Inflammatory Mediators of Cerebral Endothelium: A Role in Ischemic Brain Inflammation

Stanimirovic, Danica; Satoh, Kei

doi:10.1111/j.1750-3639.2000.tb00248.x

Cited by 283 publications

(190 citation statements)

References 126 publications

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“…One of the classic hallmarks of reperfusion (secondary) injury in the brain is an inflammatory reaction (Stanimirovic and Satoh, 2000). Neutrophil influx occurs in the first 24 h after ischemia followed by monocyte migration from 24 h up to 5 days (Hallenbeck et al, 1986;Danton and Dietrich, 2003).…”

Section: Discussionmentioning

confidence: 99%

Effects of the Chemokine CCL2 on Blood–Brain Barrier Permeability during Ischemia–Reperfusion Injury

Dimitrijevic

Stamatovic

Keep

et al. 2006

J Cereb Blood Flow Metab

225

196

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The chemokine CCL2 is considered as one of the main effectors driving postischemic infiltration of monocytes into the brain parenchyma. New experimental data, however, suggest that CCL2 could also participate in blood-brain barrier (BBB) 'opening' during the transmigration of monocytes. The current study examines the role of CCL2 in regulating BBB permeability after ischemia in vitro. To address this issue, an in vitro BBB model (coculture of astrocytes and brain endothelial cells) was subjected to 5 h of oxygen glucose deprivation, followed by reoxgenation (in vitro ischemia/ reperfusion (I/R)) for 0 to 48 h. During reperfusion, there was a biphasic enhancement of barrier permeability, with a 200-fold increase in barrier permeability to FITC-albumin at 6 h and a further period of disruption around 24 h. The latter coincided with increased secretion of CCL2 by both astrocytes and brain endothelial cells and increased levels of the CCL2 receptor, CCR2. Applying antisense oligonucleotide or neutralizing antibody to block CCL2 significantly decreased I/Rinduced enhancement of BBB permeability (approximately twofold) and redistribution of tightjunction (TJ) proteins (occludin, zonula occluden-1, 2, claudin-5). Similarly, absence of CCR2 from endothelial cells caused stabilization of TJ complexes and decreased the permeability of brain endothelial barrier during in vitro I/R. These data suggest CCL2/CCR2 has an important role in regulating brain endothelial permeability and might be a potential novel therapeutic target for stroke.

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Section: Discussionmentioning

confidence: 99%

Effects of the Chemokine CCL2 on Blood–Brain Barrier Permeability during Ischemia–Reperfusion Injury

Dimitrijevic

Stamatovic

Keep

et al. 2006

J Cereb Blood Flow Metab

225

196

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“…IL-8, which is predominantly discharged from activated macrophages and endothelial cells into the circulation, represents an important chemoattractant for neutrophil granulocytes. During the whole-body inflammation in septic shock, these granulocytes release destructive superoxide anions and lysosomal enzymes such as PMN elastase upon activation (37)(38)(39)(40). Since significant differences between patients receiving hydrocortisone or placebo were shown only for IL-8 serum concentrations compared to baseline levels, hydrocortisone does not seem to have a substantial influence on the release of PMN elastase in hyperdynamic septic shock.…”

Section: Discussionmentioning

confidence: 99%

Effect of stress doses of hydrocortisone on S-100B vs. interleukin-8 and polymorphonuclear elastase levels in human septic shock

Mussack¹,

Briegel²,

Schelling³

et al. 2005

Clinical Chemistry and Laboratory Medicine (CCLM)

