Abstract 3093: Can Inhibiting Ferroptosis And Subsequent Endothelial Glycocalyx Shedding Reduce The Morbidity And Mortality Of Hemorrhagic Shock?

Abstract

Background: Trauma patients with hemorrhagic shock accounts for 40% of preventable death. Shock-induced endotheliopathy has garnered interest recently and one aspect of this, endothelial glycocalyx shedding, 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 (LPX1) is an inhibitor of this process and can protect against oxidative damage to the endothelial cell membrane and subsequent shedding of glycocalyx. We hypothesized that LPX1 would reduce endothelial glycocalyx damage in 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=5) that received LPX1 following hemorrhage and before resuscitation. Results: Glycocalyx shedding (assessed by an increase in plasma Syndecan-1 levels) was prevented in the LPX1 treated group compared to control group. Lung tissue staining of the glycocalyx also showed a greater glycocalyx level in the LPX1 group than in the control (40.4 vs 36.3 arbitrary units). Additionally, LPX1 treated animals were able to sustain a higher mean arterial pressure (82 vs 45mmHg), and oxygen saturation throughout the resuscitation period measured at 15 and 30 minutes following LPX1 infusion (98.4% SpO2 vs. 99.0% SpO2 at 30 minutes resuscitation). Conclusions: Ferroptosis inhibitor LPX1 can reduce morbidity acutely during hemorrhagic shock and can protect the endothelial cell glycocalyx from oxidative damage due to its ability to slow the generation of reactive oxygen species and lipid hydroperoxides.