Acute on chronic exposure to endotoxin is associated with enhanced chemoreflex responses in preterm fetal sheep

Booth, Lindsea C.; Drury, Paul P.; Muir, Carlyn; Jensen, Ellen C.; Gunn, Alistair J.

doi:10.1152/ajpregu.00005.2013

Cited by 7 publications

(15 citation statements)

References 44 publications

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“…; Booth et al . ). As seen in neonatal models, in the sheep fetus the fetal adaptive responses to asphyxia are also influenced by the timing between the exposure to LPS and asphyxia, albeit very few antenatal studies have been performed.…”

Section: Introductionmentioning

confidence: 97%

“…) (Booth et al . ). Faster and more sustained peripheral vasoconstriction ensured blood pressure was higher, offsetting the lower FHR induced by LPS, and perfusion was better as fetuses entered phase three (Fig.…”

Section: Introductionmentioning

confidence: 97%

“…) (Booth et al . ). Further, this acute‐on‐chronic LPS model created neural tolerance to asphyxia, with reduced white matter injury observed (van den Heuij et al .…”

Section: Introductionmentioning

confidence: 97%

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Sex, drugs and rock and roll: tales from preterm fetal life

Bennet

2017

The Journal of Physiology

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Premature fetuses and babies are at greater risk of mortality and morbidity than their term counterparts. The underlying causes are multifactorial, but include exposure to hypoxia. Immaturity of organs and their functional control may impair the physiological defence responses to hypoxia and the preterm fetal responses, or lack thereof, to moderate hypoxia appear to support this concept. However, as this review demonstrates, despite immaturity, the preterm fetus responds to asphyxia in a qualitatively similar manner to that seen at term. This highlights the importance in understanding metabolism versus homeostatic threat when assessing fetal responses to adverse challenges such as hypoxia. Data are presented to show that the preterm fetal adaptation to asphyxia is triphasic in nature. Phase one represents the rapid institution of maximal defences, designed to maintain blood pressure and central perfusion at the expense of peripheral organs. Phase two is one of adaptive compensation. Controlled reperfusion partially offsets peripheral tissue oxygen debt, while maintaining sufficient vasoconstriction to limit the fall in perfusion. Phase three is about decompensation. Strikingly, the preterm fetus generally performs better during phases two and three, and can survive for longer without injury. Paradoxically, however, the ability to survive can lead to longer exposure to hypotension and hypoperfusion and thus potentially greater injury. The effects of fetal sex, inflammation and drugs on the triphasic adaptations are reviewed. Finally, the review highlights the need for more comprehensive studies to understand the complexity of perinatal physiology if we are to develop effective strategies to improve preterm outcomes.

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Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 97%

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Sex, drugs and rock and roll: tales from preterm fetal life

Bennet

2017

The Journal of Physiology

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“…We have recently reported that in preterm fetal sheep 48 hours exposure to a low-dose chronic infusion of LPS, that did not cause any hemodynamic disturbance, before three boluses of high-dose LPS 24 hours apart significantly reduced mortality and attenuated the nadir of hypotension after the LPS boluses [17,18]. This paradigm of acute-on-chronic LPS was associated with a fetal inflammatory response and white matter injury.…”

Section: Introductionmentioning

confidence: 99%

“…In view of the evidence discussed above that a four-hour delay after acute LPS exposure typically increases HI injury in neonatal animals [12], asphyxia was induced four hours after the last bolus of high-dose LPS. We have previously shown that a similar paradigm of acute-on-chronic LPS exposure was associated with more rapid chemoreflex adaptation to umbilical cord occlusion and did not compromise fetal hemodynamic adaptation [18]. The neural maturation of 0.7 ga fetal sheep is broadly equivalent to between 28 and 32 weeks of human development [20].…”

Section: Introductionmentioning

confidence: 99%

Synergistic white matter protection with acute-on-chronic endotoxin and subsequent asphyxia in preterm fetal sheep

Heuij

Mathai

Davidson

et al. 2014

J Neuroinflammation

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BackgroundPerinatal asphyxia and exposure to intrauterine infection are associated with impaired neurodevelopment in preterm infants. Acute exposure to non-injurious infection and/or inflammation can either protect or sensitize the brain to subsequent hypoxia-ischemia. However, the effects of subacute infection and/or inflammation are unclear. In this study we tested the hypothesis that acute-on-chronic exposure to lipopolysaccharide (LPS) would exacerbate white matter injury after subsequent asphyxia in preterm fetal sheep.MethodsFetal sheep at 0.7 gestational age received a continuous LPS infusion at 100 ng/kg for 24 hours, then 250 ng/kg/24 hours for 96 hours, plus 1 μg boluses of LPS at 48, 72, and 96 hours or the same volume of saline. Four hours after the last bolus, complete umbilical cord occlusion or sham occlusion was induced for 15 minutes. Sheep were sacrificed 10 days after the start of infusions.ResultsLPS exposure was associated with induction of microglia and astrocytes and loss of total and immature and mature oligodendrocytes (n = 9) compared to sham controls (n = 9). Umbilical cord occlusion with saline infusions was associated with induction of microglia, astrogliosis, and loss of immature and mature oligodendrocytes (n = 9). LPS exposure before asphyxia (n = 8) was associated with significantly reduced microglial activation and astrogliosis and improved numbers of immature and mature oligodendrocytes compared to either LPS exposure or asphyxia alone.ConclusionsContrary to our initial hypothesis, the combination of acute-on-chronic LPS with subsequent asphyxia reduced neuroinflammation and white matter injury compared with either intervention alone.

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Subclinical decelerations during developing hypotension in preterm fetal sheep after acute on chronic lipopolysaccharide exposure

Lear

Davidson

Galinsky

et al. 2015

Sci Rep

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Subclinical (shallow) heart rate decelerations occur during neonatal sepsis, but there is limited information on their relationship with hypotension or whether they occur before birth. We examined whether subclinical decelerations, a fall in fetal heart rate (FHR) that remained above 100 bpm, were associated with hypotension in preterm fetal sheep exposed to lipopolysaccharide (LPS). Chronically-instrumented fetal sheep at 0.7 gestation received continuous low-dose LPS infusions (n = 15, 100 ng/kg over 24 h, followed by 250 ng/kg/24 h for 96 h) or saline (n = 8). Boluses of 1 μg LPS or saline were given at 48 and 72 h. FHR variability (FHRV) was calculated, and sample asymmetry was used to assess the severity and frequency of decelerations. Low-dose LPS infusion did not affect FHR. After the first LPS bolus, 7 fetuses remained normotensive, while 8 developed hypotension (a fall in mean arterial blood pressure of ≥5 mmHg). Developing hypotension was associated with subclinical decelerations, with a corresponding increase in sample asymmetry and FHRV (p < 0.05). The second LPS bolus was associated with similar but attenuated changes in FHR and blood pressure (p < 0.05). In conclusion, subclinical decelerations are not consistently seen during prenatal exposure to LPS, but may be a useful marker of developing inflammation-related hypotension before birth.

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Acute on chronic exposure to endotoxin is associated with enhanced chemoreflex responses in preterm fetal sheep

Abstract: Acute on chronic exposure to endotoxin is associated with enhanced chemoreflex responses in preterm fetal sheep.

Cited by 7 publications

References 44 publications

Sex, drugs and rock and roll: tales from preterm fetal life

Sex, drugs and rock and roll: tales from preterm fetal life

Synergistic white matter protection with acute-on-chronic endotoxin and subsequent asphyxia in preterm fetal sheep

Subclinical decelerations during developing hypotension in preterm fetal sheep after acute on chronic lipopolysaccharide exposure

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