Altered inflammatory responses in preterm children with cerebral palsy

OBJECTIVE: Perinatal inflammatory responses contribute to periventricular leukomalacia (PVL) and cerebral palsy (CP) in preterm infants. Here, we examined whether preterm children with CP had altered inflammatory responses when school-aged. METHODS: Thirty-two preterm children with PVL-induced CP (mean +/-standard deviation age, 7.2 +/- 3.6 years) and 32 control preterm children with normal neurodevelopment (6.2 +/- 2.2 years) and matched for gestational age were recruited. We measured tumor necrosis factor (TNF)-alpha levels in the plasma and the supernatants of peripheral blood mononuclear cells (PBMCs) before and after lipopolysaccharide (LPS) stimulation, and proinflammatory gene expression in the PBMCs. RESULTS: TNF-alpha expression was significantly higher in the plasma (p < 0.001) and supernatants of LPS-stimulated PBMCs (p = 0.003) in the CP group than in the control group. After LPS stimulation, the intracellular TNF-alpha level in the PBMCs was significantly lower in the control group (p = 0.016) and significantly higher in the CP group (p = 0.01). The CP group also had, in their nonstimulated PBMCs, significantly higher mRNA levels of inflammatory molecules: toll-like receptor 4 (TLR-4) (p = 0.0023), TNF-alpha (p = 0.0016), transforming growth factor-beta-activated kinase 1 (p = 0.038), IkappaB kinase-gamma (p = 0.029), and c-Jun N-terminal kinase (p = 0.045). The TLR-4 mRNA levels in the PBMCs were highly correlated with TNF-alpha levels in LPS-stimulated PBMCs (Spearman rank correlation = 0.38, p = 0.03). INTERPRETATION: The finding that preterm children with PVL-induced CP have altered inflammatory responses indicates the possibility of programming effect of PVL or inflammation-related events during early life.