Cerebrovascular Responses in the Fetal Sheep Brain to Low-Dose Endotoxin

Yan, Edwin BingBing; Castillo‐Melendez, Margie; Nicholls, Trisha Anne; Hirst, Jonathan J.; Walker, David

doi:10.1203/01.pdr.0000115681.95957.d4

Cited by 79 publications

(52 citation statements)

References 46 publications

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“…Within the UCO fetal brains, intense albumin staining was notable in the parenchyma adjacent to blood vessels, indicative of increased blood vessel permeability (fig. 2e) [30]. We quantified the number of albumin-positive vessels and found that UCO induced a significant increase within the thalamus (fig.…”

Section: Resultsmentioning

confidence: 99%

Mechanisms of Melatonin-Induced Protection in the Brain of Late Gestation Fetal Sheep in Response to Hypoxia

et al. 2012

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Melatonin has diverse physiological actions in addition to its well-recognized maintenance roles in circadian and seasonal timing. In particular, melatonin may have a direct protective action on the developing fetal brain. We examined the cellular processes by which melatonin provides protection following an acute late gestation hypoxic insult. 15 fetal sheep at 126 days' gestation were instrumented with a brachial artery catheter and a silastic cuff around the umbilical cord. At ∼130 days' gestation, the cuff was inflated for 10 min in 10 fetuses, causing complete umbilical cord occlusion (UCO). 5 UCO fetuses received intravenous melatonin maternally for 2 h, before and after UCO (UCO + melatonin). The remaining 5 fetuses had no UCO performed (sham-operated controls). At 48 h after UCO, the fetal brain was collected from each animal. Compared to controls, UCO caused significant hypoxia, hypercapnia and acidosis in UCO and UCO + melatonin fetuses. In the UCO-alone animals there were significant increases in pyknotic cell death, in the hippocampus (>7-fold) and the cerebellum (3-fold). Maternal melatonin administration ameliorated cellular pyknosis in UCO fetuses. UCO was also associated with astrogliosis, increased albumin uptake, activated microglia and lipid peroxidation. Melatonin prevented these effects. There were no significant differences in the number of brain macrophages or microglia between any of the groups. Following acute severe hypoxia in the late gestation fetus, melatonin reduces neuronal lipid peroxidation and prevents loss of blood-brain barrier integrity and astrogliosis. These are likely key mechanisms underlying the neuroprotective actions of melatonin in the fetal brain.

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Section: Resultsmentioning

confidence: 99%

Mechanisms of Melatonin-Induced Protection in the Brain of Late Gestation Fetal Sheep in Response to Hypoxia

et al. 2012

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“…In the fetal sheep, Yan and colleagues have demonstrated that blood-brain barrier permeability is increased in the fetal brain after exposure to endotoxin, suggesting that cytotoxic and pro-inflammatory substances can pass from the circulation into the brain after peripheral inflammatory stimulation [31] . LPS has been associated with marked mitochondrial dysfunction after local injection in the striatum of adult rats [32] , and peripheral injection in adult mice [33] .…”

Section: Discussionmentioning

confidence: 99%

Acute Behavioral Effects of Intrapleural OK-432 (Picibanil) Administration in Preterm Fetal Sheep

Cowie¹,

Stone

Parry

et al. 2009

Fetal Diagn Ther

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Objective: To develop a model to study the fetal effects of intrapleural infusion of OK-432 (Picibanil), a pleurodesis agent derived from killed Gram-positive streptococci. Methods: OK-432 (0.1 mg, n = 5), or normal saline (n = 5) were infused over 20 min into the pleural space of chronically instrumented preterm fetal sheep at 0.7 gestation. Fetal physiological parameters, including breathing and nuchal activity were monitored in utero from 6 h before infusion until 12 h afterward, and fetuses were killed after 7 days recovery. Results: OK-432 was associated with transient suppression of fetal EEG activity, breathing and body movements from 3–6 h after infusion. Hypotension and hypoxia did not occur. At postmortem, local pleural adhesions were seen around the site of OK-432 infusion but not in saline treated fetuses. Conclusions: Intrapleural administration of OK-432 is associated with marked but transient fetal behavioral effects. This model will enable preclinical investigation of the neural and cardiovascular safety of OK-432 at a clinical relevant stage of development.

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“…Aggressive resuscitative procedures at delivery improve circulation and blood pressure that could eventually result in early P/IVH as a reperfusion injury. Secondly, external stimuli, including endotoxin, as well as cytokines and hypoxia, could directly affect immature vessels of the germinal matrix, increase blood-brain barrier permeability [32] and destroy their integrity [33] . Exposure to fl uctuating CBF could eventually result in hemorrhage within this region.…”

Section: Discussionmentioning

confidence: 99%

Intrauterine Inflammation and the Onset of Peri-Intraventricular Hemorrhage in Premature Infants

et al. 2006

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Background: Peri-intraventricular hemorrhage (P/IVH) is a common neonatal morbidity among premature infants. The aim of the study was to examine the association between placental and/or fetal inflammation and the onset of P/IVH in premature infants. Methods: A prospective study included 125 infants with gestational age 23–29 weeks. Placentas were examined for the presence of chorioamnionitis and funisitis, cord blood was sampled for the measurement of cytokines (IL-6 and IL-8). Fetal inflammation was defined as levels of IL-6 higher than 7.6 pg/ml. P/IVH was defined as early if diagnosed within the 1st day after birth; thereafter P/IVH was defined as late. Results: Adjusted for the influence of gestational age, early-onset sepsis (OR 3.2, p = 0.045) and no or incomplete antenatal steroid course (OR 6.0, p = 0.001) significantly predicted early P/IVH. Funisitis (OR 1.6, p = 0.06) and fetal inflammation (OR 2.6, p = 0.06) were only partially associated with early hemorrhage. Contrary to that, respiratory distress syndrome (OR 3.4, p = 0.04), mechanical ventilation (OR 5.9, p = 0.008), low blood pressure (OR 3.5, p = 0.02), and vasopressors (OR 5.7, p = 0.002) were associated with late P/IVH. In multivariate analysis no or incomplete steroid course remained independent predictors for early and use of vasopressors for late P/IVH. The interaction of fetal inflammation and vaginal delivery with no or incomplete steroid course increased the risk of early P/IVH. Conclusions: These results indicate different risk factors for early and late P/IVH. Neither funisitis nor fetal inflammation independently predicts the onset of P/IVH. However, the interaction of fetal inflammation and vaginal delivery with no or incomplete antenatal steroid course increase the risk of early but not also late P/IVH.

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Cerebrovascular Responses in the Fetal Sheep Brain to Low-Dose Endotoxin

Cited by 79 publications

References 46 publications

Mechanisms of Melatonin-Induced Protection in the Brain of Late Gestation Fetal Sheep in Response to Hypoxia

Mechanisms of Melatonin-Induced Protection in the Brain of Late Gestation Fetal Sheep in Response to Hypoxia

Acute Behavioral Effects of Intrapleural OK-432 (Picibanil) Administration in Preterm Fetal Sheep

Intrauterine Inflammation and the Onset of Peri-Intraventricular Hemorrhage in Premature Infants

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