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Wildfire smoke, long recognized as a health threat to the lungs and heart, may also pose significant risks to brain health, according to a study published in the International Journal of Molecular Sciences. The research explored how smoldering eucalyptus wood smoke extract affects human brain endothelial cells, which form the blood-brain barrier. Results showed that exposure to the smoke extract increased inflammation and reduced the levels of tight junction markers that help maintain the barrier’s integrity. These changes suggest that inhaling wildfire smoke could contribute to neuroinflammation and increase the risk of neurological disorders.
The study was motivated by growing evidence that wildfire smoke does more than harm respiratory and cardiovascular systems. Epidemiological research has linked wildfire exposure to cognitive deficits and a higher risk of neurodegenerative diseases like Alzheimer’s and Parkinson’s. Researchers at Lawrence Livermore National Laboratory aimed to better understand how smoke might directly affect the brain by investigating its impact on brain endothelial cells.
“As we are all aware, wildfires pose significant health risks, and their frequency and intensity are increasing due to climate change,” explained postdoctoral scholar Dorothy You and senior scientist Bruce Buchholz, the corresponding authors of the study.
“Although many studies have examined the impact of wildfires on the lungs and heart, few have focused on potential changes in the brain resulting from wildfire smoke exposure. Some studies have suggested that wildfire smoke exposure can affect cognitive function, and we aimed to understand its potential impact on the brain at the cellular level.”
“Neuroinflammation is linked to the protein pathologies of neurodegenerative diseases, such as amyloid plaques and neurofibrillary tangles in Alzheimer’s disease and Lewy bodies in Parkinson’s disease,” the researchers explained. “We wanted to investigate whether exposure to wood smoke could trigger neuroinflammation. Brain endothelial cells, which line the capillaries, play a crucial role in forming the blood-brain barrier.”
To examine the effects of wildfire smoke, the researchers used an in vitro approach, exposing two types of human brain endothelial cells to smoldering eucalyptus wood smoke extract for 24 hours. The two cell models included primary human brain microvascular endothelial cells and an immortalized brain endothelial cell line. The smoke extract, provided by the United States Environmental Protection Agency, was prepared from eucalyptus wood burned during its smoldering phase, which produces high levels of particulate matter and toxic chemicals.
The study involved multiple steps to assess the cellular response. After treating the cells with varying concentrations of smoke extract, the researchers measured the production of inflammatory molecules, changes in gene expression, and markers associated with the cells’ structural integrity. They also evaluated whether the smoke extract caused cell death or oxidative stress. Advanced techniques, such as RNA sequencing, were used to identify changes in gene activity, while microscopic imaging was employed to observe structural proteins.
The findings revealed that the smoke extract triggered a dose-dependent increase in interleukin-8, a pro-inflammatory cytokine. Interleukin-8 plays a role in recruiting immune cells to areas of inflammation, and its elevated levels suggest that the smoke extract incites an inflammatory response in brain endothelial cells. Notably, the primary brain endothelial cells showed a stronger response compared to the immortalized cell line, indicating that the primary cells might better mimic the effects seen in living tissues.
“It was quite surprising to observe that two different types of brain endothelial cells responded similarly to wood smoke extracts,” You and Buchholz told PsyPost. “Although both are types of brain endothelial cells, one is an immortalized cell line intended for long-term use in the lab, whereas the other is composed of primary cells that closely mimic those found in actual tissue. Both shared very similar inflammatory pathways, suggesting that wood smoke induces a specific type of inflammation in brain endothelial cells. However, the primary cells showed a more pronounced response to the wood smoke extract.”
The study also uncovered that exposure to the smoke extract disrupted the expression of tight junction proteins, including ZO-1, ZO-2, and occludin, which are essential for maintaining the blood-brain barrier’s structural integrity. While changes in these proteins were more pronounced at the genetic level than at the protein level during the 24-hour exposure, this disruption could potentially make the barrier more permeable. Such permeability would allow harmful substances, including toxins and inflammatory molecules, to enter the brain more easily.
Additionally, the smoke extract activated specific cellular pathways related to inflammation and oxidative stress. These pathways, known as the aryl hydrocarbon receptor (AhR) pathway and the nuclear factor erythroid 2-related factor 2 (NRF2) pathway, mediate the body’s response to toxic environmental substances. Both pathways have been implicated in neuroinflammation and damage to the blood-brain barrier in prior research. The study also identified genes associated with ferroptosis, a type of cell death linked to oxidative stress and lipid damage, suggesting that smoke exposure may have broader implications for brain cell health.
“The main takeaway from this study is that inhaling wildfire smoke not only impacts the lungs and heart, but it can also potentially affect brain health,” the researchers said. “So, It is best to stay indoors when air quality is hazardous and wear a mask if you must go outside during poor air quality.”
Despite the significant findings, the study has some limitations. It focused solely on two types of brain endothelial cells and did not account for the interactions between endothelial cells and other brain cell types, such as neurons or astrocytes, which play important roles in brain health and disease. Furthermore, the study examined the effects of acute exposure to smoke extract over 24 hours.
“Given that many communities experiencing wildfires are exposed to wildfire smoke and poor air quality for extended periods, future studies should explore the long-term, chronic effects of repeated or prolonged exposure to wildfire smoke,” You and Buchholz said.
The researchers also noted that the composition of wildfire smoke varies depending on factors such as the type of biomass burned and the combustion conditions. For example, smoldering fires produce more fine particulate matter and toxic compounds than flaming fires.
“Smoke travels long distances and changes chemically as it ages,” the researchers noted. “The composition of smoke in exposures to firefighters is not the same as to the general population downwind.”
This variability underscores the importance of assessing the neurotoxicity of different types of biomass beyond smoldering eucalyptus to determine which might pose greater risks to brain health.
The ultimate aim of this line of research is, as the researchers put it, “to understand the impact of wildfire smoke on the brain, with a focus on identifying the potential route of entrance for wildfire smoke particles into the brain, which has been unclear to the scientific community.”
“Smoke consists of particles ranging from ultrafine sizes (less than 0.1 micrometers or 100 nanometers) to relatively large condensed agglomerations greater than 10 micrometers, along with thousands of chemical combustion products that tend to condense onto particles as the smoke cools,” You and Buchholz explained. “The smallest particles can be inhaled deep into the lungs and deposited there. This study examined the response of brain endothelial cells to combustion products delivered through the bloodstream. Evidence in the literature suggests that small particles can also be deposited in nasal tissues and transported to the olfactory bulb in the brain. It is likely that smoke particles and condensates can reach the brain through both routes.”
The study, “Eucalyptus Wood Smoke Extract Elicits a Dose-Dependent Effect in Brain Endothelial Cells,” was authored by Dorothy J. You, Bria M. Gorman, Noah Goshi, Nicholas R. Hum, Aimy Sebastian, Yong Ho Kim, Heather A. Enright, and Bruce A. Buchholz.
