Interaction of Inflammation and Hyperoxia in a Rat Model of Neonatal White Matter Damage

Abstract

Intrauterine infection and inflammation are major reasons for preterm birth. The switch from placenta-mediated to lung-mediated oxygen supply during birth is associated with a sudden rise of tissue oxygen tension that amounts to relative hyperoxia in preterm infants. Both infection/inflammation and hyperoxia have been shown to be involved in brain injury of preterm infants. Hypothesizing that they might be additive or synergistic, we investigated the influence of a systemic lipopolysaccharide (LPS) application on hyperoxia-induced white matter damage (WMD) in newborn rats. Three-day-old Wistar rat pups received 0.25 mg/kg LPS i.p. and were subjected to 80% oxygen on P6 for 24 h. The extent of WMD was assessed by immunohistochemistry, western blots, and diffusion tensor (DT) magnetic resonance imaging (MRI). In addition, the effects of LPS and hyperoxia were studied in an in vitro co-culture system of primary rat oligodendrocytes and microglia cells. Both noxious stimuli, hyperoxia, and LPS caused hypomyelination as revealed by western blot, immunohistochemistry, and altered WM microstructure on DT-MRI. Even so, cellular changes resulting in hypomyelination seem to be different. While hyperoxia induces cell death, LPS induces oligodendrocyte maturity arrest without cell death as revealed by TUNEL-staining and immunohistological maturation analysis. In the two-hit scenario cell death is reduced compared with hyperoxia treated animals, nevertheless white matter alterations persist. Concordantly with these in vivo findings we demonstrate that LPS pre-incubation reduced premyelinating-oligodendrocyte susceptibility towards hyperoxia in vitro. This protective effect might be caused by upregulation of interleukin-10 and superoxide dismutase expression after LPS stimulation. Reduced expression of transcription factors controlling oligodendrocyte development and maturation further indicates oligodendrocyte maturity arrest. The knowledge about mechanisms that triggered hypomyelination contributes to a better understanding of WMD in premature born infants.

Intratracheal transplantation of mesenchymal stem cells simultaneously attenuates both lung and brain injuries in hyperoxic newborn rats

“…These findings suggest that only severe BPD constitutes an independent risk factor for associated brain injury and poor long-term neurodevelopmental outcome in very-lowbirth-weight infants (1,17). Besides hyperoxia, infection and inflammation have also been implicated in preterm infant brain injury (18,19). In the present study, lung MLI, an indicator of alveolarization, showed a significant negative correlation with brain weight and MBP, and a significant positive correlation with the number of TUNEL-positive cells in the brain, measured at P14.…”

A Critical Review of Models of Perinatal Infection

“…was reported to produce a limited CNS cytokine/chemokine response [87], while 0.25 mg/kg i.p. LPS to P3 rat pups caused white matter injury characterized by impaired oligodendrocyte progenitor maturation, but not cell death, with an associated decrease in white matter fractional anisotropy [23]. Similarly, a higher dose of LPS (10 mg/kg s.c.) in P2 mice was associated with impaired oligodendrocyte maturation and reduced myelin production, without oligodendrocyte cell death or axonal injury, while a similar insult at P3, P4 or P5 had no obvious effects [88].…”

“…The precise reasons are unclear, although we may speculate that killing bacteria will release more inflammatory bacterial fragments. Infection/inflammation can also either dramatically exacerbate or alleviate neural damage from subsequent insults such as hypoxia-ischemia, hyperoxia and mechanical ventilation, depending on the precise timing and pattern of the insults [21,22,23,24]. Moreover, whereas brief hypoxia or low-dose Gram-negative lipopolysaccharide (LPS) exposure alone or in combination did not cause neural injury in very immature (postnatal day (P)1) rat pups, brief hyperthermia superimposed on combined hypoxia/LPS upregulated apoptosis and increased cell loss [25], illustrating the potential importance of multimodal injury.…”

Animal models of bronchopulmonary dysplasia. The term rat models

“…This double-hit model, incorporating the added effect of antenatal inflammation to mimic chorioamnionitis, showed that the administration of LPS exacerbated the already damaging effects of hyperoxia on the developing alveolar structure. Since severe BPD is associated with adverse neurodevelopment, several investigators have now taken further advantage of this model by exploring the effects of perinatal events on the developing brain (7).…”