SummaryInfection and inflammation can be antecedents of neonatal encephalopathy (NE) and increase the risk of neurological sequelae. Activated protein C (APC) has anti-coagulant and anti-inflammatory effects and provides neuroprotection in brain and spinal cord injury. We examined neutrophil and monocyte responses to lipopolysaccharide (LPS) in infants with NE compared with healthy adult and neonatal controls, and also studied the effect of APC. Whole blood was incubated with LPS and APC and Toll-like receptor (TLR)-4 (LPS recognition), CD11b expression (activation) and intracellular reactive oxygen intermediate (ROI; function) release from neutrophils and monocytes was examined by flow cytometry serially from days 1 to 7. We found a significant increase in neutrophil ROI in infants with NE on day 3 following LPS compared to neonatal controls and this augmented response was reduced significantly by APC. Neutrophil and monocyte CD11b expression was increased significantly on day 1 in infants with NE compared to neonatal controls. LPSinduced neutrophil TLR-4 expression was increased significantly in infants with NE on days 3 and 7 and was reduced by APC. LPS-induced monocyte TLR-4 was increased significantly in infants with NE on day 7. Neutrophil and monocyte activation and production of ROIs may mediate tissue damage in infants with NE. APC modified LPS responses in infants with NE. APC may reduce the inflammatory responses in NE and may ameliorate multi-organ dysfunction. Further study of the immunomodulatory effects of protein C may be warranted using mutant forms with decreased bleeding potential.
Background Brain injury and inflammation are common mechanisms of disease in preterm infants. VEGF is an endothelial growth factor which has been shown to be neuro-protective in adult stroke. Infants less than 32 weeks’ gestation who suffer from respiratory distress syndrome (RDS) have been shown to have significantly lower VEGF levels than those without RDS. However little is known about the mechanisms of VEGF in the premature brain. Aim We aimed to investigate the relationship between brain injury and chorioamnionitis and serum VEGF levels in preterm infants. Methods Preterm infants <32 weeks’ gestation were recruited. Details of their demographics and neonatal intensive care unit stay were recorded, as well as cranial ultrasound and placental pathology results. Serial serum VEGF levels were measured by multiplex ELISA over the first week of life. Results Preterm infants (n = 86) had a mean gestation of 28+4 ± 0+2 weeks and Birth weight of 1165 ± 326 kg. Infants (n = 29) with abnormal cranial ultrasounds (n = 9) had a decreased mean VEGF level (227 ± 322 pg/mL versus normal 324 ± 528 pg/mL). Serum VEGF levels on Day 1 were significantly associated with histological chorioamnionitis (p = 0.0006). The mean serum VEGF levels were 116 ± 182 pg/mL in those without chorioamnionitis compared to 735 ± 683 pg/mL in those with chorioamnionitis. Conclusion Elevated serum VEGF is associated with choriomanionitis in preterm infants.
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