Bacterial sepsis and systemic inflammation potentiates neonatal hypoxic-ischemic brain injury
Jacqueline Lai1, Pernilla Svedin1, Joakim Ek1, Amin Mottahedin1, Xiaoyang Wang1, Tobias Strunk2, Andrew Currie3, Ofer Levy4 and Carina Mallard1* 1Dept. of Physiology, Univ. of Gothenburg, Sweden; 2Centre for Neonatal Research & Education, Univ. of Western Australia; Neonatal Clinical Care Unit, King Edward Memorial Hospital, Australia; 3School of Veterinary & Life Sciences, Murdoch Univ., Australia; 4Dept. of Medicine, Boston Children's Hospital, Harvard Medical School, USA *Corresponding author
Sepsis represents a major problem of the neonatal period in preterm infants and often leads to complications including episodes of hypoxia-ischemia. Ischemia and inflammation are major factors that can independently trigger injury to the developing brain, but also act in concert to potentiate the brain damage.
Inflammation in preterm neonates is often caused by infections, with Staphylococcus epidermidis emerging as the leading cause for hospital-acquired late-onset sepsis. Here, we present a clinically relevant mouse model of bacterial infection with subsequent hypoxia-ischemia insult on the neonatal brain. S. epidermidis administered intraperitoneally into postnatal day 4 mice led to self-limiting bacteremia. Systemic production of pro-inflammatory cytokines was detected in the serum with levels peaking between 14 to 24 hours. In the brain, neutrophil and monocyte chemotactic cytokines (CXCL-1 and MCP-1), granulocyte-colony stimulating factor, and caspase-3 activity were transiently elevated. Permeability of the blood-brain barrier was significantly increased in the infected animals compared to controls, but cerebral blood flow was not significantly altered upon infection. While infection alone did not lead to changes in the gray and white matter volume, when hypoxic-ischemic insult (right carotid artery ligation and exposure to 10% O2) was induced 14 or 24 hours after the infection, more severe brain damage was observed in infected animals compared to controls. This infection-potentiated brain injury was not observed when hypoxia-ischemia was induced 5 days post infection, a time when the systemic inflammation has resolved.
In conclusion, increased vulnerability of the immature brain to hypoxia-ischemia insult is affected by concurrent inflammation, and suppressing inflammation could be a neuroprotection strategy for treating infants experiencing sepsis and hypoxic-ischemic encephalopathy.
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