Abstract | November 16, 2023

Can Inhibiting Ferroptosis and Subsequent Endothelial Glycocalyx Shedding Reduce the Morbidity and Mortality of Hemorrhagic Shock?

Aditya Vinjamuri, MS, MS3, Tulane School of Medicine, New Orleans, LA

Zander Gerberg, Tulane University, New Orelans, LA; Farhana Shaheen MS, Tulane University Department of Surgery, New Orleans, LA; Juan Duchesne, MD, Chief, Trauma, Acute Care & Critical Care Surgery, Tulane University Department of Surgery, New Orleans, LA; Sharven Taghavi, MD, MPH, MS, FACS, FCCP, Associate Professor, Tulane University Department of Surgery, New Orleans, LA; Olan Jackson-Weaver, PhD, Assistant Professor, Tulane University Department of Surgery, New Orleans, LA

Learning Objectives

  1. Understand the role of Liproxstatin-1, a ferroptosis inhibitor in preventing cell damage/ death in-vivo.
  2. Understand the mechanisms driving coagulopathy following hemorrhagic shock.
  3. Understand the relationship of succinate and vascular endothelial damage driving morbidity and mortality of hemorrhagic shock and subsequent coagulopathy.

Background/Purpose
Trauma is the leading cause of death in people under 44 years old. Hemorrhagic shock (HS) is often a consequence of trauma and contributes to morbidity and mortality in these patients. 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.

Goals
To determine if 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/Design
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/Findings
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.

Conclusions/Implication
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.

References and Resources

  1. Abdullah S, Ghio M, Cotton-Betteridge A, Vinjamuri A, Drury R, Packer J, Aras O, Friedman J, Karim M, Engelhardt D, Kosowski E, Duong K, Shaheen F, McGrew PR, Harris CT, Reily R, Sammarco M, Chandra PK, Pociask D, Kolls J, Katakam PV, Smith A, Taghavi S, Duchesne J, Jackson-Weaver O. Succinate metabolism and membrane reorganization drives the endotheliopathy and coagulopathy of traumatic hemorrhage. Sci Adv. 2023 Jun 16;9(24):eadf6600. doi: 10.1126/sciadv.adf6600. Epub 2023 Jun 14. PMID: 37315138; PMCID: PMC10266735.
  2. Abdullah S, Karim M, Legendre M, Rodriguez L, Friedman J, Cotton-Betteridge A, Drury R, Packer J, Guidry C, Duchesne J, Taghavi S, Jackson-Weaver O. Hemorrhagic Shock and Resuscitation Causes Glycocalyx Shedding and Endothelial Oxidative Stress Preferentially in the Lung and Intestinal Vasculature. Shock. 2021 Nov 1;56(5):803-812. doi: 10.1097/SHK.0000000000001764. PMID: 34259440.
  3. Jackson-Weaver O, Friedman JK, Rodriguez LA, Hoof MA, Drury RH, Packer JT, Smith A, Guidry C, Duchesne JC. Hypoxia/reoxygenation decreases endothelial glycocalyx via reactive oxygen species and calcium signaling in a cellular model for shock. J Trauma Acute Care Surg. 2019 Nov;87(5):1070-1076. doi: 10.1097/TA.0000000000002427. PMID: 31658237.
  4. Zilka O, Shah R, Li B, Friedmann Angeli JP, Griesser M, Conrad M, Pratt DA. On the Mechanism of Cytoprotection by Ferrostatin-1 and Liproxstatin-1 and the Role of Lipid Peroxidation in Ferroptotic Cell Death. ACS Cent Sci. 2017 Mar 22;3(3):232-243. doi: 10.1021/acscentsci.7b00028. Epub 2017 Mar 7. PMID: 28386601; PMCID: PMC5364454.
  5. Taghavi S, Abdullah S, Toraih E, Packer J, Drury RH, Aras OAZ, Kosowski EM, Cotton-Betteridge A, Karim M, Bitonti N, Shaheen F, Duchesne J, Jackson-Weaver O. Dimethyl malonate slows succinate accumulation and preserves cardiac function in a swine model of hemorrhagic shock. J Trauma Acute Care Surg. 2022 Jul 1;93(1):13-20. doi: 10.1097/TA.0000000000003593. Epub 2022 Mar 1. PMID: 35234713; PMCID: PMC9232889.
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