Grant: Travel Awards - Institute Community Support

Late-onset sepsis (LOS) is a life-threatening host response to infection in newborns. LOS commonly occurs in preterm infants and those with very low birth weight. Recently, a new way for cells to die was discovered and named ferroptosis because it depends on iron. Iron is critical in the production of signaling molecules named reactive oxygen species (ROS) that could cause lipid peroxidation. Interestingly, LOS is characterized by an increase in the production of these signaling molecules. We found that LOS also results in liver injury 24h after sepsis begins, so we wanted to study whether ferroptosis is involved in the development of liver injury. To test this, we used an established model of LOS using three-day old Sprague Dawley pups which are approximately equivalent to the development of premature human babies. These rat pups received either fecal slurry to induce sepsis or 5% dextrose in control babies. We monitored their health and collected liver tissues to study liver iron levels, lipid peroxidation levels, and some regulators of ferroptosis at the gene and protein level. We found that the fecal slurry dose we used caused 30% of our septic pups to die, and these pups lost ~10% of their body weight by 24h. LOS caused a 60% increase in liver total iron. We also found that despite not seeing any changes in lipid peroxidation levels in the liver, another indication of ROS production, DNA oxidation, was increased in the septic pups. This could be attributed to a more active glutathione antioxidant pathway which is responsible for reducing lipid peroxidation, but a depleted glutathione pathway is characteristic of ferroptosis. Thus, whether ferroptosis contributes to the liver injury observed at 24h is still under investigation.