The induction of ICAM-1 in human cerebromicrovascular endothelial cells (HCEC) by ischemia-like conditions promotes enhanced neutrophil/HCEC adhesion

Stanimirovic, Danica; Shapiro, Anthony; Wong, Josée; Hutchison, James S.; Durkin, Jon P.

doi:10.1016/s0165-5728(97)00057-x

Cited by 90 publications

(76 citation statements)

References 49 publications

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“…Such changes are best examined with in vitro cell culture models. A variety of approaches for inducing a hypoxic environment have been used in peripheral and cerebral cell culture models, including O 2 chelating agents (gas-paks) and anaerobic chambers infused with various gas mixtures (100% N 2 , 95% N 2 -5% CO 2 , or a mix of 85% N 2 -10% H 2 -5% CO 2 ) to maintain an anoxic or hypoxic environment for periods ranging from 20 min to 72 h. To date, few studies have reported PO 2 , PCO 2 , and pH values from cell culture models of hypoxic insult (3,54,56,60). In rat mesangial cells, Archer et al (3) examined the effects of graded hypoxia on inducible nitric oxide (NO) synthase function using atmospheric O 2 levels of 0, 2.5, 10, and 21%, resulting in culture medium PO 2 levels of 32, 46, 85, and 140 mmHg, respectively (3).…”

Section: Discussionmentioning

confidence: 99%

Cerebral microvascular changes in permeability and tight junctions induced by hypoxia-reoxygenation

Mark

Davis

2002

American Journal of Physiology-Heart and Circulatory Physiology

342

272

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Mark, Karen S., and Thomas P. Davis. Cerebral microvascular changes in permeability and tight junctions induced by hypoxia-reoxygenation. Am J Physiol Heart Circ Physiol 282: H1485-H1494, 2002; 10.1152/ajpheart.00645.2001.-Cerebral microvessel endothelial cells that form the bloodbrain barrier (BBB) have tight junctions (TJ) that are critical for maintaining brain homeostasis and low permeability. Both integral (claudin-1 and occludin) and membrane-associated zonula occluden-1 and -2 (ZO-1 and ZO-2) proteins combine to form these TJ complexes that are anchored to the cytoskeletal architecture (actin). Disruptions of the BBB have been attributed to hypoxic conditions that occur with ischemic stroke, pathologies of decreased perfusion, and high-altitude exposure. The effects of hypoxia and posthypoxic reoxygenation in cerebral microvasculature and corresponding cellular mechanisms involved in disrupting the BBB remain unclear. This study examined hypoxia and posthypoxic reoxygenation effects on paracellular permeability and changes in actin and TJ proteins using primary bovine brain microvessel endothelial cells (BBMEC). Hypoxia induced a 2.6-fold increase in [ 14 C]sucrose, a marker of paracellular permeability. This effect was significantly reduced (ϳ58%) with posthypoxic reoxygenation. After hypoxia and posthypoxic reoxygenation, actin expression was increased (1.4-and 2.3-fold, respectively). Whereas little change was observed in TJ protein expression immediately after hypoxia, a twofold increase in expression was seen with posthypoxic reoxygenation. Furthermore, immunofluorescence studies showed alterations in occludin, ZO-1, and ZO-2 protein localization during hypoxia and posthypoxic reoxygenation that correlate with the observed changes in BBMEC permeability. The results of this study show hypoxia-induced changes in paracellular permeability may be due to perturbation of TJ complexes and that posthypoxic reoxygenation reverses these effects. endothelial cells; cytoarchitecture; blood-brain barrier; immunofluorescence WHEREAS RESEARCH INVOLVING hypoxic stress has traditionally focused on identifying and treating risk factors associated with ischemic stroke (17,18,43), hypoxia as a result of high-altitude exposure has also been associated with impairment in neurological function (26,37). Early intervention after ischemic stroke has been shown to reduce tissue damage associated with increased cerebrovascular permeability (7, 39). Recently, research has expanded into examining cellular effects of cerebral ischemia-reperfusion. Ischemic stroke is a reduction or cessation of blood flow to the brain, which deprives the cerebral tissue of important nutrients and oxygen as well as removal of metabolic waste products. Whereas this decrease in oxygen supply to the brain (i.e., hypoxia) has been shown to increase cerebrovascular permeability (1,19), there are also reports (42, 66) of increased permeability in peripheral and cerebral endothelial cells during posthypoxic reperfusion (i.e., reoxygenation). Little is know...

