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Molecular Mechanisms of Ischemia/Reperfusion

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 May 2023) | Viewed by 21636

Special Issue Editor

Anaesthesiology and Intensive Care Medicine, Ulm University, Ulm, Germany
Interests: trauma-and-hemorrhage; traumatic brain injury; septic shock

Special Issue Information

Dear Colleagues,

Ischemia/reperfusion sequences contribute to morbidity and mortality during various critical illnesses, both in surgical and medical contexts. They are characterized by an initial imbalance between metabolic supply and demand, resulting in profound tissue hypoxia with hypoxia-related inflammation and excess formation of reactive oxygen and nitrogen species, and subsequent reperfusion, which further aggravates both hyperactivation of the immune response, oxidative and nitrosative stress, and cell death programs. New advances in the understanding of the molecular, metabolic and immunological consequences of ischemia/reperfusion sequences may allow us to develop innovative therapeutic strategies to limit or even prevent the often-occurring subsequent organ dysfunction in patients experiencing this clinical condition.

The aim of this Special Issue is to collect high-quality research and review articles focusing on the molecular mechanisms and innovative therapeutic strategies related to all kinds of ischemia/reperfusion sequences in the context of both “low” and/or even “no flow” conditions, and subsequent restoration of blood flow, as well as hypoxia and re-oxygenation. A special focus will be paid to trauma and hemorrhage and resuscitation. However, articles related to other kinds of ischemia/reperfusion are welcome, e.g., aortic cross clamping, restoration of spontaneous circulation after cardiac arrest, cardiopulmonary bypass, organ transplantation, myocardial infarction and ischemic stroke.

Since IJMS is a journal of molecular science, pure clinical studies will not be suitable; however, clinical submissions including biomolecular experiments focusing on the above-mentioned topics are welcomed.

Prof. Dr. Peter Radermacher
Guest Editor

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Keywords

  • oxygen radical
  • nitrogen radicals
  • mitochondrial dysfunction
  • multi-organ failure
  • massive transfusion
  • acute kidney injury

Published Papers (8 papers)

