It is unclear whether severe acute respiratory syndrome coronavirus 2, which causes coronavirus disease 2019, can enter the brain. Severe acute respiratory syndrome coronavirus 2 binds to cells via ...the S1 subunit of its spike protein. We show that intravenously injected radioiodinated S1 (I-S1) readily crossed the blood-brain barrier in male mice, was taken up by brain regions and entered the parenchymal brain space. I-S1 was also taken up by the lung, spleen, kidney and liver. Intranasally administered I-S1 also entered the brain, although at levels roughly ten times lower than after intravenous administration. APOE genotype and sex did not affect whole-brain I-S1 uptake but had variable effects on uptake by the olfactory bulb, liver, spleen and kidney. I-S1 uptake in the hippocampus and olfactory bulb was reduced by lipopolysaccharide-induced inflammation. Mechanistic studies indicated that I-S1 crosses the blood-brain barrier by adsorptive transcytosis and that murine angiotensin-converting enzyme 2 is involved in brain and lung uptake, but not in kidney, liver or spleen uptake.
Systemic inflammation has been implicated in the progression of Alzheimer's disease (AD); however, less is understood about how existing AD pathology contributes to adverse outcomes following acute ...inflammatory insults. In the present study, our goal was to determine how AD-associated amyloid beta (Aβ) pathology influences the acute neuroinflammatory and behavioral responses to a moderate systemic inflammatory insult. We treated 16-18-month-old female Tg2576 (Tg) mice, which overproduce human Aβ and develop plaques, and age-matched wild-type (WT) littermate mice with an intraperitoneal injection of 0.33 mg/kg lipopolysaccharide (LPS) or saline. Mice were then evaluated over the next 28 h for sickness/depressive-like behaviors (food intake, weight loss, locomotion, and sucrose preference), systemic inflammation (serum amyloid A, SAA), blood-brain barrier (BBB) disruption, astrogliosis (glial fibrillary acidic protein/GFAP), Aβ, and cytokine levels in the brain. We found that LPS caused a larger reduction in body weight in Tg vs. WT mice, but that other behavioral responses to LPS did not differ by genotype. BBB disruption was not apparent in either genotype following LPS. Concentrations of the systemic inflammatory marker, SAA, in the blood and brain were significantly increased with LPS but did not significantly differ by genotype. GFAP was increased in Tg mice vs. WT but was not significantly affected by LPS in either genotype. Finally, LPS-induced increases of eight cytokines (IL-1β, IL-6, IL-12 (p40), IL-10, IL-17A, MIP-1α/CCL3, MIP-1β/CCL4, and RANTES/CCL5) were found to be significantly higher in Tg mice vs. WT. In summary, our data show that Aβ pathology exacerbates the neuroinflammatory response to LPS and identifies cytokines that are selectively regulated by Aβ. The association of worse neuroinflammation with greater weight loss in Tg mice suggests that Aβ pathology could contribute to poor outcomes following a systemic inflammatory insult.
Ozone (O
) is an air pollutant that primarily damages the lungs, but growing evidence supports the idea that O
also harms the brain; acute exposure to O
has been linked to central nervous system ...(CNS) symptoms such as depressed mood and sickness behaviors. However, the mechanisms by which O
inhalation causes neurobehavioral changes are limited. One hypothesis is that factors in the circulation bridge communication between the lungs and brain following O
exposure. In this study, our goals were to characterize neurobehavioral endpoints of O
exposure as they relate to markers of systemic and pulmonary inflammation, with a particular focus on serum amyloid A (SAA) and kynurenine as candidate mediators of O
behavioral effects. We evaluated O
-induced dose-, time- and sex-dependent changes in pulmonary inflammation, circulating SAA and kynurenine and its metabolic enzymes, and sickness and depressive-like behaviors in Balb/c and CD-1 mice. We found that 3 parts per million (ppm) O
, but not 2 or 1 ppm O
, increased circulating SAA and lung inflammation, which were resolved by 48 h and was worse in females. We also found that indoleamine 2,3-dioxygenase (
) mRNA expression was increased in the brain and spleen 24 h after 3 ppm O
and that kynurenine was increased in blood. Sickness and depressive-like behaviors were observed at all O
doses (1-3 ppm), suggesting that behavioral responses to O
can occur independently of increased SAA or neutrophils in the lungs. Using SAA knockout mice, we found that SAA did not contribute to O
-induced pulmonary damage or inflammation, systemic increases in kynurenine post-O
, or depressive-like behavior but did contribute to weight loss. Together, these findings indicate that acute O
exposure induces transient symptoms of sickness and depressive-like behaviors that may occur in the presence or absence of overt pulmonary neutrophilia and systemic increases of SAA. SAA does not appear to contribute to pulmonary inflammation induced by O
, although it may contribute to other aspects of sickness behavior, as reflected by a modest effect on weight loss.
