Timing of Neutrophil Depletion Influences Long-Term Neuroprotection in Neonatal Rat Hypoxic-Ischemic Brain Injury

Palmer, Charles; Roberts, Rebecca; Young, Pamela

doi:10.1203/01.pdr.0000113546.03897.fc

Cited by 82 publications

(78 citation statements)

References 61 publications

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“…Morphometric evaluation of damage at 1 to 4 weeks was determined based on the shrinkage of the ipsilateral to contralateral hemisphere. 21,22 Neuronal damage/death was assessed with activated caspase-3 (1:200, Cell Signaling) and Neuronspecific-Nuclear Protein (NeuN 1:1000, Millipore) and evaluated with confocal fluorescence microscopy (LSM 510, 40ϫ objective, laser Argon 488 and Hene 543, Zeiss Inc) or using Fluoro-Jade-B (Chemicon) according to the protocol of Schmued and Hopkins 23 and used previously in our HI experiments. 7 Sections were examined by fluorescence microscopy (Olympus) with a QImaging CCD camera (QImaging) using blue light excitation.…”

Section: Neuropathological Analysismentioning

confidence: 99%

Mast Cells Are Early Responders After Hypoxia-Ischemia in Immature Rat Brain

Jin

Silverman

Vannucci

2009

Stroke

127

105

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Background and Purpose-Perinatal hypoxia-ischemia (HI) produces acute and prolonged inflammation of the brain.Mast cells (MCs), numerous in the pia and CNS of neonatal rats, can initiate inflammation attributable to preformed mediators. MCs contribute to HI brain damage in the neonatal rat; MC stabilization protects through 48 hours of reperfusion. Here we hypothesize that HI induces early MC migration, activation, and release of proinflammatory molecules. Methods-HI

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Section: Neuropathological Analysismentioning

confidence: 99%

Mast Cells Are Early Responders After Hypoxia-Ischemia in Immature Rat Brain

Jin

Silverman

Vannucci

2009

Stroke

127

105

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“…Neutrophils are known to contribute significantly to HI-induced brain damage (Hudome et al, 1997;Palmer et al, 2004). In addition, there is evidence that GRK2 can regulate chemotactic activity (Vroon et al, 2006).…”

Section: Neutrophil Infiltrationmentioning

confidence: 99%

“…Moreover, HI induces an inflammatory reaction characterized by increased numbers of cerebral neutrophils and microglial/macrophage activation. Prevention of cerebral neutrophil infiltration markedly reduced brain damage (Hudome et al, 1997;Palmer et al, 2004). Inhibition of microglial/macrophage activation can also attenuate brain damage (Clarkson et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Low Endogenous G-Protein-Coupled Receptor Kinase 2 Sensitizes the Immature Brain to Hypoxia–Ischemia-Induced Gray and White Matter Damage

Nijboer¹,

Kavelaars²,

Vroon³

et al. 2008

J. Neurosci.

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Hypoxic-ischemic brain injury is regulated in part by neurotransmitter and chemokine signaling via G-protein-coupled receptors (GPCRs). GPCR-kinase 2 (GRK2) protects these receptors against overstimulation by inducing desensitization. Neonatal hypoxic-ischemic brain damage is preceded by a reduction in cerebral GRK2 expression. We determined the functional importance of GRK2 in hypoxic-ischemic brain damage.Nine-day-old wild-type and GRK2 ϩ/Ϫ mice with a ϳ50% reduction in GRK2 protein were exposed to unilateral carotid artery occlusion and hypoxia. In GRK2 ϩ/Ϫ animals, gray and white matter damage was aggravated at 3 weeks after hypoxia-ischemia. In addition, cerebral neutrophil infiltration was increased in GRK2 ϩ/Ϫ animals. Neutrophil depletion reduced brain damage, but neuronal loss was still more pronounced in GRK2 ϩ/Ϫ animals. Onset of neuronal loss was advanced in GRK2 ϩ/Ϫ animals regardless of neutrophil depletion. White matter injury was advanced in GRK2 ϩ/Ϫ animals and was not affected by neutrophil depletion. Activation/infiltration of microglia/macrophages was stronger in GRK2 ϩ/Ϫ brains but only occurred 24 h after hypoxia-ischemia and is therefore not the primary cause of increased damage. During hypoxia, cerebral blood flow was reduced to the same extent in both genotypes. In vitro, GRK2 ϩ/Ϫ hippocampal slices and cerebellar granular neurons were more sensitive to glutamate-induced death.We propose the novel concept that the kinase GRK2 regulates onset and magnitude of hypoxic-ischemic brain damage. Increased gray and white matter damage in GRK2 ϩ/Ϫ animals was not dependent on infiltrating neutrophils and occurred before microglia/macrophage activation was detected. Collectively, our data suggest that cerebral GRK2 has an important endogenous neuroprotective role in ischemic cerebral damage.