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Research

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17 pages, 5333 KiB  
Article
The Protective Effect of Nutraceuticals on Hepatic Ischemia-Reperfusion Injury in Wistar Rats
by Carlos Andrés Pantanali, Vinicius Rocha-Santos, Márcia Saldanha Kubrusly, Inar Alves Castro, Luiz Augusto Carneiro-D’Albuquerque and Flávio Henrique Galvão
Int. J. Mol. Sci. 2023, 24(12), 10264; https://doi.org/10.3390/ijms241210264 - 17 Jun 2023
Viewed by 1054
Abstract
Nutraceuticals are bioactive compounds present in foods, utilized to ameliorate health, prevent diseases, and support the proper functioning of the human body. They have gained attention due to their ability to hit multiple targets and act as antioxidants, anti-inflammatory agents, and modulators of [...] Read more.
Nutraceuticals are bioactive compounds present in foods, utilized to ameliorate health, prevent diseases, and support the proper functioning of the human body. They have gained attention due to their ability to hit multiple targets and act as antioxidants, anti-inflammatory agents, and modulators of immune response and cell death. Therefore, nutraceuticals are being studied to prevent and treat liver ischemia–reperfusion injury (IRI). This study evaluated the effect of a nutraceutical solution formed by resveratrol, quercetin, omega-3 fatty acid, selenium, ginger, avocado, leucine, and niacin on liver IRI. IRI was performed with 60 min of ischemia and 4 h of reperfusion in male Wistar rats. Afterward, the animals were euthanized to study hepatocellular injury, cytokines, oxidative stress, gene expression of apoptosis-related genes, TNF-α and caspase-3 proteins, and histology. Our results show that the nutraceutical solution was able to decrease apoptosis and histologic injury. The suggested mechanisms of action are a reduction in gene expression and the caspase-3 protein and a reduction in the TNF-α protein in liver tissue. The nutraceutical solution was unable to decrease transaminases and cytokines. These findings suggest that the nutraceuticals used favored the protection of hepatocytes, and their combination represents a promising therapeutic proposal against liver IRI. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Ischemia/Reperfusion)
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16 pages, 13220 KiB  
Article
Immunohistochemical Pattern of Histone H2A Variant Expression in an Experimental Model of Ischemia–Reperfusion-Induced Acute Kidney Injury
by Jelena Nesovic Ostojic, Maja Zivotic, Sanjin Kovacevic, Milan Ivanov, Predrag Brkic, Nevena Mihailovic-Stanojevic, Danijela Karanovic, Una Jovana Vajic, Zoran Miloradovic, Djurdjica Jovovic and Sanja Radojevic Skodric
Int. J. Mol. Sci. 2023, 24(9), 8085; https://doi.org/10.3390/ijms24098085 - 30 Apr 2023
Viewed by 1469
Abstract
Ischemia–reperfusion injury (IRI) is a frequent cause of AKI, resulting in vasoconstriction, cellular dysfunction, inflammation and the induction of oxidative stress. DNA damage, including physical DNA strand breaks, is also a potential consequence of renal IRI. The histone H2A variants, primary H2AX and [...] Read more.
Ischemia–reperfusion injury (IRI) is a frequent cause of AKI, resulting in vasoconstriction, cellular dysfunction, inflammation and the induction of oxidative stress. DNA damage, including physical DNA strand breaks, is also a potential consequence of renal IRI. The histone H2A variants, primary H2AX and H2AZ participate in DNA damage response pathways to promote genome stability. The aim of this study was to evaluate the immunohistochemical pattern of histone H2A variants’ (H2AX, γH2AX(S139), H2AXY142ph and H2AZ) expression in an experimental model of ischemia–reperfusion-induced acute kidney injury in spontaneously hypertensive rats. Comparing the immunohistochemical nuclear expression of γH2AX(S139) and H2AXY142ph in AKI, we observed that there is an inverse ratio of these two histone H2AX variants. If we follow different regions from the subcapsular structures to the medulla, there is an increasing extent gradient in the nuclear expression of H2AXY142ph, accompanied by a decreasing nuclear expression of γH2AX. In addition, we observed that different structures dominated when γH2AX and H2AXY142ph expression levels were compared. γH2AX was expressed only in the proximal tubule, with the exception of when they were dilated. In the medulla, H2AXY142ph is predominantly expressed in the loop of Henle and the collecting ducts. Our results show moderate sporadic nuclear H2AZ expression mainly in the cells of the distal tubules and the collecting ducts that were surrounded by dilated tubules with PAS (periodic acid–Schiff stain)-positive casts. These findings may indicate the degree of DNA damage, followed by postischemic AKI, with potential clinical and prognostic implications regarding this condition. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Ischemia/Reperfusion)
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13 pages, 1428 KiB  
Article
Sex Difference in Cardioprotection against Acute Myocardial Infarction in MAO-B Knockout Mice In Vivo
by Jacqueline Heger, Tamara Szabados, Paulin Brosinsky, Péter Bencsik, Péter Ferdinandy and Rainer Schulz
Int. J. Mol. Sci. 2023, 24(7), 6443; https://doi.org/10.3390/ijms24076443 - 29 Mar 2023
Cited by 3 | Viewed by 1270
Abstract
The cardiomyocyte-specific knockout (KO) of monoamine oxidase (MAO)-B, an enzyme involved in the formation of reactive oxygen species (ROS), reduced myocardial ischemia/reperfusion (I/R) injury in vitro. Because sex hormones have a strong impact on MAO metabolic pathways, we analyzed the myocardial infarct size [...] Read more.
The cardiomyocyte-specific knockout (KO) of monoamine oxidase (MAO)-B, an enzyme involved in the formation of reactive oxygen species (ROS), reduced myocardial ischemia/reperfusion (I/R) injury in vitro. Because sex hormones have a strong impact on MAO metabolic pathways, we analyzed the myocardial infarct size (IS) following I/R in female and male MAO-B KO mice in vivo. Method and Results: To induce the deletion of MAO-B, MAO-B KO mice (Myh6 Cre+/MAO-Bfl/fl) and wild-type (WT, Cre-negative MAO-Bfl/fl littermates) were fed with tamoxifen for 2 weeks followed by 10 weeks of normal mice chow. Myocardial infarction (assessed by TTC staining and expressed as a percentage of the area at risk as determined by Evans blue staining)) was induced by 45 min coronary occlusion followed by 120 min of reperfusion. Results: The mortality following I/R was higher in male compared to female mice, with the lowest mortality found in MAO-B KO female mice. IS was significantly higher in male WT mice compared to female WT mice. MAO-B KO reduced IS in male mice but had no further impact on IS in female MAO-B KO mice. Interestingly, there was no difference in the plasma estradiol levels among the groups. Conclusion: The cardiomyocyte-specific knockout of MAO-B protects male mice against acute myocardial infarction but had no effect on the infarct size in female mice. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Ischemia/Reperfusion)
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15 pages, 4077 KiB  
Article
Protective Effect of Oxygen and Isoflurane in Rodent Model of Intestinal Ischemia-Reperfusion Injury
by Mathias Clarysse, Alison Accarie, Ricard Farré, Emilio Canovai, Diethard Monbaliu, Jan Gunst, Gert De Hertogh, Tim Vanuytsel, Jacques Pirenne and Laurens J. Ceulemans