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Stress doses of hydrocortisone are known to have immunomodulatory effects in patients with hyperdynamic septic shock. The prognosis correlates with the presence and severity of septic encephalopathy. However, neurological evaluation is influenced by the use of analgesia sedation during artificial ventilation. The objective of this study was to demonstrate the effect of stress doses of hydrocortisone during the initial phase of human septic shock on the serum values of the neurospecific protein S-100B in comparison to the inflammation markers interleukin (IL)-8 in serum and polymorphonuclear (PMN) elastase in plasma. A total of 24 consecutive patients, who met the American College of Chest Physicians/Society of Critical Care Medicine criteria for septic shock, were enrolled in this prospective, randomized, double-blind, singlecenter trial. The severity of illness at recruitment was graded using the Acute Physiology and Chronic Health Evaluation II and the Simplified Acute Physiology Score II scoring systems. Multi-organ dysfunction syndrome was described by the Sepsis-related Organ Failure Assessment (SOFA) score. All patients were prospectively randomized to receive either stress doses of hydrocortisone or placebo. Hydrocortisone was started in 12 patients with a loading dose of 100 mg and followed by a continuous infusion of 0.18 mg/kg/h for 6 days. Median S-100B serum levels of the hydrocortisone group decreased from 0.32 ng/mL at study entry to 0.07 ng/mL 6 days later without significant differences compared to the placebo group. Initial IL-8 serum levels were significantly higher in the hydrocortisone group up to 12 h after study entry, and significantly decreased from 715 to 17 pg/mL at the end of the observation period. Median PMN elastase plasma levels were not affected by hydrocortisone infusion. Patients with initial S-100B *Corresponding author: Thomas Mussack, MD, Department of Surgery Innenstadt, Klinikum der Universitä t Mü nchen, Nussbaumstraße 20, 80336 Mü nchen, Germany Phone: q49-89-5160-2638, Fax: q49-89-5160-4489, E-mail: thomas.mussack@med.uni-muenchen.de serum levels )0.50 ng/mL revealed significantly higher SOFA scores up to 30 h, IL-8 serum levels up to 12 h, and PMN elastase plasma levels up to 36 h after study entry than those patients with F0.50 ng/mL. These effects were independent of the amount of fluid correction for hemodilution. Starting S-100B, IL-8 and PMN elastase values of the hydrocortisone group were within the ranges already known in patients with out-of-hospital cardiac arrest or severe traumatic brain injury. Stress doses of hydrocortisone resulted in a significant reduction in IL-8 serum, but not in S-100B serum and PMN elastase plasma concentrations in patients with hyperdynamic septic shock. For the first time, a similar extent of S-100B increase in serum of septic patients at the time of diagnosis was shown as reported for cardiac arrest or severe traumatic brain injury.

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“…However, increased microvascular permeability during inflammatory responses is closely correlated with the expression of proinflammatory mediators (Stanimirovic and Satoh, 2000;Petty and Lo, 2002). While BBB disruption may lead to the entry of leukocytes into brain, some recent studies indicate that migration of leukocytes may contribute to the persistence of increased vascular permeability (Merrill and Murphy, 1997;Couraud, 1998).…”

Section: Introductionmentioning

confidence: 99%

Monocyte Chemoattractant Protein-1 Regulation of Blood–Brain Barrier Permeability

Stamatovic

Shakui

Keep

et al. 2005

J Cereb Blood Flow Metab

347

316

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The present study was designed to elucidate the effects of the chemokine monocyte chemoattractant protein (MCP-1) on blood-brain barrier (BBB) permeability. Experiments were conducted under in vitro conditions (coculture of brain endothelial cells and astrocytes) to study the cellular effects of MCP-1 and under in vivo conditions (intracerebral and intracerebroventricular administration of MCP-1) to study the potential contribution of MCP-1 to BBB disruption in vivo. Our results showed that MCP-1 induces a significant increase in the BBB permeability surface area product for fluorescein isothiocyanate (FITC)-albumin under in vivo conditions, particularly during prolonged (3 or 7 days) exposure (0.09670.008 versus 0.03170.005 lL/g min in controls at 3 days, Po0.001). Monocyte chemoattractant protein-1 also enhanced (17-fold compared with control) the permeability of the in vitro BBB (coculture) model. At the cellular level, MCP-1 causes alteration of tight junction (TJ) proteins in endothelial cells (redistribution of TJ proteins determined by Western blotting and loss of immunostaining for occludin, claudin-5, ZO-1, ZO-2). Monocyte chemoattractant protein-1-induced alterations in BBB permeability are mostly realized through the CCR2 receptor. Absence of CCR2 diminishes any effect of MCP-1 on BBB permeability in vitro and in vivo. The permeability surface area product for FITC-albumin after 3 days exposure to MCP-1 was 0.09670.006 and 0.0327 0.007 lL/g min, in CCR2 þ / þ and CCR2À/À mice, respectively (Po0.001). Monocytes/macrophages also participate in MCP-1-induced alterations in BBB permeability in vivo. Monocytes/macrophages depletion (by clodronate liposomes) reduced the effect of MCP-1 on BBB permeability in vivo B2 fold. Our results suggest that, besides its main function of recruiting leukocytes at sites of inflammation, MCP-1 also plays a role in 'opening' the BBB.

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Inflammatory Mediators of Cerebral Endothelium: A Role in Ischemic Brain Inflammation

Cited by 283 publications

References 126 publications

Effects of the Chemokine CCL2 on Blood–Brain Barrier Permeability during Ischemia–Reperfusion Injury

Effects of the Chemokine CCL2 on Blood–Brain Barrier Permeability during Ischemia–Reperfusion Injury

Effect of stress doses of hydrocortisone on S-100B vs. interleukin-8 and polymorphonuclear elastase levels in human septic shock

Monocyte Chemoattractant Protein-1 Regulation of Blood–Brain Barrier Permeability

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