One important function of the vascular blood-brain barrier (BBB) is to facilitate neuroimmune communication. The BBB fulfills this function, in part, through its ability to transport cytokines and ...chemokines. C-C motif chemokine receptor 2 (CCL2) (MCP-1) and C-C motif chemokine receptor 5 (CCL5) (RANTES) are proinflammatory chemokines that mediate neuroimmune responses to acute insults and aspects of brain injury and neurodegenerative diseases; however, a blood-to-brain transport system has not been evaluated for either chemokine in vivo. Therefore, we determined whether CCL2 and CCL5 in blood can cross the intact BBB and enter the brain. Using CD-1 mice, we found that
I-labeled CCL2 and CCL5 crossed the BBB and entered the brain parenchyma. We next aimed to identify the mechanisms of
I-CCL2 and
I-CCL5 transport in an in situ brain perfusion model. We found that both heparin and eprodisate inhibited brain uptake of
I-CCL2 and
I-CCL5 in situ, whereas antagonists of their receptors, CCR2 or CCR5, respectively, did not, suggesting that heparan sulfates at the endothelial surface mediate BBB transport. Finally, we showed that CCL2 and CCL5 transport across the BBB increased following a single injection of 0.3 mg/kg lipopolysaccharide. These data demonstrate that CCL2 and CCL5 in the brain can derive, in part, from the circulation, especially during systemic inflammation. Further, binding to the BBB-associated heparan sulfate is a mechanism by which both chemokines can cross the intact BBB, highlighting a novel therapeutic target for treating neuroinflammation. SIGNIFICANCE STATEMENT: Our work demonstrates that C-C motif chemokine ligand 2 (CCL2) and C-C motif chemokine ligand 5 (CCL5) can cross the intact blood-brain barrier and that transport is robustly increased during inflammation. These data suggest that circulating CCL2 and CCL5 can contribute to brain levels of each chemokine. We further show that the transport of both chemokines is inhibited by heparin and eprodisate, suggesting that CCL2/CCL5-heparan sulfate interactions could be therapeutically targeted to limit accumulation of these chemokines in the brain.
•Two models of SARS-CoV-2 and all S1 protein Variants of Concern readily cross the BBB.•The SARS-CoV-2 pseudovirus is taken up by microglia and induce neuroinflammation.•The S1-induced ...neuroinflammation is exacerbated in a mouse model of Alzheimer’s disease.
COVID-19 and especially Long COVID are associated with severe CNS symptoms and may place persons at risk to develop long-term cognitive impairments. Here, we show that two non-infective models of SARS-CoV-2 can cross the blood–brain barrier (BBB) and induce neuroinflammation, a major mechanism underpinning CNS and cognitive impairments, even in the absence of productive infection. The viral models cross the BBB by the mechanism of adsorptive transcytosis with the sugar N-acetylglucosamine being key. The delta and omicron variants cross the BB B faster than the other variants of concern, with peripheral tissue uptake rates also differing for the variants. Neuroinflammation induced by icv injection of S1 protein was greatly enhanced in young and especially in aged SAMP8 mice, a model of Alzheimer’s disease, whereas sex and obesity had little effect.
Purpose
Anesthetics are required for procedures that deliver drugs/biologics, infectious/inflammatory agents, and toxicants directly to the lungs. However, the possible confounding effects of ...anesthesia on lung inflammation and injury are underreported. Here, we evaluated the effects of two commonly used anesthetic regimens on lung inflammatory responses to ozone in mice.
Methods
We tested the effects of brief isoflurane (Iso) or ketamine/xylazine/atipamezole (K/X/A) anesthesia prior to ozone exposure (4 h, 3 ppm) on lung inflammatory responses in mice. Anesthesia regimens modeled those used for non-surgical intratracheal instillations and were administered 1–2 h or 24 h prior to initiating ozone exposure.
Results
We found that Iso given 1–2 h prior to ozone inhibited inflammatory responses in the lung, and this effect was absent when Iso was given 23–24 h prior to ozone. In contrast, K/X/A given 1–2 h prior to ozone increased lung and systemic inflammation.
Conclusion
Our results highlight the need to comprehensively evaluate anesthesia as an experimental variable in the assessment of lung inflammation in response to ozone and other inflammatory stimuli.
Best practice for prevention, diagnosis, and management of venous thromboembolism (VTE) in patients with coronavirus disease 2019 (COVID‐19) is unknown due to limited published data in this ...population.
We aimed to assess current global practice and experience in management of COVID‐19–associated coagulopathy to identify information to guide prospective and randomized studies.
Physicians were queried about their current approach to prophylaxis, diagnosis, and treatment of VTE in patients with COVID‐19 using an online survey tool distributed through multiple international organizations between April 10 and 14, 2020.
Five hundred fifteen physicians from 41 countries responded. The majority of respondents (78%) recommended prophylactic anticoagulation for all hospitalized patients with COVID‐19, with most recommending use of low‐molecular‐weight heparin or unfractionated heparin. Significant practice variation was found regarding the need for dose escalation of anticoagulation outside the setting of confirmed or suspected VTE. Respondents reported the use of bedside testing when unable to perform standard diagnostic imaging for diagnosis of VTE. Two hundred ninety‐one respondents reported observing thrombotic complications in their patients, with 64% noting that the complication was pulmonary embolism. Of the 44% of respondents who estimated incidence of thrombosis in patients with COVID‐19 in their hospital, estimates ranged widely from 1% to 50%. One hundred seventy‐four respondents noted bleeding complications (34% minor bleeding, 14% clinically relevant nonmajor bleeding, and 12% major bleeding).
Well‐designed epidemiologic studies are urgently needed to understand the incidence and risk factors of VTE and bleeding complications in patients with COVID‐19. Randomized clinical trials addressing use of anticoagulation are also needed. Display omitted
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Bundles of multi-walled carbon nanotubes of uniform diameter decorated with Ni nanoparticles were synthesized using mesoporous silicates as templates. The ordered morphology and the narrow pore size ...distribution of mesoporous silicates provide an ideal platform to synthesize uniformly sized carbon nanotubes. In addition, homogeneous sub-10 nm pore sizes of the templates allow in situ formation of catalytic nanoparticles with uniform diameters which end up decorating the carbon nanotubes. The resulting carbon nanotubes are multi-walled with a uniform diameter corresponding to the pore diameter of the template used during the synthesis that are decorated with the catalysts used to synthesize them. They have a narrow size distribution which can be used in many energy related fields of research.
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