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Section: Discussionmentioning

confidence: 99%

Cerebral microvascular changes in permeability and tight junctions induced by hypoxia-reoxygenation

Mark

Davis

2002

American Journal of Physiology-Heart and Circulatory Physiology

342

272

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“…After hypoxic injury, up-regulation of the adhesion molecules vascular cell adhesion molecule (VCAM), intercellular adhesion molecule (ICAM), and E-selectin on cerebrovascular endothelial cells can be inhibited by indomethacin (92,93). These adhesion molecules happen to be down-regulated by arachidonic acid-derived 11,12-EET in cardiac endothelial cells (66).…”

Section: Discussionmentioning

confidence: 99%

Cyclooxygenase-2-specific Inhibitor Improves Functional Outcomes, Provides Neuroprotection, and Reduces Inflammation in a Rat Model of Traumatic Brain Injury

Gopez¹,

Yue²,

Vasudevan³

et al. 2005

Neurosurgery

104

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OBJECTIVE-Increases in brain cyclooxygenase-2 (COX2) are associated with the central inflammatory response and with delayed neuronal death, events that cause secondary insults after traumatic brain injury. A growing literature supports the benefit of COX2-specific inhibitors in treating brain injuries. [5,5-dimethyl-3(3-fluorophenyl)-4(4-methylsulfonyl)phenyl-2( 5 H)-furanone] is a third-generation, highly specific COX2 enzyme inhibitor. DFU treatments (1 or 10 mg/kg intraperitoneally, twice daily for 3 d) were initiated either before or after traumatic brain injury in a lateral cortical contusion rat model. METHODS-DFU NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript RESULTS-DFU treatments initiated 10 minutes before injury or up to 6 hours after injury enhanced functional recovery at 3 days compared with vehicle-treated controls. Significant improvements in neurological reflexes and memory were observed. DFU initiated 10 minutes before injury improved histopathology and altered eicosanoid profiles in the brain. DFU 1 mg/kg reduced the rise in prostaglandin E 2 in the brain at 24 hours after injury. DFU 10 mg/kg attenuated injuryinduced COX2 immunoreactivity in the cortex (24 and 72 h) and hippocampus (6 and 72 h). This treatment also decreased the total number of activated caspase-3-immunoreactive cells in the injured cortex and hippocampus, significantly reducing the number of activated caspase-3-immunoreactive neurons at 72 hours after injury. DFU 1 mg/kg amplified potentially anti-inflammatory epoxyeicosatrienoic acid levels by more than fourfold in the injured brain. DFU 10 mg/kg protected the levels of 2-arachidonoyl glycerol, a neuro-protective endocannabinoid, in the injured brain.CONCLUSION-These improvements, particularly when treatment began up to 6 hours after injury, suggest exciting neuroprotective potential for COX2 inhibitors in the treatment of traumatic brain injury and support the consideration of Phase I/II clinical trials.Keywords 2-Arachidonoyl glycerol; Caspase-3; COX2 inhibitor; Eicosanoids; Endocannabinoid; Neuroinflammation; Rat behavior Traumatic brain injury (TBI) initiates a central inflammatory response that results in the increased production of prostaglandins and reactive oxygen species. These products may cause secondary insults to the brain (55,90,94). Cyclooxygenases catalyze the first step in the formation of prostaglandins from arachidonic acid, producing reactive oxygen species in the process. Cyclooxygenase-1 (COX1), present normally in most tissues, is thought to maintain essential physiological functions, such as gastric mucosal integrity, renal function, and platelet homeostasis (87,101). COX2, the inducible isoform, is expressed in the normal brain (30,87) but is rare or absent in most organs under normal conditions. As in the periphery (32,79), COX2 in the brain can be regulated by inflammatory cytokines (87), and prostaglandin production increases in response to pathological conditions of the central nervous system (3,70,72,89,107). ...

