Neutrophils both reduce and increase permeability in a cell culture model of the blood–brain barrier

Inglis, Victoria I.; Jones, Michael P.; Tse, Arthur D.Y.; Easton, Alexander

doi:10.1016/j.brainres.2003.11.031

Cited by 30 publications

(25 citation statements)

References 45 publications

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“…Other in vitro studies have demonstrated that neutrophils increase permeability during migration across cultured primary brain endothelium, both bovine (Inglis et al, 2004) and human (Wong et al, 2007). However, our previous work (Inglis et al, 2004) suggests that neutrophils also reduce permeability in the period preceding migration, so that little net increase occurs.…”

Section: Accepted M Manuscriptmentioning

confidence: 98%

“…Previous work carried out by our group determined that untreated neutrophils (untreated in the sense that inflammatory factors were not applied to induce neutrophil activation) reduce permeability across an in vitro model of the BBB made up of cerebral endothelial cells. When neutrophils were induced to migrate through the endothelial barrier they tended to return the permeability to baseline without inducing net permeability increases (Inglis et al, 2004). This may function to preserve the integrity of the BBB during neutrophil diapedesis.…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

“…Untreated neutrophils were applied above the monolayers at a density of 5 X 10 6 /ml, which reflects neutrophil counts in whole blood (4-11 X 10 6 /ml). We previously observed that it took 30min to see maximum changes in permeability (Inglis et al, 2004) so neutrophils were left for 30min before permeability was measured. Untreated neutrophils reduced permeability to 47.67 ± 2.57 % of baseline (n=7), a significant reduction.…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

“…When untreated neutrophils were applied to the hCMEC/D3 monolayers, they induced a significant reduction in permeability 30min after application. We did not explore the mechanism, but our previous work (Inglis et al, 2004) showed that neutrophils reduce permeability through adenosine and ROS. Treatment with TNF and LtB 4 resulted in generation of ROS, assessed in an independent assay (fig 2A).…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

“…This small increase in permeability back to baseline was blocked with the ROS scavengers catalase and superoxide dismutase. It is of interest that ROS reduce permeability when untreated neutrophils are applied to brain endothelial monolayers (Inglis et al, 2004), but mediate small increases in permeability when neutrophils are activated.…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

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Modulation of blood–brain barrier permeability by neutrophils: in vitro and in vivo studies

et al. 2009

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Abstract.The blood-brain barrier (BBB) restricts solute permeability across healthy cerebral endothelial cells. However, during inflammation, permeability is increased and can lead to deleterious cerebral edema. Neutrophils are early cellular participants in acute inflammation, but their effect on BBB permeability is unclear. To study this, neutrophils were applied in a resting and activated state to in vitro and in vivo models of the BBB. In vitro, human neutrophils (5 X 10 6 /ml) were activated with tumor necrosis factor (100U/ml) and leukotriene B 4 (10 -7 mol/l).Untreated neutrophils reduced permeability across the human brain endothelial cell line hCMEC/ D3. Activated neutrophils returned permeability to baseline, an effect blocked by the reactive oxygen scavengers superoxide dismutase (10U/ml) and catalase (1000U/ml). In vivo, human neutrophils (2.5 X 10 5 in 4μl) were injected into the striatum of anesthetized juvenile Wistar rats, and BBB permeability measured 30 minutes later. This was compared to control injections (4μl) of vehicle (0.9% saline) and arachidonic acid (10 -3 mol/l). The injection generated a small hematoma around the injection tract (<3μl). Untreated neutrophils induced significantly lower permeability in their vicinity than activated neutrophils, with a trend to lowered permeability compared to the vehicle control. Neither untreated nor activated neutrophils induced permeability increases, while arachidonic acid increased permeability as a positive control. This study further delineates the effect of neutrophils on the BBB, and demonstrates that resting neutrophils induce acute reductions in permeability while activated neutrophils have a neutral effect. The in vivo model reiterates some aspects of acute intracerebral hemorrhage.Section: Cellular and molecular biology of nervous systems.

