Be On the Look Out (BOLO) alert: Protein kinase C epsilon activation improves early survival in an acute porcine model of controlled hemorrhage
Myron Yaster MD and Shawn Jackson MD PhD
As a clinician and a laboratory and clinical researcher, I’ve long recognized the translation from promising animal studies to successful human clinical practice is a path fraught with challenges and failure. Indeed, many laboratory “breakthroughs” trumpeted in journals and the media fail in clinical practice. Because of this, I infrequently choose animal studies for the PAAD. However, today’s study by Simchoni et al.1 offers intriguing potential improvements for hemorrhagic trauma management that I think really warrants the spotlight and your attention! Myron Yaster MD
Original article
Simchoni M, Wagnert-Avraham L, Derazne E, Nachman D, Gershon Y, Cohen Levi E, Horesh A, Cohen Y, Nitecki M, Glick Y, Eisenkraft A, Suissa N, Twig G, Gertz SD, Saada A, Furer A. Protein kinase C epsilon activation improves early survival in an acute porcine model of controlled hemorrhage. Sci Rep. 2025 Mar 17;15(1):9126. doi: 10.1038/s41598-025-92310-3. PMID: 40097491; PMCID: PMC11914495.
“Of all trauma-related complications, hemorrhage remains the most prevalent cause of preventable death in military and civilian settings, contributing to an estimated 60–90% of cases2-5 and totaling approximately 1.5 million deaths annually worldwide. In hemorrhagic shock, reduced blood flow to the tissues causes an insufficient supply of oxygen and essential substances necessary for normal cell function.” Traditional severe hemorrhage management, as broken down by the authors, centers arounds two fundamental principles:
Hemostasis: Direct pressure, tourniquets, clotting agents, or advanced techniques like resuscitative endovascular balloon occlusion of the aorta (REBOA).
Volume Resuscitation: Crystalloid and blood products including red blood cells, fresh-frozen plasma or whole blood. Blood products are preferred in significant trauma.
“However, following volume resuscitation, tissues have altered perfusion and consequent ischemia with additional damage due to re-perfusion injury. Insights related to the pathogenetic mechanisms of hemorrhage-associated ischemia–reperfusion injury have led to many attempts to test novel therapeutic approaches. Multiple studies have suggested that protein kinase C epsilon (PKC-ε) activation plays a pivotal role in cardio-protection by activating structural, signaling, and stress-related proteins, as well as by diminishing mitochondrial dysfunction and oxidative stress. Its phosphorylation targets include cardiac troponin I, cardiac troponin T, alpha actin and myosin light chain which regulate muscle contraction, MAPK, MEK, ERK and other tyrosine kinases which are involved in signal transduction and redox processes, and mitochondrial proteins responsible for ATP synthesis.”1
Simchoni et al.1 hypothesized that activating PKC-ε may modulate global ischemia-reperfusion-related damage. In their study, the authors induced hemorrhagic shock was induced in 25 pigs by removing 35% of the estimated blood volume. A PKC-ε activator was administered to 15 pigs five minutes after bleeding initiation, with 8 untreated controls and 2 control animals without hemorrhage who were administered PKC-ε activator for safety assessment. Hemodynamic and biochemical parameters were monitored for 7 hours along with mitochondrial function markers.
What did they find? “Eleven of 15 (73.3%) pigs treated with the PKC-ε activator peptide survived the hemorrhage until the end of the 7-h follow-up period compared to only 2 of 8 (25%) non-treated control animals. Kaplan–Meier analysis showed a significant difference in survival across the entire 7-h period between the two groups (p = 0.044) (figure below)
Figure caption: “A Kaplan–Meier survival analysis and Log Rank test comparing survival between study groups: PKC-ε (blue) and control (red). Note significant difference between the groups (p = 0.044). The table below the graph details the number of animals in each group and time point.”1
The treatment demonstrated a clear early survival advantage, with 73.3% of PKC-ε treated pigs surviving the 7-hour period versus 25% in the control group, with Kaplan–Meier analysis revealing significant survival differences (p = 0.044).
These results further demonstrated association of early peptide administration with hemodynamic stability, as evidenced by improved blood pressure, heart rate, cardiac output, and acid-base balance. One unanswered question in this study is the degree of neurological injury in the animals that survived the experiment.
Considerations remain regarding the window of effectiveness, potential human application, and administration logistics in a field or prehospital setting. While questions persist, the possibilities are promising.
Send your thoughts and comments to Myron who will post in a Friday reader response.
References
1. Simchoni M, Wagnert-Avraham L, Derazne E, Nachman D, Gershon Y, Cohen Levi E, Horesh A, Cohen Y, Nitecki M, Glick Y, Eisenkraft A, Suissa N, Twig G, Gertz SD, Saada A, Furer A: Protein kinase C epsilon activation improves early survival in an acute porcine model of controlled hemorrhage. Sci Rep 2025; 15: 9126
2. Murphy SL, Kochanek KD, Xu J, Arias E: Mortality in the United States, 2020. NCHS Data Brief 2021: 1–8
3. Butler FK, Jr., Blackbourne LH: Battlefield trauma care then and now: a decade of Tactical Combat Casualty Care. J Trauma Acute Care Surg 2012; 73: S395–402
4. Rentas F, Lincoln D, Harding A, Maas P, Giglio J, Fryar R, Elder K, Fahie R, Whitlock K, Vinluan J, Gonzales R: The Armed Services Blood Program: blood support to combat casualty care 2001 to 2011. J Trauma Acute Care Surg 2012; 73: S472–8
5. Cannon JW: Hemorrhagic Shock. N Engl J Med 2018; 378: 370–379