Utilizing a mobile laboratory located >300 km away from wildfire smoke (WFS) sources, this study examined the systemic immune response profile, with a focus on neuroinflammatory and neurometabolomic consequences, resulting from inhalation exposure to naturally occurring wildfires in California, Arizona, and Washington in 2020. After a 20-day (4 h/d) exposure period in a mobile lab stationed in New Mexico, WFS-derived particulate matter (WFPM) inhalation resulted in significant neuroinflammation while immune activity in the peripheral (lung, bone marrow) appeared to be resolved in C57BL/6 mice. Importantly, WFPM exposure increased cerebrovascular endothelial cell activation and expression of adhesion molecules (VCAM-1 and ICAM-1) in addition to increased glial activation and peripheral immune cell infiltration into the brain. Flow cytometry analysis revealed proinflammatory phenotypes of microglia and peripheral immune subsets in the brain of WFPM-exposed mice. Interestingly, endothelial cell neuroimmune activity was differentially associated with levels of PECAM-1 expression, suggesting that subsets of cerebrovascular endothelial cells were transitioning to resolution of inflammation following the 20-day exposure. Neurometabolites related to protection against aging, such as NAD+ and taurine, were decreased by WFPM exposure. Additionally, increased pathological amyloid-beta protein accumulation, a hallmark of neurodegeneration, was observed. Neuroinflammation, together with decreased levels of key neurometabolites, reflect a cluster of outcomes with important implications in priming inflammaging and aging-related neurodegenerative phenotypes.

Exposure to air pollutants such as ozone (O3) is associated with adverse pregnancy outcomes, including higher incidence of gestational hypertension, preeclampsia and peripartum cardiomyopathy; however, the underlying mechanisms of this association remain unclear. We hypothesized that O3 exposures during early placental formation would lead to more adverse cardiovascular effects at term for exposed dams, as compared to late-term exposures. Pregnant Sprague-Dawley rats were exposed (4 h) to either filtered air (FA) or O3 (0.3 or 1.0 ppm) at either gestational day (GD)10 or GD20, with longitudinal functional assessments and molecular endpoints conducted at term. Exposure at GD10 led to placental transcriptional changes at term that were consistent with markers in human preeclampsia, including reduced mmp10 and increased cd36, fzd1, and col1a1. O3 exposure, at both early and late gestation, induced a significant increase in maternal circulating soluble FMS-like tyrosine kinase-1 (sFlt-1), a known driver of preeclampsia. Otherwise, exposure to 0.3 ppm O3 at GD10 led to several late-stage cardiovascular outcomes in dams that were not evident in GD20-exposed dams, including elevated uterine artery resistance index and reduced cardiac output and stroke volume. GD10 O3 exposure proteomic profile in maternal hearts characterized by a reduction in proteins with essential roles in metabolism and mitochondrial function, while phosphoproteomic changes were consistent with pathways involved in cardiomyopathic responses. Thus, the developing placenta is an indirect target of inhaled O3 and that systemic maternal cardiovascular abnormalities may be induced by O3 exposure at a specific window of gestation.

Background Multiwalled carbon nanotubes (MWCNT) are an increasingly utilized engineered nanomaterial that pose the potential for significant risk of exposure-related health outcomes. The mechanism(s) underlying MWCNT-induced toxicity to extrapulmonary sites are still being defined. MWCNT-induced serum-borne bioactivity appears to dysregulate systemic endothelial cell function. The serum compositional changes after MWCNT exposure have been identified as a surge of fragmented endogenous peptides, likely derived from matrix metalloproteinase (MMP) activity. In the present study, we utilize a broad-spectrum MMP inhibitor, Marimastat, along with a previously described oropharyngeal aspiration model of MWCNT administration to investigate the role of MMPs in MWCNT-derived serum peptide generation and endothelial bioactivity. Results C57BL/6 mice were treated with Marimastat or vehicle by oropharyngeal aspiration 1 h prior to MWCNT treatment. Pulmonary neutrophil infiltration and total bronchoalveolar lavage fluid protein increased independent of MMP blockade. The lung cytokine profile similarly increased following MWCNT exposure for major inflammatory markers (IL-1β, IL-6, and TNF-α), with minimal impact from MMP inhibition. However, serum peptidomic analysis revealed differential peptide compositional profiles, with MMP blockade abrogating MWCNT-derived serum peptide fragments. The serum, in turn, exhibited differential potency in terms of inflammatory bioactivity when incubated with primary murine cerebrovascular endothelial cells. Serum from MWCNT-treated mice led to inflammatory responses in endothelial cells that were significantly blunted with serum from Marimastat-treated mice. Conclusions Thus, MWCNT exposure induced pulmonary inflammation that was largely independent of MMP activity but generated circulating bioactive peptides through predominantly MMP-dependent pathways. This MWCNT-induced lung-derived bioactivity caused pathological consequences of endothelial inflammation and barrier disruption.

for the guidance, advice, patience, and overall continued support of my studies as well as giving me the extra push. I would also like to acknowledge Dr. Akshay Sood for his excitement and the work being done and his continued helpful insights. I would also like to acknowledge Dr. Tione Buranda, for his directional support. It has been an honor to have such a trio of a committee, all of whom are brilliant and continue to push me outside of my comfort zone. I would also like to formerly acknowledge the community members of Blue Gap Tachee, AZ. Specifically, I would like to thank Chris Nez, Aaron Yazzie, and Sadie Bill for their enthusiasm and support of us while in Blue Gap. Sadie, thank you for the use of your cabin to house and shelter us from the unforgiving rez winter. Thank you, also for the great conversations, and being patient with what Navajo I could speak. Special acknowledgements also go to all the Campen Lab members (past and present) who took me in as their own and have been supportive of my goals and made the Lab another home for me. I also acknowledge UNM and the Biomedical Sciences Graduate Program for selecting me and providing further guidance. I also acknowledge the support from NIH and from Dr. Campen's grant (NIEHS ES026673), as well as any additional financial support that was provided from the

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