The Stroke-Induced Blood-Brain Barrier Disruption: Current Progress of Inspection Technique, Mechanism, and Therapeutic Target

Stroke is one of the leading causes of mortality and morbidity worldwide. The bloodbrain barrier (BBB) is a characteristic structure of microvessel within the brain. Under normal physiological conditions, the BBB plays a role in the prevention of harmful substances entering into the brain parenchyma within the central nervous system. However, stroke stimuli induce the breakdown of BBB leading to the influx of cytotoxic substances, vasogenic brain edema, and hemorrhagic transformation. Therefore, BBB disruption is a major complication, which needs to be addressed in order to improve clinical outcomes in stroke. In this review, we first discuss the structure and function of the BBB. Next, we discuss the progress of the techniques utilized to study BBB breakdown in in-vitro and in-vivo studies, along with biomarkers and imaging techniques in clinical settings. Lastly, we highlight the mechanisms of stroke-induced neuroinflammation and apoptotic process of endothelial cells causing BBB breakdown, and the potential therapeutic targets to protect BBB integrity after stroke. Secondary products arising from stroke-induced tissue damage provide transformation of myeloid cells such as microglia and macrophages to pro-inflammatory phenotype followed by further BBB disruption via neuroinflammation and apoptosis of endothelial cells. In contrast, these myeloid cells are also polarized to anti-inflammatory phenotype, repairing compromised BBB. Therefore, therapeutic strategies to induce anti-inflammatory phenotypes of the myeloid cells may protect BBB in order to improve clinical outcomes of stroke patients.

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Caveolae control the anti‐inflammatory phenotype of senescent endothelial cells

Aging Cell ◽

10.1111/acel.12270 ◽

2014 ◽

Vol 14 (1) ◽

pp. 102-111 ◽

Cited By ~ 20

Author(s):

Elizabeth E. Powter ◽

Paul R. Coleman ◽

Mai H. Tran ◽

Angelina J. Lay ◽

Patrick Bertolino ◽

...

Keyword(s):

Endothelial Cells ◽

Inflammatory Phenotype ◽

Anti Inflammatory

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SIK inhibition in human myeloid cells modulates TLR and IL-1R signaling and induces an anti-inflammatory phenotype

Journal of Leukocyte Biology ◽

10.1189/jlb.2a0715-307r ◽

2015 ◽

Vol 99 (5) ◽

pp. 711-721 ◽

Cited By ~ 19

Author(s):

Maria Stella Lombardi ◽

Corine Gilliéron ◽

Damien Dietrich ◽

Cem Gabay

Keyword(s):

Myeloid Cells ◽

Inflammatory Phenotype ◽

Anti Inflammatory

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Imaging of Neurotrauma in Acute and Chronic Settings

Current Neuropharmacology ◽

10.2174/1570159x19666210517114823 ◽

2021 ◽

Vol 19 ◽

Author(s):

Shane Mallon ◽

Jacek M. Kwiecien ◽

John P. Karis

Keyword(s):

Spinal Cord ◽

Imaging Techniques ◽

Vasogenic Edema ◽

Prognostic Information ◽

Cord Injury ◽

Exciting Potential ◽

Anti Inflammatory ◽

Work Up ◽

Brain And Spinal Cord ◽

The Brain

: Traumatic injuries of the brain and spinal cord are a significant source of mortality and long-term disability. A recent systematic study in a rat model of spinal cord injury (SCI) indicates severe, destructive, and very protracted inflammation as the key mechanism initiated by the massive injury involving the white matter. Although the severe inflammation is localized and counteracted by astrogliosis, it has a damaging effect on the blood vessels in the surrounding spinal cord, leading to persistent vasogenic edema. To evaluate these injuries, imaging of the brain and spinal cord plays a crucial role in the acute trauma work-up, allowing clinicians to quickly identify abnormalities that require immediate medical or surgical intervention or to exclude them from the work-up. Recently, anti-inflammatory agents have been shown to inhibit and accelerate the elimination of post-SCI inflammation in preclinical studies, and an exciting potential has arisen for the use of anti-inflammatory drugs in clinical studies to achieve neuroprotection (i.e., inhibition of destruction caused by inflammation) and to inhibit vasogenic edema in SCI, traumatic brain injury, and stroke. In both subacute and chronic settings, imaging can be a guide to therapy and provide important prognostic information. In this review, we discuss the imaging work-up and evolving imaging findings of neurotrauma in the acute and chronic setting, including conventional and advanced imaging techniques. As neuroimaging is the primary mode of diagnostic analysis in neurotrauma, it is a critical component in future clinical trials evaluating neuroprotective therapies.

