Document text
Principal Investigator: Matthew J Campen
Organization: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
Fiscal Year: 2024
Award: $592,021
Funding agency: National Institute of Environmental Health Sciences
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.
Terms: <Acceleration><Acclimatization><Acute><Address><Adhesion Molecule><Aging><Area><Arizona><Arsenic><Astrocytes><Astrocytus><Astroglia><Automobile Driving><Biomass><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Blood leukocyte><Brain><Brain Nervous System><Brain Vascular><CCL2><CCL2 gene><CD106><CD106 Antigens><CD31><CD54 Antigens><Cadmium><California><Cd element><Cell Adhesion Molecule Gene><Cell Adhesion Molecules><Cell Body><Cell surface><Cells><Chemicals><Chemokine, CC Motif, Ligand 2><Chromium><Circulation><Communities><Consumption><Cr element><Data><Development><Diet><Elderly><Encephalon><Endothelial Cells><Endothelium><Event><Exhibits><Exposure to><Fire - disasters><Fires><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Foundations><Frequencies><Hortega cell><Household><ICAM-1><INCAM-110><Immune><Immune infiltrates><Immunes><Inducible Cell Adhesion Molecule 110><Inflammation><Inflammatory><Inhalation><Inhalation Exposure><Inhaling><Injury><Intercellular adhesion molecule 1><Knowledge><Laboratories><Learning><Leukocytes><Leukocytes Reticuloendothelial System><Lung><Lung Inflammation><Lung Respiratory System><MCAF><MCP-1><MCP1><Marrow Neutrophil><Marrow leukocyte><Metal exposure><Metals><Mice><Mice Mammals><Microglia><Mining><Modeling><Molecular><Monocyte Chemoattractant Protein-1><Monocyte Chemotactic Protein-1><Monocyte Chemotactic and Activating Factor><Monocyte Chemotactic and Activating Protein><Monocyte Chemotactive and Activating Factor><Monocyte Secretory Protein JE><Murine><Mus><Nature><Navaho><Navajo><Nerve Degeneration><Neuron Degeneration><Neutrophilic Granulocyte><Neutrophilic Leukocyte><New Mexico><Ni element><Nickel><Nuclear><Outcome><PECAM1><PECAM1 gene><Particulate Matter><Pathway interactions><Peripheral><Persons><Phenotype><Pneumonitis><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Pueblo><Pueblo Race><Pulmonary Inflammation><Resolution><Risk><Role><SCYA2><Sampling><Saturated Fatty Acids><Severities><Site><Small Inducible Cytokine A2><Smoke><Source><Stimulus><System><Testing><Therapeutic><Therapeutic Intervention><Time><Toxic effect><Toxicities><U element><Uranium><Urine><Utah><V element><VCAM><VCAM-1><Vanadium><Vascular Cell Adhesion Molecule><Vascular Cell Adhesion Molecule-1><White Blood Cells><White Cell><Wildfire><Wood><Wood material><Work><advanced age><aged group><aged groups><aged individual><aged individuals><aged people><aged person><aged persons><aged population><aged populations><aging population><anthropogenesis><anthropogenic><arsenics><astrocytic glia><biomass fuel><cell adhesion protein><cerebral vascular><cerebro-vascular><cerebrovascular><climate change><climatic changes><developmental><dietary><diets><driving><endothelial dysfunction><environmental stresses><environmental stressor><exposure to metal><fire><first responder><flow cytophotometry><geriatric><gitter cell><global climate change><immune cell infiltrate><injuries><intervention therapy><lipid mediator><mesoglia><microglial cell><microgliocyte><neural degeneration><neural inflammation><neuro-vascular><neuro-vascular unit><neurodegeneration><neurodegenerative><neuroinflammation><neuroinflammatory><neurological degeneration><neuronal degeneration><neurovascular><neurovascular unit><neutrophil><pathway><perivascular glial cell><population aging><pulmonary><recruit><resolutions><response><senior citizen><smoke inhalation><social role><toxic metal><trend><white blood cell><white blood corpuscle><wild fire><wildland fire><wood smoke><woodsmoke>