Int. J. Mol. Sci. 2023, 24(3), 2587; https://doi.org/10.3390/ijms24032587 - 30 Jan 2023
Cited by 5 | Viewed by 1668
Abstract
Animal research in intestinal ischemia-reperfusion injury (IRI) is mainly performed in rodent models. Previously, intraperitoneal (I.P.) injections with ketamine–xylazine mixtures were used. Nowadays, volatile anesthetics (isoflurane) are more common. However, the impact of the anesthetic method on intestinal IRI has not been investigated. [...] Read more.
Animal research in intestinal ischemia-reperfusion injury (IRI) is mainly performed in rodent models. Previously, intraperitoneal (I.P.) injections with ketamine–xylazine mixtures were used. Nowadays, volatile anesthetics (isoflurane) are more common. However, the impact of the anesthetic method on intestinal IRI has not been investigated. We aim to analyze the different anesthetic methods and their influence on the extent of intestinal IRI in a rat model. Male Sprague–Dawley rats were used to investigate the effect of I.P. anesthesia on 60 min of intestinal ischemia and 60 min of reperfusion in comparison to hyperoxygenation (100% O2) and volatile isoflurane anesthesia. In comparison to I.P. anesthesia with room air (21% O2), supplying 100% O2 improved 7-day survival by cardiovascular stabilization, reducing lactic acidosis and preventing vascular leakage. However, this had no effect on the intestinal epithelial damage, permeability, and inflammatory response observed after intestinal IRI. In contrast to I.P. + 100% O2, isoflurane anesthesia reduced intestinal IRI by preventing ongoing low-flow reperfusion hypotension, limiting intestinal epithelial damage and permeability, and by having anti-inflammatory effects. When translating the aforementioned results of this study to clinical situations, such as intestinal ischemia or transplantation, the potential protective effects of hyperoxygenation and volatile anesthetics require further research. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Ischemia/Reperfusion)
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19 pages, 3774 KiB  
Article
Activating Transcription Factor 3 Diminishes Ischemic Cerebral Infarct and Behavioral Deficit by Downregulating Carboxyl-Terminal Modulator Protein
by Mei-Han Kao, Chien-Yu Huang, Wai-Mui Cheung, Yu-Ting Yan, Jin-Jer Chen, Yuan-Soon Ho, Chung Y. Hsu and Teng-Nan Lin
Int. J. Mol. Sci. 2023, 24(3), 2306; https://doi.org/10.3390/ijms24032306 - 24 Jan 2023
Viewed by 1506
Abstract
Activating transcription factor 3 (ATF3) is a stress-induced transcription factor and a familiar neuronal marker for nerve injury. This factor has been shown to protect neurons from hypoxic insult in vitro by suppressing carboxyl-terminal modulator protein (CTMP) transcription, and indirectly activating the anti-apoptotic [...] Read more.
Activating transcription factor 3 (ATF3) is a stress-induced transcription factor and a familiar neuronal marker for nerve injury. This factor has been shown to protect neurons from hypoxic insult in vitro by suppressing carboxyl-terminal modulator protein (CTMP) transcription, and indirectly activating the anti-apoptotic Akt/PKB cascade. Despite prior studies in vitro, whether this neuroprotective pathway also exists in the brain in vivo after ischemic insult remains to be determined. In the present study, we showed a rapid and marked induction of ATF3 mRNA throughout ischemia-reperfusion in a middle cerebral artery (MCA) occlusion model. Although the level of CTMP mRNA was quickly induced upon ischemia, its level showed only a mild increase after reperfusion. With the gain-of-function approach, both pre- and post-ischemic administration of Ad-ATF3 ameliorated brain infarct and neurological deficits. Whereas, with the loss-of-function approach, ATF3 knockout (KO) mice showed bigger infarct and worse functional outcome after ischemia. In addition, these congenital defects were rescued upon reintroducing ATF3 to the brain of KO mice. ATF3 overexpression led to a lower level of CTMP and a higher level of p-Akt(473) in the ischemic brain. On the contrary, ATF3 KO resulted in upregulation of CTMP and downregulation of p-Akt(473) instead. Furthermore, post-ischemic CTMP siRNA knockdown led to smaller infarct and better behaviors. CTMP siRNA knockdown increased the level of p-Akt(473), but did not alter the ATF3 level in the ischemic brain, upholding the ATF3→CTMP signal cascade. In summary, our proof-of-principle experiments support the existence of neuroprotective ATF3→CTMP signal cascade regulating the ischemic brain. Furthermore, these results suggest the therapeutic potential for both ATF3 overexpression and CTMP knockdown for stroke treatment. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Ischemia/Reperfusion)
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11 pages, 983 KiB  
Article
Onset of Adverse Abdominal Events Due to Intestinal Ischemia-Reperfusion Injury after Aortic Cross-Clamping Is Associated with Elevated HSP70 Serum Levels in the Early Postoperative Phase
by Panagiotis Doukas, Gabriel Hellfritsch, Hanif Krabbe, Jelle Frankort, Michael J. Jacobs, Alexander Gombert and Florian Simon
Int. J. Mol. Sci. 2022, 23(23), 15063; https://doi.org/10.3390/ijms232315063 - 01 Dec 2022
Cited by 4 | Viewed by 1050
Abstract
Tissue injury of the viscera during open thoracoabdominal aortic (TAA) reconstructions has been reported as the aftermath of the ischemia-reperfusion mechanism following supracoeliac aortic cross-clamping. Abdominal complications after open aortic reconstructions, although rare through the intraoperative implementation of selective visceral artery blood perfusion, [...] Read more.
Tissue injury of the viscera during open thoracoabdominal aortic (TAA) reconstructions has been reported as the aftermath of the ischemia-reperfusion mechanism following supracoeliac aortic cross-clamping. Abdominal complications after open aortic reconstructions, although rare through the intraoperative implementation of selective visceral artery blood perfusion, are associated with high rates of reinterventions and a poor prognosis. Recent animal experiments demonstrated that provoking mesenteric ischemia in rats induces the leukocyte-mediated transcription of heat-shock protein 70 (HSP70), a chaperone belonging to the danger-associated molecular pattern proteins (DAMPs). Translating these findings clinically, we investigated the serum levels of HSP70 in patients undergoing open aortic reconstructions with supracoeliac clamping. We postoperatively observed a relevant induction of HSP70, which remained significantly elevated in cases of postoperative abdominal complications (paralytic ileus, abdominal compartment syndrome, and visceral malperfusion). The receiver–operator curve analysis revealed the reliable prognostic accuracy of HSP70 as a biomarker for these complications as soon as 12 h post-operation (AUC 0.908, sensitivity 88.9%, specificity 83.3%). In conclusion, measuring HSP70 serum levels in the early postoperative phase may serve as a further adjutant in the diagnostic decision making for both the vascular surgeon and intensivist for the timely detection and management of abdominal complications following open TAA surgery. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Ischemia/Reperfusion)
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Review

