧吸入金属的毒性影响。我们假设，木材获得近 一个废弃的铀矿点，富含几种金属污染物，具有更大的潜力比类似的 非受影响地点的生物质燃料。在第二个目标中，我们将阐明内皮粘附的作用， 分子驱动的木材烟雾吸入的神经炎症后果。我们假设 木烟的神经炎症结果依赖于脑血管粘连表达 分子（例如，ICAM-1，VCAM-1），吸入暴露后由循环因子诱导。在Aim 3中 我们建议描述和加速WFS暴露后神经炎症的消退。我们 假设暴露于木烟后神经炎症消退，从 激活的小胶质细胞，实际上是依赖于有效的招募外周免疫细胞通过 神经血管单位因此，我们将确定神经血管耐受进展的潜在机制 木材烟雾吸入，从而确定潜在的分子基础的脆弱性，长期 反复暴露的后果。此外，我们还将评估促消退脂质介质的价值， 作为急性WFS暴露的潜在饮食或治疗策略。

SUMMARY Wildland fire disasters raged throughout the western US in recent years, continuing a trend for increasing frequency and severity of such events driven by climate change. Smoke arising from these events covered much of the continent, exposing over 100 million people. Wildland fires in the New Mexico region can cross over regions of legacy mining contamination or nuclear development. Evidence from past fires in Los Alamos, for instance, revealed significant elevations of arsenic, nickel, and cadmium in the urine from first responders. We have further identified that wood obtained near abandoned uranium mine sites that have elevated uranium, chromium, nickel and vanadium. Our recent studies with naturally-occurring wildland fire smoke (WFS) exposures from the California October 2020 wildfires demonstrate clear neuroinflammatory outcomes in otherwise healthy mice. Interestingly, however, after 20 days of exposure, cerebrovascular endothelial cells exhibited an evolving phenotype, with signs of reduced inflammation, signifying an adaptation to the relatively acute circulating inflammatory stimulus. There is a significant gap in knowledge regarding how environmental stressors like WFS promote cerebrovascular inflammation, and even less appreciation for mechanisms governing neuroinflammatory resolution. In the present renewal proposal, we will take what we have learned from extensive field work on uranium mine sites in Laguna Pueblo and Navajo Nation, and return to more precise, laboratory-based exposure systems to address pulmonary and neuroinflammatory risks of wood smoke from metals-contaminated biomass obtained from these regions. Thus, in Aim 1, we will determine the toxic influence of metals in biomass combustion inhalation. We hypothesize that wood obtained near abandoned uranium mine sites, enriched with several metal contaminants, has a greater potency than similar biomass fuels from non-impacted sites. In the 2nd Aim we will elucidate the role of endothelial adhesion molecules in driving neuroinflammatory consequences of wood smoke inhalation. We hypothesize that neuroinflammatory outcomes of woodsmoke are dependent on cerebrovascular expression of adhesion molecules (e.g., ICAM-1, VCAM-1), induced by circulating factors following inhalation exposure. Lastly in Aim 3 we propose to delineate and accelerate the resolution of neuroinflammation after WFS exposures. We hypothesize that neuroinflammatory resolution following woodsmoke exposure, from the standpoint of activated microglia, is actually dependent on the effective recruitment of peripheral immune cells through the neurovascular unit. We will thus ascertain mechanisms underlying the progression of neurovascular tolerance to wood smoke inhalation, thereby identifying potential molecular foundations of vulnerability to long-term consequences of repeated exposure. Furthermore, we will assess the value of pro-resolving lipid mediators in accelerating the resolution, as a potential dietary or therapeutic strategy for acute WFS exposure.