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Schistosoma mansoni Activates Host Microvascular Endothelial Cells To Acquire an Anti-Inflammatory Phenotype

Infection and Immunity ◽

10.1128/iai.67.7.3403-3409.1999 ◽

1999 ◽

Vol 67 (7) ◽

pp. 3403-3409 ◽

Cited By ~ 22

Author(s):

Francois Trottein ◽

Laurence Descamps ◽

Sophie Nutten ◽

Marie-Pierre Dehouck ◽

Veronique Angeli ◽

...

Keyword(s):

Endothelial Cells ◽

Schistosoma Mansoni ◽

Kinase Inhibitors ◽

Microscopic Analysis ◽

Immune Defense ◽

Inflammatory Factor ◽

Microvascular Endothelium ◽

Inflammatory Phenotype ◽

Anti Inflammatory

ABSTRACT Since endothelial cells (ECs) play a key role in immune defense mechanisms and in immunopathology, we investigated whether the intravascular helminth parasite Schistosoma mansoni could interact with and activate resting ECs in vitro. Microscopic analysis revealed that the lung-stage schistosomula specifically attached to microvascular ECs. This adherence was associated to active cellular processes involving actin filament formation. Since variation of permeability of cultured capillary brain ECs is a good marker for endothelial activation, the transendothelial passage of a low-molecular-weight molecule (inulin) on monolayers of bovine brain capillary ECs (BBCEC) was measured in response to parasites. Schistosomula induced a dramatic decrease in transendothelial permeability, a characteristic marker for the generation of an anti-inflammatory phenotype to ECs. This paracellular barrier enhancing effect on endothelial monolayers was due to a soluble substance(s) (below 1 kDa in size) secreted from S. mansonischistosomula and not by mechanisms associated to adherence between parasites and ECs. The reinforcement of the endothelial barrier function was accompanied by an elevation of intracellular concentration of cyclic AMP (cAMP). The use of specific kinase inhibitors confirms that schistosomula activate ECs through a cAMP/protein kinase A pathway that leads to an increased phosphorylation of the myosin light-chain kinase. These combined findings suggest that the secretory/excretory products from schistosomula possess anti-inflammatory factor(s) that signal host microvascular endothelium. The immunological consequences of such activation are discussed.

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Multicellular 3D Neurovascular Unit Model for Assessing Hypoxia and Neuroinflammation Induced Blood-Brain Barrier Dysfunction

Scientific Reports ◽

10.1038/s41598-020-66487-8 ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 3

Author(s):

Goodwell Nzou ◽

Robert T. Wicks ◽

Nicole R. VanOstrand ◽

Gehad A. Mekky ◽

Stephanie A. Seale ◽

...

Keyword(s):

Endothelial Cells ◽

Blood Brain Barrier ◽

Inflammatory Cytokine ◽

Disease Modeling ◽

Neurovascular Unit ◽

Brain Barrier ◽

Dynamic Component ◽

Blood Brain ◽

Anti Inflammatory ◽

The Brain

AbstractThe blood-brain barrier (BBB) is a dynamic component of the brain-vascular interface that maintains brain homeostasis and regulates solute permeability into brain tissue. The expression of tight junction proteins between adjacent endothelial cells and the presence of efflux proteins prevents entry of foreign substances into the brain parenchyma. BBB dysfunction, however, is evident in many neurological disorders including ischemic stroke, trauma, and chronic neurodegenerative diseases. Currently, major contributors to BBB dysfunction are not well understood. Here, we employed a multicellular 3D neurovascular unit organoid containing human brain microvascular endothelial cells, pericytes, astrocytes, microglia, oligodendrocytes and neurons to model the effects of hypoxia and neuroinflammation on BBB function. Organoids were cultured in hypoxic chamber with 0.1% O2 for 24 hours. Organoids cultured under this hypoxic condition showed increased permeability, pro-inflammatory cytokine production, and increased oxidative stress. The anti-inflammatory agents, secoisolariciresinol diglucoside and 2-arachidonoyl glycerol, demonstrated protection by reducing inflammatory cytokine levels in the organoids under hypoxic conditions. Through the assessment of a free radical scavenger and an anti-inflammatory endocannabinoid, we hereby report the utility of the model in drug development for drug candidates that may reduce the effects of ROS and inflammation under disease conditions. This 3D organoid model recapitulates characteristics of BBB dysfunction under hypoxic physiological conditions and when exposed to exogenous neuroinflammatory mediators and hence may have potential in disease modeling and therapeutic development.

