Introduction: Antenatal exposure to systemic inflammation/infection is a major risk factor for injury and long-term disability in late preterm/term infants. Limited preclinical and clinical studies suggest the efficacy of therapeutic hypothermia in infants exposed to systemic inflammation/infection may be impaired in babies exposed to gram negative infection. Therefore, it is vital to establish a translational model of inflammation-induced brain injury in the near-term/term infant to identify therapeutic interventions for infants that are not responsive to current hypothermia protocols. Thus, we aimed to establish a large animal translational model of systemic inflammation-induced brain injury that can be used to test potential therapeutic interventions.
Materials and methods: Chronically instrumented near-term fetal sheep (0.85 gestation) were randomly assigned to receive either saline (control; n=7) or lipopolysaccharide (LPS, derived from the outer cell wall of gram-negative bacteria) boluses (300 ng/24 h then doubled every 24 h for 2 d) to induce systemic inflammation; n=8). Five days after infusion, fetal brains were collected for histopathology.
Results: LPS-exposure in late preterm fetuses was associated with transient moderate hypoxia, and metabolic and respiratory acidosis (P<0.05 vs. control). In the periventricular and intragyral white matter tracts, LPS exposure increased microglial infiltration (P<0.05 vs. control), and reduced total numbers of (Olig-2+) oligodendrocytes (P<0.05 vs. control) and GFAP positive astrocytes (P<0.05 vs. control). IL-1β immunoreactivity was increased in the periventricular white matter.
Discussion: Subacute perinatal inflammation in near-term fetal sheep was associated with white matter gliosis and upregulation of IL-1β that may modify subsequent responses to acute hypoxia-ischaemia and its treatment.