Oral Presentation 46th Annual Meeting of the Fetal and Neonatal Physiological Society 2019

Chorioamnionitis and postnatal dexamethasone interact to exacerbate brain injury in preterm lambs (#38)

Andrew Warnock 1 , Nathanael Yates 2 , Ellen Williams 1 , Dominique Blache 3 , Siavash Ahmadi-Noorbakhsh 1 , Jane Pillow 1
  1. School of Human Sciences, University of Western Australia, Perth, WA, Australia
  2. Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia
  3. School of Agriculture and Environment , University of Western Australia, Perth, WA, Australia

 

Background: Chorioamnionitis is a common antecedent of preterm birth, impairs brain development, and exacerbates inflammatory responses to adverse stimuli. The prefrontal cortex (PFC) and the periventricular region (PVR) are particularly vulnerable to lesions following chorioamnionitis. Dexamethasone (Dex) is a potent anti-inflammatory agent that may ameliorate postnatal neuroinflammation. The effects of low-dose postnatal dexamethasone on neuroinflammation following chorioamnionitis are unknown.

Hypothesis: We hypothesised that low-dose postnatal dexamethasone would reduce markers of preterm brain injury following chorioamnionitis.

Methods: Pregnant ewes received intra-amniotic lipopolysaccharide (LPS; 4mg) or saline (Sal) at 126d gestation, six hours prior to intramuscular betamethasone (11.4mg) given 48 and 24 hours prior to delivery. Lambs were delivered at 128d gestation and received a 7d tapered dose of Dex (0.75mg/kg total) or Sal, resulting in 4 groups: Sal/Sal, Sal/Dex, LPS/Sal and LPS/Dex (N = 7-8/group). Brains were harvested at day 135. Brain injury was quantified with immunohistochemistry in the PFC and the PVR. Data were analysed with 2-way ANOVA.

Results: LPS reduced neuron density in white and grey matter of the PFC (p<0.01) and the PVR (p< 0.0001). There was an interaction between LPS and dexamethasone in the PVR grey matter neuron density (p<0.01): neuron density was significantly lower in the LPS/Dex versus Sal/Sal lambs (p<0.05). There was an interaction between LPS and dexamethasone in the PFC white matter oligodendrocyte density (p<0.05) but not the PVR white matter (p=0.076). LPS increased proliferating microglia in the grey (p<0.05) and white matter (p<0.01) of the PVR. Dexamethasone decreased proliferating astrocytes in the grey (p<0.05) but not the white matter of the PVR.

Conclusions: Postnatal dexamethasone did not reduce most of the negative effects of chorioamnionitis on brain tissue. Rather, dexamethasone exacerbated markers of cerebral injury in a regionally and cell-type specific manner.   

Grant support: NHMRC 1057514, 1057759, 1077691; TPCHRF; MHRIF