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14 pages, 1747 KiB  
Review
Molecular Mechanisms of Ischaemia-Reperfusion Injury and Regeneration in the Liver-Shock and Surgery-Associated Changes
by Elise Pretzsch, Hanno Nieß, Najib Ben Khaled, Florian Bösch, Markus Guba, Jens Werner, Martin Angele and Irshad H. Chaudry
Int. J. Mol. Sci. 2022, 23(21), 12942; https://doi.org/10.3390/ijms232112942 - 26 Oct 2022
Cited by 7 | Viewed by 1764
Abstract
Hepatic ischemia-reperfusion injury (IRI) represents a major challenge during liver surgery, liver preservation for transplantation, and can cause hemorrhagic shock with severe hypoxemia and trauma. The reduction of blood supply with a concomitant deficit in oxygen delivery initiates various molecular mechanisms involving the [...] Read more.
Hepatic ischemia-reperfusion injury (IRI) represents a major challenge during liver surgery, liver preservation for transplantation, and can cause hemorrhagic shock with severe hypoxemia and trauma. The reduction of blood supply with a concomitant deficit in oxygen delivery initiates various molecular mechanisms involving the innate and adaptive immune response, alterations in gene transcription, induction of cell death programs, and changes in metabolic state and vascular function. Hepatic IRI is a major cause of morbidity and mortality, and is associated with an increased risk for tumor growth and recurrence after oncologic surgery for primary and secondary hepatobiliary malignancies. Therapeutic strategies to prevent or treat hepatic IRI have been investigated in animal models but, for the most part, have failed to provide a protective effect in a clinical setting. This review focuses on the molecular mechanisms underlying hepatic IRI and regeneration, as well as its clinical implications. A better understanding of this complex and highly dynamic process may allow for the development of innovative therapeutic approaches and optimize patient outcomes. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Ischemia/Reperfusion)
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Other