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“…Although some data are published on cerebral microvascular cells from adult human brain (12)(13)(14), no experimental data on human fetal or neonatal brain endothelial cells are available. Endothelium-dependent mechanisms that regulate cerebral blood flow are species-specific and age-dependent (1).…”

Section: Discussionmentioning

confidence: 99%

COX-1 and COX-2 Contributions to Basal and IL-1β-Stimulated Prostanoid Synthesis in Human Neonatal Cerebral Microvascular Endothelial Cells

et al. 2002

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Mechanisms of endothelium-dependent regulation of cerebral circulation in human neonates are poorly understood owing to the lack of experimental data. Prostanoids, the products of the cyclooxygenase (COX) pathway, appear to be important regulators of blood flow in neonates. COX activity in cultured endothelial cells from small (60 -300 m) and large (Ͼ300 m) microvessels from the autopsy specimens of neonatal human cerebral cortex and cerebellum (22-26 wk gestational age) was detected as production of vasodilator prostanoids, prostacyclin [as 6-keto-prostaglandin (PG) F 1␣ ] and PGE 2 from arachidonic acid. Treatment of neonatal human cerebral microvascular endothelial cells (hCMVEC) with IL-1␤ (50 ng/mL, 17 h) stimulated COX activity 5-to 20-fold. Basal and IL-1␤-stimulated COX activities were inhibited by NS-398, indicating substantial COX-2 contribution to endothelial prostanoid synthesis in neonatal human brain cortex and cerebellum at rest and when mimicking the inflammatory conditions. Increased COX-2-linked activity in response to IL-1␤ was observed in hCMVEC from both cerebrum and cerebellum (5-to 20-fold), while under the same conditions elevated COX-1-linked activity was detected only in hCMVEC from cerebellum (5-to 10-fold). In IL-1␤-treated hCMVEC, a shift toward PGE 2 as the major vasodilator product of the COX pathway was observed. Acute treatment with the protein tyrosine kinase inhibitor, tyrphostin 25, inhibited basal and IL-1␤-induced COX activities, suggesting the importance of posttranslational modifications in endothelial COX-2 activation in human brain. Altogether, these data indicate that both COX-1 and COX-2 contribute to endothelial prostanoid synthesis in the neonatal human brain under basal conditions and in response to proinflammatory cytokine IL-1␤. Cerebral circulatory disorders produce serious complications in human neonates, such as cerebral hemorrhages and hypoxicischemic injuries, that can result in life-long neurologic dysfunction in survivors including cerebral palsy, epilepsy, and mental retardation. Mechanisms of the regulation of cerebral circulation in neonates are understood incompletely, and experimental data are very limited. Vascular endothelium-derived dilator prostanoids, NO, and carbon monoxide are vasorelaxant factors essential in the regulation of cerebral blood flow. There are speciesspecific and age-dependent differences in physiologically relevant endothelial vasorelaxants in the cerebral circulation (1). In human newborns, prostanoids appear to be major factors that contribute to regulation of cerebral blood flow in response to hypercapnia, asphyxia, ischemia, and cerebral hemorrhage (1-3), and indomethacin is widely used in neonatal practice (2,4,5). Similarly, in newborn pigs, prostanoids contribute to the regulation of cerebral blood flow under basal conditions and in response to physiologically important stimuli, such as CO 2 , oxygen, and changes in blood pressure (1). Prostanoids are also important in the pathogenesis of inflammation because they alter in...

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The induction of ICAM-1 in human cerebromicrovascular endothelial cells (HCEC) by ischemia-like conditions promotes enhanced neutrophil/HCEC adhesion

Cited by 90 publications

References 49 publications

Cerebral microvascular changes in permeability and tight junctions induced by hypoxia-reoxygenation

Cerebral microvascular changes in permeability and tight junctions induced by hypoxia-reoxygenation

Cyclooxygenase-2-specific Inhibitor Improves Functional Outcomes, Provides Neuroprotection, and Reduces Inflammation in a Rat Model of Traumatic Brain Injury

COX-1 and COX-2 Contributions to Basal and IL-1β-Stimulated Prostanoid Synthesis in Human Neonatal Cerebral Microvascular Endothelial Cells

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