Contaminant Metal Content in Wildfire Smoke and Neuroinflammation

摘要 近年来，美国西部野地火灾肆虐，继续呈上升趋势 气候变化驱动的此类事件的频率和严重程度。报道了这些活动产生的烟雾 非洲大陆的大部分地区，暴露了超过1亿人。新墨西哥州地区的荒地大火可能会越过 在遗留采矿污染或核开发地区上空。洛斯阿拉莫斯过去火灾的证据， 例如，从急救人员的尿液中发现砷、镍和镉的显著升高。 我们进一步确认，在废弃的铀矿场附近获得的木材已经提炼了铀， 铬、镍和钒。我们最近对自然产生的野地火灾烟雾(WFS)的研究 加州2020年10月野火的暴露显示出明显的神经炎性结果 其他方面健康的小鼠。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，伴随着炎症减轻的迹象，意味着对相对 急性循环炎症刺激。在环境方面的知识有一个很大的差距 像WFS这样的应激源会促进脑血管炎症，甚至对机制的了解更少 管理神经炎性疾病的消解。在目前的更新建议中，我们将把我们所了解到的 在拉古纳·普韦布洛和纳瓦霍民族的铀矿场进行广泛的实地工作，并返回更多 以实验室为基础的精确暴露系统，以解决木材的肺部和神经炎性风险 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 生物质燃烧吸入中金属的毒性影响。我们推测木头接近于 富含多种金属污染物的废弃铀矿矿场具有比类似矿场更大的潜力。 来自未受影响地点的生物质燃料。在第二个目标中，我们将阐明内皮细胞黏附的作用 影响吸入木材烟雾的神经炎性后果的分子。我们假设 木烟引起的神经炎性反应依赖于脑血管粘连的表达 分子(如ICAM-1、VCAM-1)，由吸入暴露后的循环因素诱导。最后，在目标3中 我们建议描述和加速WFS暴露后神经炎症的消退。我们 假设接触木烟后的神经炎性消退，从以下角度来看 激活的小胶质细胞，实际上依赖于外周免疫细胞通过 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。 吸入木材烟雾，从而确定长期易感的潜在分子基础 反复暴露的后果。此外，我们将评估促分解脂质介体在 加速分解，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.