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13 pages, 603 KiB  
Perspective
Norepinephrine and Vasopressin in Hemorrhagic Shock: A Focus on Renal Hemodynamics
by Nicolas Fage, Pierre Asfar, Peter Radermacher and Julien Demiselle
Int. J. Mol. Sci. 2023, 24(4), 4103; https://doi.org/10.3390/ijms24044103 - 17 Feb 2023
Cited by 1 | Viewed by 11239
Abstract
During hemorrhagic shock, blood loss causes a fall in blood pressure, decreases cardiac output, and, consequently, O2 transport. The current guidelines recommend the administration of vasopressors in addition to fluids to maintain arterial pressure when life-threatening hypotension occurs in order to prevent [...] Read more.
During hemorrhagic shock, blood loss causes a fall in blood pressure, decreases cardiac output, and, consequently, O2 transport. The current guidelines recommend the administration of vasopressors in addition to fluids to maintain arterial pressure when life-threatening hypotension occurs in order to prevent the risk of organ failure, especially acute kidney injury. However, different vasopressors exert variable effects on the kidney, depending on the nature and dose of the substance chosen as follows: Norepinephrine increases mean arterial pressure both via its α-1-mediated vasoconstriction leading to increased systemic vascular resistance and its β1-related increase in cardiac output. Vasopressin, through activation of V1-a receptors, induces vasoconstriction, thus increasing mean arterial pressure. In addition, these vasopressors have the following different effects on renal hemodynamics: Norepinephrine constricts both the afferent and efferent arterioles, whereas vasopressin exerts its vasoconstrictor properties mainly on the efferent arteriole. Therefore, this narrative review discusses the current knowledge of the renal hemodynamic effects of norepinephrine and vasopressin during hemorrhagic shock. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Ischemia/Reperfusion)
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