Contaminant Metal Content in Wildfire Smoke and Neuroinflammation

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.