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©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
Protective effects of treprostinil and ischemic preconditioning on hepatic ischemia-reperfusion injury and biomarkers in experimental studies in rats
Christina Mouratidou, Efstathios T Pavlidis, Georgios Katsanos, Serafeim-Chrysovalantis Kotoulas, Maria Papaioannou, Georgios Tsoulfas, Emmanouela Apostolopoulou, Georgia D Brellou, Ioannis N Galanis, Theodoros E Pavlidis
Christina Mouratidou, Serafeim-Chrysovalantis Kotoulas, Intensive Care Unit, Hippokration General Hospital, Thessaloniki 54642, Greece
Efstathios T Pavlidis, Ioannis N Galanis, Theodoros E Pavlidis, The Second Department of Propaedeutic Surgery, Hippokration General Hospital, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
Georgios Katsanos, Georgios Tsoulfas, Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
Maria Papaioannou, Laboratory of Biological Chemistry, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece
Emmanouela Apostolopoulou, Georgia D Brellou, Department of Pathology, Faculty of Health Sciences, School of Veterinary Medicine, Aristotle University of Thessaloniki, Thessaloniki 54627, Greece
Co-corresponding authors: Efstathios T Pavlidis and Theodoros E Pavlidis.
Author contributions: Mouratidou C, Pavlidis ET, Katsanos G, and Galanis IN conceived the study, developed the methodology, and drafted the initial version of the manuscript; Kotoulas SC, Apostolopoulou E, Papaioannou M, and Brellou GD performed data analysis and contributed to manuscript revisions; Tsoulfas G and Pavlidis TE analyzed data and supervised the project; Pavlidis ET and Pavlidis TE contributed equally as co-corresponding authors. All authors reviewed and approved the final version of the manuscript.
Institutional animal care and use committee statement: The experimental protocol was approved by the Medical School of Aristotle University of Thessaloniki and the Department of Animal Health, Directorate of Veterinary Policy, Prefecture of Thessaloniki, Greece, No. 493502(2223). The experimental portion of the study was conducted at the Laboratory of Development-Breeding of Animal Models and Biomedical Research, School of Veterinary Medicine, Aristotle University of Thessaloniki, No. EL-54-BIOexp-10.
Conflict-of-interest statement: The authors report no relevant conflicts of interest for this article.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: No additional data are available.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Theodoros E Pavlidis, MD, PhD, Professor, The Second Department of Propaedeutic Surgery, Hippokration General Hospital, School of Medicine, Aristotle University of Thessaloniki, Konstantinoupoleos 49, Thessaloniki 54642, Greece.
pavlidth@auth.gr
Received: June 18, 2025
Revised: July 24, 2025
Accepted: September 22, 2025
Published online: November 27, 2025
Processing time: 160 Days and 22.1 Hours
BACKGROUND
Hepatic ischemia-reperfusion injury (HIRI) remains one of the major causes of postoperative liver dysfunction following extensive hepatectomy and liver transplantation. Owing to its progressive and dynamic nature, HIRI may lead to multiple organ failure and a worsened outcome. Treprostinil is a relatively new synthetic prostacyclin analog with a potential beneficial effect against HIRI. Ischemic preconditioning (IP) is a promising method to protect against HIRI.
AIM
To investigate HIRI biomarkers, their effects on liver and heart, and the effects of treprostinil and IP on these processes.
METHODS
Forty male Wistar albino rats aged 3-4 months were randomly assigned to four groups of ten, subjected to a 3-hour surgical intervention, and then sacrificed. Hepatic ischemia was induced by clamping the hepatoduodenal ligament for 30 minutes, followed by reperfusion for 120 minutes. Treprostinil (100 ng/kg/minute for 24 hours) or IP before HIRI, no protection, and a sham operation were applied accordingly in each group. Liver and heart histopathology and specific serum and hepatic tissue biomarkers were assessed.
RESULTS
HIRI deteriorated hepatocellular function and exacerbated liver and myocardial damage in the control group. Furthermore, HIRI triggered cytokine overexpression and protein carbonyl content (P < 0.001). Compared with those in the HIRI group, lower troponin I, tumor necrosis factor-α, endothelin-1, and interleukin-1β in serum and liver tissue were significantly correlated with reduced cellular necrosis and improved hepatocellular function in the treprostinil group (P < 0.001). Similar but less pronounced effects were observed in the IP group. Both treprostinil and IP had protective effects in hepatic and cardiac tissues. However, treprostinil showed slightly superior cardioprotective efficacy, as evidenced by a statistically significant difference in troponin I levels (P < 0.05) and histopathological scoring of myocardium samples, but there were no differences in the other parameters.
CONCLUSION
HIRI results in oxidative stress and cytokine overexpression, which deteriorate hepatic function and accelerates myocardial damage. Treprostinil and IP are promising strategies for preventing reperfusion-induced cellular and systemic damage.
Core Tip: Hepatic ischemia-reperfusion injury is a serious condition that causes oxidative stress with a systemic inflammatory response. In addition to the liver, it may cause damage to remote organs, particularly the myocardium, with disastrous results. Consequently, its prevention is crucial, especially in liver surgery and transplantation. This experimental preclinical study in rats evaluated the cytoprotective effect of treprostinil compared with ischemic preconditioning on the liver and heart. Biomarkers were assessed for a better understanding of the pathophysiology of systemic manifestations, thus opening new future perspectives for the design of clinical trials assessing treprostinil efficacy.
