Journal
AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY
Volume 315, Issue 6, Pages R1183-R1194Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpregu.00171.2018
Keywords
blood-brain barrier; FGR; IUGR; neuroinflammation; oxidative stress
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Funding
- National Health and Medical Research Council (NHMRC) [APP1083520]
- Cerebral Palsy Alliance Research Grant [PG0414]
- Royal Australasian College of Physicians Research Scholarship
- NHMRC Career Development Fellowship
- Australian Research Council Future Fellowship
- Victorian Government's Operational Infrastructure Program
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Fetal growth restriction (FUR) and prematurity are associated with high risk of brain injury and long-term neurological deficits. FGR infants born preterm are commonly exposed to mechanical ventilation, but it is not known whether ventilation differentially induces brain pathology in FGR infants compared with appropriate for gestational age (AGA) infants. We investigated markers of neuropathology in moderate- to late-preterm FGR lambs, compared with AGA lambs, delivered by caesarean birth and ventilated under standard neonatal conditions for 24 h. FGR was induced by single umbilical artery ligation in fetal sheep at 88-day gestation (term. 150 days). At 125-day gestation. FGR and AGA lambs were delivered, dried. incubated, and commenced on noninjurious ventilation, with surfactant administration at 10 min. A group of unventilated FGR and AGA lambs at the same gestation was also examined. Over 24 h, circulating pH. Po-2, and lactate levels were similar between groups. Ventilated FGR lambs had lower cerebral blood flow compared with AGA lambs (P = 0.01). The brain of ventilated FGR lambs showed neuropathology compared with unventilated FGR, and unventilated and ventilated AGA lambs, with increased apoptosis (caspase-3), blood-brain barrier dysfunction (albumin extravasation), activated microglia (Iba-1), and increased expression of cellular oxidative stress (4-hydroxynonenal). The neuropathologies seen in the ventilated FGR brain were most pronounced in the periventricular and subcortical white matter but also evident in the subventricular zone, cortical gray matter, and hippocampus. Ventilation of preterm FGR lambs increased brain injury compared with AGA preterm lambs and unventilated FGR lambs, mediated via increased vascular permeability, neuroinflammation and oxidative stress.
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