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“…However, PMN are a major source of oxygen radicals (48,49), and evidence has shown a link between the depletion of PMN and a diminished development of inflammation in a variety of animal models (42,50,51).…”

mentioning

confidence: 99%

Neonatal Neutrophils with Prolonged Survival Exhibit Enhanced Inflammatory and Cytotoxic Responsiveness

et al. 2005

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Apoptosis is critical to the resolution of inflammation, as it promotes the removal of neutrophils (PMN) by the reticuloendothelial system. In contrast, PMN persistence characterizes the early stages of chronic inflammation. Adult PMN with delayed senescence retain some functionality, although this has not been described for neonatal PMN. We hypothesized that neonatal PMN with prolonged survival retain cytotoxic and inflammatory function. To test one aspect of inflammatory function, we determined surface CD11b expression on 0-h and 24-h PMN after chemotactic formyl-methionine-leucine-phenylalanine (fMLP) stimulation. Although fMLP induced a greater percentage upregulation of CD11b on 0-h adult PMN, this was similar between nonapoptotic cord blood and adult PMN at 24 h. Furthermore, percentage up-regulation of CD11b was more robust for 24-h than for 0-h cord blood PMN. In contrast, there was no difference in responsiveness between 0-h and 24-h adult PMN. In studies of cytotoxic potential, we determined the expression of reactive oxygen intermediates (ROI) in phorbol 12-myristate 13-acetatestimulated cord blood and adult PMN at 0 h and in 24-h nonapoptotic PMN, using the dihydrorhodamine 123 assay.Stimulated cord blood PMN generated more ROI than did adult PMN at both 0 h and 24 h; in addition, ROI levels in 24-h cord blood PMN were similar to those of 0-h adult PMN. We conclude that PMN with prolonged survival retain specific cytotoxic and inflammatory functions, and these are enhanced in cord blood PMN. We speculate that neonatal PMN with prolonged survival have the functional capacity to contribute to the pathogenesis of inflammatory disorders. Abbreviations CLD, chronic lung disease DHR, dihydrorhodamine 123 fMLP, formyl-methionine-leucine-phenylalanine PE, phycoerythrin PMA, phorbol 12-myristate 13-acetate PMN, neutrophil(s) ROI, reactive oxygen intermediates 7-AAD, 7-aminoactinomycin PMN serve as the primary line of host defense during the early stages of sepsis and inflammation (1). After activation by systemic or local factors, primed endothelial cells interact with PMN through adhesion molecules that include selectins and integrins (2). These adhesive interactions initiate a process that allows the extravasation of PMN into inflamed tissue with the goal of neutralizing the inciting stimulus. In the case of inflammation mediated by bacterial or fungal microorganisms, phagocytosis and subsequent killing of these invaders occurs through mechanisms that partly involve ROI and proteases (3,4).The concept that apoptosis of inflammatory PMN and their timely removal by resident macrophages are critical to the resolution of inflammation has been well established (5,6). During the resolution phase, PMN typically undergo the phenotypic changes associated with apoptosis, which promotes their removal by resident macrophages (7). PMN can also undergo necrosis and lysis, a process that induces cytotoxicity in surrounding tissues (8), although apoptosis is the more common and physiologically preferable route. All cells a...

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Timing of Neutrophil Depletion Influences Long-Term Neuroprotection in Neonatal Rat Hypoxic-Ischemic Brain Injury

Cited by 82 publications

References 61 publications

Mast Cells Are Early Responders After Hypoxia-Ischemia in Immature Rat Brain

Mast Cells Are Early Responders After Hypoxia-Ischemia in Immature Rat Brain

Low Endogenous G-Protein-Coupled Receptor Kinase 2 Sensitizes the Immature Brain to Hypoxia–Ischemia-Induced Gray and White Matter Damage

Neonatal Neutrophils with Prolonged Survival Exhibit Enhanced Inflammatory and Cytotoxic Responsiveness

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