Grant: Travel Awards - Institute Community Support

Late-onset sepsis (LOS) is a life-threatening emergency that happens when babies mount an extreme response to an infection. Even in those babies that survive, they face a lifetime of health problems that remain after recovery. In this project, we studied a recently discovered pathway that could play a role in the development of organ injury in LOS. Ferroptosis is a form of cell death that depends on iron, and iron accumulation occurs in sepsis. Excess iron can produce potentially toxic molecules named free radicals. These toxic molecules damage cells and trigger cell death (i.e. ferroptosis). We believe ferroptosis could be involved in liver injury and eventual death in LOS because iron accumulates in the liver. To test this, we used an established model of LOS using three-day old Sprague Dawley rat 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 pups. We monitored their health and collected liver tissues to study liver iron levels, antioxidant (glutathione) levels, free radical levels, and other regulators of ferroptosis. We found that 29% of septic pups died within 24h, and those that survived have signs of liver injury. Septic pups also showed an increase in total liver iron and free radical production. We found that septic pups have a more active glutathione synthesis pathway, likely in response to a depletion of total glutathione levels, and this could be driven by a transcription factor named signal transducer and activator of transcription 3 (STAT3). We continued our investigation by treating septic pups with a ferroptosis inhibitor named ferrostatin-1 (fer-1) to see if it can prevent liver injury and promote survival. Fer-1 acts by reducing free radicals. Treating septic pups with fer-1 increased septic pup mortality to 80%, suggesting that free radical generation may be required for survival in LOS.