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Factor VIIa suppresses inflammation and barrier disruption through the release of EEVs and transfer of microRNA 10a

Blood ◽

10.1182/blood.2021012358 ◽

2021 ◽

Author(s):

Kaushik Das ◽

Shiva Keshava ◽

Usha R. Pendurthi ◽

L. Vijaya Mohan Rao

Keyword(s):

Endothelial Cells ◽

Factor Viia ◽

In Vivo Studies ◽

Cell Protein ◽

Protective Effects ◽

Rock Inhibitor ◽

In Vivo Models ◽

Micro Rnas ◽

Anti Inflammatory

Coagulation protease, factor VIIa (FVIIa) binds endothelial cell protein C receptor (EPCR) and induces anti-inflammatory and endothelial barrier protective responses via protease-activated receptor-1 (PAR1)-mediated biased signaling. Our recent studies showed that the FVIIa-EPCR-PAR1 axis induces the release of extracellular vesicles (EVs) from endothelial cells. The present study investigates the mechanism of FVIIa release of endothelial EVs (EEVs) and the contribution of FVIIa-released EEVs to anti-inflammatory and vascular barrier protective effects both in vitro and in vivo models. Data presented in the manuscript show multiple signaling pathways regulate FVIIa release of EVs from endothelial cells, but the ROCK-dependent pathway appears to be a major mechanism. FVIIa-released EEVs are enriched with anti-inflammatory micro RNAs, mostly miR10a. FVIIa-released EEVs were taken up readily by monocytes/macrophages and endothelial cells. The uptake of FVIIa-released EEVs by monocytes conferred anti-inflammatory phenotype to monocytes, whereas EEVs uptake by endothelial cells resulted in barrier protection. Additional studies showed that EEVs-mediated delivery of miR10a to monocytes downregulates the expression of TAK1 and activation of the NF-ĸB-mediated inflammatory pathway. In vivo studies showed that administering FVIIa-released EEVs to wild-type mice attenuated LPS-induced increased inflammatory cytokines in plasma and vascular leakage into vital tissues. The incorporation of anti-miR10a into FVIIa-released EEVs diminished the ability of FVIIa-released EEVs to confer cytoprotective effects. Administration of ROCK inhibitor Y27632 to mice, which significantly inhibits FVIIa release of EEVs into circulation, attenuates the cytoprotective effects of FVIIa. Overall, our present study reveals novel insights into how FVIIa induces cytoprotective effects and communicates with various cell types.

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IL-4: PREDIKTOR ANTI INFLAMASI PADA STROKE ISKEMIK ?

Medicinus ◽

10.19166/med.v5i1.1178 ◽

2018 ◽

Vol 5 (1) ◽

Author(s):

Lucia Herminawati ◽

Julius July

Keyword(s):

Ischemic Stroke ◽

Immune Cell ◽

Vascular Occlusion ◽

Vital Role ◽

Interleukin 4 ◽

Mhc Ii ◽

Inflammatory Phenotype ◽

Anti Inflammatory ◽

The Brain ◽

Stimulation Of

The brain ischemia due to vascular occlusion, especially in the main cerebral artery, could trigger the microglia as a natural immune cell in the brain. These activated microglia will turn up the inflammation cascade in the ischemic area. Interleukin-4 (IL-4) has a vital role in the microglial alteration to become an anti-inflammatory phenotype, which wind up the expression of MHC II and CD11c. Moreover, previous studies has supported that the stimulation of IL-4 in the culture of microglia/macrophage will produce this kind of “alternative” phenotype or neuroprotective phenotype, through the fall of TNF and rise of IGF-1. However, only a few have discussed the role and profile of IL-4 in ischemic stroke. This review article will cover the possibility of IL-4 role as an anti-inflammatory predictor in ischemic stroke.Keywords: Interleukin-4, microglia, ischemic stroke, inflammation

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Endotoxin Alteration of the Mucopolysaccharide Blood Vessel Coating in Rats

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100050755 ◽

1974 ◽

Vol 32 ◽

pp. 148-149

Author(s):

D. E. Philpott ◽

A. Takahashi

Keyword(s):

Skeletal Muscle ◽

Endothelial Cells ◽

Salivary Gland ◽

Carotid Artery ◽

Basement Membrane ◽

Coronary Vessels ◽

Ruthenium Red ◽

E Coli ◽

Old Rats ◽

The Brain

Two month, eight month and two year old rats were treated with 10 or 20 mg/kg of E. Coli endotoxin I. P. The eight month old rats proved most resistant to the endotoxin. During fixation the aorta, carotid artery, basil arartery of the brain, coronary vessels of the heart, inner surfaces of the heart chambers, heart and skeletal muscle, lung, liver, kidney, spleen, brain, retina, trachae, intestine, salivary gland, adrenal gland and gingiva were treated with ruthenium red or alcian blue to preserve the mucopolysaccharide (MPS) coating. Five, 8 and 24 hrs of endotoxin treatment produced increasingly marked capillary damage, disappearance of the MPS coating, edema, destruction of endothelial cells and damage to the basement membrane in the liver, kidney and lung.

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