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Section: Accepted M Manuscriptmentioning

confidence: 98%

Section: Accepted M Manuscriptmentioning

confidence: 99%

Section: Accepted M Manuscriptmentioning

confidence: 99%

Section: Accepted M Manuscriptmentioning

confidence: 99%

Section: Accepted M Manuscriptmentioning

confidence: 99%

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Modulation of blood–brain barrier permeability by neutrophils: in vitro and in vivo studies

et al. 2009

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Rethinking CRITID Procedure of Brain Targeting Drug Delivery: Circulation, Blood Brain Barrier Recognition, Intracellular Transport, Diseased Cell Targeting, Internalization, and Drug Release

et al. 2021

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The past decades have witnessed great progress in nanoparticle (NP)‐based brain‐targeting drug delivery systems, while their therapeutic potentials are yet to be fully exploited given that the majority of them are lost during the delivery process. Rational design of brain‐targeting drug delivery systems requires a deep understanding of the entire delivery process along with the issues that they may encounter. Herein, this review first analyzes the typical delivery process of a systemically administrated NPs‐based brain‐targeting drug delivery system and proposes a six‐step CRITID delivery cascade: circulation in systemic blood, recognizing receptor on blood‐brain barrier (BBB), intracellular transport, diseased cell targeting after entering into parenchyma, internalization by diseased cells, and finally intracellular drug release. By dissecting the entire delivery process into six steps, this review seeks to provide a deep understanding of the issues that may restrict the delivery efficiency of brain‐targeting drug delivery systems as well as the specific requirements that may guarantee minimal loss at each step. Currently developed strategies used for troubleshooting these issues are reviewed and some state‐of‐the‐art design features meeting these requirements are highlighted. The CRITID delivery cascade can serve as a guideline for designing more efficient and specific brain‐targeting drug delivery systems.

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Into rather unexplored terrain—transcellular transport across the blood–brain barrier

Bock

Haver

Vandenbroucke

et al. 2016

Glia

129

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Efficient neuronal signaling in the central nervous system strictly depends on a well-balanced microenvironment around glial cells, synapses, and axons. Unique features of the blood-brain barrier (BBB) endothelium largely determine the composition of this micro-milieu and are dependent on the tight interplay with surrounding astrocytes and pericytes. BBB endothelial cells are endowed with a highly restrictive junctional complex that occludes the intercellular cleft, thereby preventing paracellular diffusion. The paracellular pathway is subject to extensive research as integrity loss of the junctional complex is associated with many neuropathologies, inflammation, and edema. Another important feature of the BBB endothelium is the low prevalence of nonspecific, transcytotic events, including (macro)pinocytosis, clathrin-dependent and caveolin-dependent endocytosis and the subsequent trafficking of vesicles to the opposite membrane. Although less studied, evidence is accruing that this pathway importantly contributes to increased BBB permeability, often when the junctional complex remains intact. Here, we review current knowledge on the contribution of the transcellular pathway to the BBB leak observed in different pathologic conditions. In addition, we hypothesize that nonselective, large pore connexin and pannexin channels may contribute to transcellular transport, either by providing a direct diffusion pathway across the endothelial monolayer, or indirectly, by exerting control over intracellular levels of the signaling ion Ca(2+) that is involved in many steps of the vesicular pathway. We conclude that transcytotic events at the BBB, despite being less acknowledged, cannot be simply dismissed as done in the past, but actively contribute to BBB leakage in many different pathologies. GLIA 2016;64:1097-1123.

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Neutrophils both reduce and increase permeability in a cell culture model of the blood–brain barrier

Cited by 30 publications

References 45 publications

Modulation of blood–brain barrier permeability by neutrophils: in vitro and in vivo studies

Modulation of blood–brain barrier permeability by neutrophils: in vitro and in vivo studies

Rethinking CRITID Procedure of Brain Targeting Drug Delivery: Circulation, Blood Brain Barrier Recognition, Intracellular Transport, Diseased Cell Targeting, Internalization, and Drug Release

Into rather unexplored terrain—transcellular transport across the blood–brain barrier

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