Lipopolysaccharide administration enhances hypoxic‐ischemic brain damage in newborn rats

Yang, Li; Sameshima, Hiroshi; Ikeda, Tomoaki; Ikenoue, Tsuyomu

doi:10.1111/j.1447-0756.2003.00174.x

Cited by 62 publications

(51 citation statements)

References 27 publications

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“…inflammatory and apoptotic response could help to explain the primary sensitizing effect of LPS found in the immature brain in vivo (6,(21)(22)(23).We also found that LPS sensitized the immature brain if given 72 h before HI either at PND 4 or PND 7. This is interesting in that the animals have completely recovered from the systemic effects of LPS after 3 d. Early physiologic changes found after LPS injection, related to blood glucose, heart rate, temperature, and behavior, returned to normal after 3 d (24 -26).…”

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confidence: 64%

Lipopolysaccharide Induces Both a Primary and a Secondary Phase of Sensitization in the Developing Rat Brain

et al. 2005

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Data indicate that bacterial products in combination with other antenatal or postnatal exposures increase the risk of perinatal brain injury. We have previously shown that administration of lipopolysaccharide (LPS) 4 h before hypoxia-ischemia (HI) increases brain injury in 7-d-old rats. The mechanisms behind such sensitization are unclear, but contrasts against a preconditioning effect of LPS given 1-3 d before ischemia in adult animals. To investigate how the effects of LPS depend on the time interval between administration and HI in the developing brain, we evaluated the effect of varying time interval (2-72 h) between LPS and HI, the duration of HI (20 or 50 min), and age of the rat pups (postnatal d 4 or 7). Outcome was assessed by brain injury scoring of specific regions. We found that LPS reduced brain injury (by 78%) when administered 24 h before 50 min of HI. However, when LPS was administered 6 h before either 20 or 50 min of HI, brain injury was increased by 2026% and 137%, respectively. Even LPS given 72 h before HI increased injury, both when LPS was administered at postnatal d 4 (by 446%) and 7 (by 77%). In conclusion, LPS enhanced vulnerability in the developing brain both in the acute (4 -6 h) and the chronic (72 h) phase after administration, whereas an intermediate interval between LPS and HI had the opposite effect. The long-term sensitizing effect of LPS has not been previously described. (Pediatr Res 58: 112-116, 2005) Abbreviations DAB, 3,3-diaminobenzidine HI, hypoxia-ischemia LPS, lipopolysaccharide MAP-2, microtubule-associated protein-2 MCAO, middle cerebral artery occlusion NF-B, nuclear factor-kappaB PND, postnatal day TGF-␤1, transforming growth factor-␤1 TNF-␣, tumor necrosis factor-␣ The etiology of newborn encephalopathy is complex and many causal pathways have been suggested to operate antenatally and to interact with intrapartal and postnatal factors (1,2). Antenatal infection has been identified as one cause of encephalopathy and cerebral palsy (1,3,4), acting alone or in combination with other events such as potentially asphyxiating conditions during birth (5).We previously showed that the combination of a low-dose LPS and a sub-threshold period of HI results in increased brain damage in 7-d-old rats, implicating that bacterial products sensitize the immature brain (6). We also detected an increase in CD14 mRNA in the neonatal brain, suggesting activation of the innate immune system. Recently, we explored the effect of peripheral LPS on global gene expression in the immature CNS (unpublished observations). Multiple genes were regulated in a sequential manner with specific patterns of expression at different time points after LPS, suggesting that CNS vulnerability may depend on the time interval between LPS and the subsequent insult. Indeed, previous studies in the adult setting show that a single dose of LPS before permanent MCAO reduced brain injury when LPS was injected 2-4 d before MCAO (7,8). Furthermore, it is well recognized that the neurodevelopmental stage is important ...

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confidence: 64%

Lipopolysaccharide Induces Both a Primary and a Secondary Phase of Sensitization in the Developing Rat Brain

et al. 2005

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“…[3][4][5] This synergistic effect was also reproduced in mammalian and avian animal models, combining HI insult and the lipopolysaccharide break-down product of bacteria in HI animal models. [6][7][8][9][10] However, the molecular mediators of this endotoxin effect in vivo are currently still unknown.…”

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TNF gene cluster deletion abolishes lipopolysaccharide-mediated sensitization of the neonatal brain to hypoxic ischemic insult

