Background Trauma patients with hemorrhagic shock (HS) accounts for 40% of preventable death. Shock-induced endotheliopathy has garnered interest recently and one aspect of this, endothelial glycocalyx shedding (EGX), has shown to promote coagulopathy following hemorrhage. Ferroptosis is an iron dependent, non-apoptotic form of controlled cell death triggered by the oxidation of membrane phospholipids. Liproxstatin-1 is an inhibitor of this process and can protect against oxidative damage to the endothelial cell membrane and subsequent shedding of glycocalyx. Our goal is to determine if administration of Liproxstatin-1, a ferroptosis inhibitor can reduce glycocalyx shedding in hemorrhaged rats providing evidence of its therapeutic value in the setting of hemorrhagic shock.

Methods A rat model of hemorrhagic shock and resuscitation was used to assess glycocalyx disruption in the lungs via fluorescent-labeled wheat germ agglutinin staining in frozen tissue and by syndecan-1 ELISA on plasma samples. A control group (n=5) resuscitated only with Lactated Ringer’s solution, following hemorrhage and resuscitation (H/R) was compared against an experimental group (n=1) that received Liproxstatin-1 following hemorrhage and before resuscitation.

Results Glycocalyx shedding (assessed by an increase in plasma syndecan-1 levels) was significantly lower in the Liproxstatin-1 treated group compared to control group. Additionally, Liproxstatin-1 treated animals were able to sustain a higher mean arterial pressure (MAP), and oxygen saturation throughout the resuscitation period measured at 15- and 30-minutes following Liproxstatin-1 infusion.

Conclusion Ferroptosis inhibitor Liproxstatin-1 can reduce morbidity acutely during hemorrhagic shock and protect endothelial cell membrane from oxidative damage due to its ability to slow the generation of reactive oxygen species (ROS) and lipid hydroperoxides.

Further experiments will be performed to complete the Liproxstatin-1 experimental group (n=5) as well as a control group using Cyrene (n=5), a DMSO-like solvent used to dissolve Liproxstatin-1 for intravenous administration. Additionally, tissue staining of lung vasculature will be performed to evaluate the glycocalyx disruption in the vascular beds of the lungs in the Cyrene, and Liproxstatin-1 groups as well as a group resuscitated with Lactated Ringers solution (H/R) alone.