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Intrauterine inflammation and the requirement for mechanical ventilation independently increase the risk of perinatal brain injury and adverse neurodevelopmental outcomes. We aimed to investigate the effects of mechanical ventilation for 24 h, with and without prior exposure to intrauterine inflammation, on markers of brain inflammation and injury in the preterm sheep brain. Chronically instrumented fetal sheep at ~115 days of gestation were randomly allocated to receive a single intratracheal dose of 1 mg lipopolysaccharide (LPS) or isovolumetric saline, then further randomly allocated 1 h after to receive mechanical ventilation with room air or no mechanical ventilation (unventilated control + saline [UVC,  = 7]; mechanical ventilation + saline [VENT,  = 8], unventilated control + intratracheal LPS [UVC + LPS,  = 7]; ventilation + intratracheal LPS [VENT + LPS,  = 7]). Serial fetal blood and plasma samples were collected throughout the experimental protocol for assessment of blood biochemistry and plasma interleukin (IL)-6 levels. After 24 h of mechanical ventilation, fetal brains were collected for RT-qPCR and immunohistochemical analyses. LPS exposure increased numbers of microglia and upregulated pro-inflammatory related genes within the cortical gray matter (GM) and subcortical white matter (SCWM) (  < 0.05). Mechanical ventilation alone increased astrocytic cell density in the periventricular white matter (PVWM) (  = 0.03) but had no effect on pro-inflammatory gene expression. The combination of ventilation and LPS increased plasma IL-6 levels (  < 0.02 vs. UVC and VENT groups), and exacerbated expression of pro-inflammatory-related genes ( , , , ) and microglial density (  < 0.05 vs. VENT). This study demonstrates that 24 h of mechanical ventilation after exposure to intrauterine inflammation increased markers of systemic and brain inflammation and led to the upregulation of pro-inflammatory genes in the white matter. We conclude that 24 h of mechanical ventilation following intrauterine inflammation may precondition the preterm brain toward being more susceptible to inflammation-induced injury.

Fetal growth restriction (FGR) arises from chronic hypoxia and increases the risk of cardiovascular dysfunction following perinatal asphyxia, although the underlying mechanisms are unknown. We investigated whether FGR lambs have altered cardiovascular responses to perinatal asphyxia compared to control lambs, and whether impairments in α1 and β1 adrenergic receptor function underlie these responses. Single or twin-bearing ewes underwent sterile fetal surgery at 89 days gestation (dGA; term=148d) to induce FGR (single umbilical artery ligation) or sham surgery (Control). At 126dGA, lambs were delivered via caesarean section, instrumented and randomised to immediate ventilation (ControlVENT n=6; FGRVENT n=6), or asphyxia (ControlASPHYXIA n=12; FGRASPHYXIA n=11) induced by umbilical cord occlusion while withholding resuscitation until diastolic blood pressure (BP) decreased to 10mmHg. Lambs were ventilated for 8 hours before baseline ex vivo cardiac function was assessed via Langendorff perfusion to measure left ventricular developed pressure (LVDP), heart rate (HR) and coronary perfusion pressure (CPP). Ex vivo α1 and β1 adrenergic responses were assessed via phenylephrine (10−5 to 10−2 mmol/L) and dobutamine (10−7 to 10−4) administration, respectively. FGRASPHYXIA lambs had lower BP during asphyxia (p<0.05 vs ControlASPHYXIA) and took longer to reach a diastolic BP of 10mmHg (14.5 ± 0.8 min vs. 19.2 ± 1.3 min; p=0.005). FGRASPHYXIA lambs had lower BP in the first 5 minutes after return of spontaneous circulation (p<0.05) due to impaired vascular contractility, with reduced Tau, dP/dtmax and dP/dtmin (p<0.03 vs ControlASPHYXIA). Baseline LVDP, HR and CPP were similar between groups, however FGRASPHYXIA lambs had increased LVDP responses to phenylephrine and dobutamine (p<0.05 vs ControlASPHYXIA), without significant changes to HR or CPP. FGR lambs have altered physiological responses to perinatal asphyxia due to impaired vascular contractility and dysregulated cardiac α1 and β1 adrenergic receptor function, which may increase susceptibility to cardiovascular dysfunction in the neonatal period.