Kendall

Hirstova

Horn

et al. 2011

Laboratory Investigation

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In the current study, we explored the role of TNF cluster cytokines on the lipopolysaccharide (LPS)-mediated, synergistic increase in brain injury after hypoxic ischemic insult in postnatal day 7 mice. Pretreatment with moderate doses of LPS (0.3 mg/g) resulted in particularly pronounced synergistic injury within 12 h. Systemic application of LPS alone resulted in a strong upregulation of inflammation-associated cytokines TNFa, LTb, interleukin (IL) 1b, IL6, chemokines, such as CXCL1, and adhesion molecules E-Selectin, P-Selectin and intercellular adhesion molecule-1 (ICAM1), as well as a trend toward increased LTa levels in day 7 mouse forebrain. In addition, it was also associated with strong activation of brain blood vessel endothelia and local microglial cells. Here, deletion of the entire TNF gene cluster, removing TNFa, LTb and LTa completely abolished endotoxin-mediated increase in the volume of cerebral infarct. Interestingly, the same deletion also prevented endothelial and microglial activation following application of LPS alone, suggesting the involvement of these cell types in bringing about the LPS-mediated sensitization to neonatal brain injury. KEYWORDS: encephalopathy; hypoxia; inflammation; ischemia; neonate; TNF Although bacteria and viruses can directly infect and injure developing brain, infections occurring outside the brain frequently will also have a damaging effect. Congenital infections appear to contribute up to 5% of cerebral palsy cases 1,2 and may sensitize the brain to perinatal hypoxic ischemic (HI) insult. [3][4][5] This synergistic effect was also reproduced in mammalian and avian animal models, combining HI insult and the lipopolysaccharide break-down product of bacteria in HI animal models.6-10 However, the molecular mediators of this endotoxin effect in vivo are currently still unknown.Both in vitro and in vivo studies show that endotoxin will upregulate numerous cytokines and chemokines, 11 upregulate signaling enzymes, such as inducible nitrogen oxide synthase (iNOS), and cyclo-oxygenase-2 (COX2) and enhance the expression of adhesion molecules on parenchymal microglia and the brain vascular endothelium. 12-15Follow on molecular studies reveal that these effects are transmitted through the classical endotoxin receptors, primarily the toll-like receptor 4 (TLR4), on blood vessel endothelia and microglia, 16,17 and involve MyD88 and NF-kappa-B components of the innate immunity cascade. 17In particular, endotoxin-induced pro-inflammatory cytokines, including TNFa and interleukin 1b (IL1b) are known to have a number of deleterious effects, including a direct toxic effect on neurones and vulnerable oligodendrocyte precursors, 18,19 astrogliosis with release of nitric oxide, and mitochondrial dysfunction, 20 as well as microglial activation with release of nitric oxide, superoxide and a panel of other inflammation-associated molecules.

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“…The combined exposure to perinatal inflammation and neonatal HI results in a complex interplay of various signaling pathways of which the exact underlying mechanism has not been elucidated yet. Experimental peripheral inflammation induced by LPS is known to induce an inflammatory cerebral state leading to sensitization of the brain to HI injury [15,16,19,21,36,37]. Possible mechanisms via which peripheral LPS can sensitize the brain have been described extensively and consist of: (i) stimulation of endothelial cells of the blood-brain barrier (BBB), (ii) activation/priming of microglia via immune signals produced by endothelial and choroid plexus cells at the level of the BBB, (iii) direct transport of peripheral inflammatory molecules across the BBB, (iv) increased permeability of the BBB, which enhances the influx of peripheral immune cells into the brain, (v) stimulation of the vagal nerve by peripheral cytokines leading to signaling in the brain and (vi) the effects of inflammation on G-protein-coupled receptor signaling in the brain [17,38,39,40,41].…”

Section: Discussionmentioning

confidence: 99%

“…The general view is that inflammation before HI sensitizes the brain and thereby aggravates HI cerebral injury. However, the exact mechanisms underlying proinflammatory sensitization are still unclear [15,16,17,18,19,20,21]. To date, the exact timing of the sensitizing effect of LPS on the intensity of cerebral gray and white matter injury and the formation of an acellular cyst after HI have not been investigated in detail.…”

Section: Introductionmentioning

confidence: 99%

Development of Cerebral Gray and White Matter Injury and Cerebral Inflammation over Time after Inflammatory Perinatal Asphyxia

Bonestroo¹,

Heijnen²,

Groenendaal

et al. 2015

Dev Neurosci

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Antenatal inflammation is associated with increased severity of hypoxic-ischemic (HI) encephalopathy and adverse outcome in human neonates and experimental rodents. We investigated the effect of lipopolysaccharide (LPS) on the timing of HI-induced cerebral tissue loss and gray matter injury, white matter injury and integrity, and the cerebral inflammatory response. On postnatal day 9, mice underwent HI by unilateral carotid artery occlusion followed by systemic hypoxia which resulted in early neuronal damage (MAP2 loss) at 3 h that did not increase up to day 15. LPS injection 14 h before HI (LPS+HI) significantly and gradually aggravated MAP2 loss from 3 h up to day 15, resulting in an acellular cystic lesion. LPS+HI increased white matter damage, reduced myelination in the corpus callosum and increased white matter fiber coherency in the cingulum. The number of oligodendrocytes throughout the lineage (Olig2-positive) was increased whereas more mature myelinating (CNPase-positive) oligodendrocytes were strongly decreased after LPS+HI. LPS+HI induced an increased and prolonged expression of cerebral cytokines/chemokines compared to HI. Additionally, LPS+HI increased macrophage/microglia activation and influx of neutrophils in the brain compared to HI. This study demonstrates the sensitizing effect of LPS on neonatal HI brain injury for an extended time-frame up to 15 days postinsult. LPS before HI induced a gradual increase in gray and white matter deficits, including reduced numbers of more mature myelinating oligodendrocytes and a decrease in white matter integrity. Moreover, LPS+HI prolonged and intensified the cerebral inflammatory response, including cellular infiltration. In conclusion, as the timing of damage and/or involved pathways are changed when HI is preceded by inflammation, experimental therapies might require modifications in the time window, dosage or combinations of therapies for efficacious neuroprotection.

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Lipopolysaccharide administration enhances hypoxic‐ischemic brain damage in newborn rats

Abstract: LPS potentiates hypoxic-ischemic insult in a dose-dependent fashion to cause brain damage in neonatal rats.

Cited by 62 publications

References 27 publications

Lipopolysaccharide Induces Both a Primary and a Secondary Phase of Sensitization in the Developing Rat Brain

Lipopolysaccharide Induces Both a Primary and a Secondary Phase of Sensitization in the Developing Rat Brain

TNF gene cluster deletion abolishes lipopolysaccharide-mediated sensitization of the neonatal brain to hypoxic ischemic insult

Development of Cerebral Gray and White Matter Injury and Cerebral Inflammation over Time after Inflammatory Perinatal Asphyxia

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