Does growth restriction increase the vulnerability to acute ventilation-induced brain injury in newborn lambs? Implications for future health and disease

Abstract

Fetal growth restriction (FGR) and preterm birth are frequent co-morbidities, both are independent risks for brain injury. However, few studies have examined the mechanisms by which preterm FGR increases the risk of adverse neurological outcomes. We aimed to determine the effects of prematurity and mechanical ventilation (VENT) on the brain of FGR and appropriately grown (AG, control) lambs. We hypothesized that FGR preterm lambs are more vulnerable to ventilation-induced acute brain injury. FGR was surgically induced in fetal sheep (0.7 gestation) by ligation of a single umbilical artery. After 4 weeks, preterm lambs were euthanized at delivery or delivered and ventilated for 2 h before euthanasia. Brains and cerebrospinal fluid (CSF) were collected for analysis of molecular and structural indices of early brain injury. FGRVENT lambs had increased oxidative cell damage and brain injury marker S100B levels compared with all other groups. Mechanical ventilation increased inflammatory marker IL-8 within the brain of FGRVENT and AGVENT lambs. Abnormalities in the neurovascular unit and increased blood-brain barrier permeability were observed in FGRVENT lambs, as well as an altered density of vascular tight junctions markers. FGR and AG preterm lambs have different responses to acute injurious mechanical ventilation, changes which appear to have been developmentally programmed in utero.

Cognitive Development and Quality of Life Associated With BPD in 10-Year-Olds Born Preterm

“…72 The complexity of the situation is suggested by the observation that newborn lambs who are growth restricted are at increased risk of ventilation-induced brain damage. 73…”

Neurovascular effects of umbilical cord blood-derived stem cells in growth-restricted newborn lambs

“…Mechanical ventilation can have detrimental effects on the immature preterm brain [3,4]. In preterm FGR offspring, neonatal ventilation leads to increased risk of brain injury [5,6], contributed by a greater susceptibility to neuroinflammation and blood-brain barrier (BBB) breakdown in FGR offspring [6].…”

Respiratory Support of the Preterm Neonate: Lessons About Ventilation-Induced Brain Injury From Large Animal Models

“…Preterm growth-restricted lambs ventilated with a gentle non-injurious strategy for 24 h had disrupted interaction of astrocyte end-feet with cerebral blood vessels, increased microgliosis, and increased oxidative stress compared to their unventilated counterparts and to ventilated preterm appropriately-grown lambs (68). Notably, differences between growth-restricted and appropriately grown lambs were evident after 2 h of ventilation (110). This suggests that growth restricted infants may be at increased risk of VIBI, perhaps in part due to differences in the neurovascular unit and blood-brain barrier properties (68,110).…”

“…Additionally, the effects of shorter durations of controlled NICU respiratory support have been investigated in sheep. Preterm lambs (125 days of term 148 days; 0.85 gestation) ventilated with a non-injurious strategy (V T at 5-7 ml/kg) had increased IL-8 and connective tissue growth factor (CTGF) mRNA levels and decreased vascular occludin protein density in the white matter after 2 h (110). When the length of ventilation was extended to 24 h, ventilated lambs had increased astrogliosis within cortical gray matter but otherwise no apparent neuropathology or changes in glial cell populations compared to unventilated control lambs (68).…”