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1. Unravelling Secondary Brain Injury: Insights from a Human-Sized Porcine Model of Acute Subdural Haematoma.

Author

Kapapa, Thomas, Wernheimer, Vanida, Hoffmann, Andrea, Merz, Tamara, Zink, Fabia, Wolfschmitt, Eva-Maria, McCook, Oscar, Vogt, Josef, Wepler, Martin, Messerer, David Alexander Christian, Hartmann, Claire, Scheuerle, Angelika, Mathieu, René, Mayer, Simon, Gröger, Michael, Denoix, Nicole, Clazia, Enrico, Radermacher, Peter, Röhrer, Stefan, and Datzmann, Thomas

Abstract

Traumatic brain injury (TBI) remains one of the leading causes of death. Because of the individual nature of the trauma (brain, circumstances and forces), humans experience individual TBIs. This makes it difficult to generalise therapies. Clinical management issues such as whether intracranial pressure (ICP), cerebral perfusion pressure (CPP) or decompressive craniectomy improve patient outcome remain partly unanswered. Experimental drug approaches for the treatment of secondary brain injury (SBI) have not found clinical application. The complex, cellular and molecular pathways of SBI remain incompletely understood, and there are insufficient experimental (animal) models that reflect the pathophysiology of human TBI to develop translational therapeutic approaches. Therefore, we investigated different injury patterns after acute subdural hematoma (ASDH) as TBI in a post-hoc approach to assess the impact on SBI in a long-term, human-sized porcine TBI animal model. Post-mortem brain tissue analysis, after ASDH, bilateral ICP, CPP, cerebral oxygenation and temperature monitoring, and biomarker analysis were performed. Extracerebral, intraparenchymal–extraventricular and intraventricular blood, combined with brainstem and basal ganglia injury, influenced the experiment and its outcome. Basal ganglia injury affects the duration of the experiment. Recognition of these different injury patterns is important for translational interpretation of results in this animal model of SBI after TBI. [ABSTRACT FROM AUTHOR]

Published
2025
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8. To the Editor

Author

Radermacher, Peter, Calzia, Enrico, McCook, Oscar, Wachter, Ulrich, and Szabo, Csaba

Published
2021
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10. The Mitochondria-Targeted H2S-Donor AP39 in a Murine Model of Combined Hemorrhagic Shock and Blunt Chest Trauma

Author

Wepler, Martin, Merz, Tamara, Wachter, Ulrich, Vogt, Josef, Calzia, Enrico, Scheuerle, Angelika, Möller, Peter, Gröger, Michael, Kress, Sandra, Fink, Marina, Lukaschewski, Britta, Rumm, Grégoire, Stahl, Bettina, Georgieff, Michael, Huber-Lang, Markus, Torregrossa, Roberta, Whiteman, Matthew, McCook, Oscar, Radermacher, Peter, and Hartmann, Clair

Published
2019
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18. Role of Hemorrhagic Shock in Experimental Polytrauma

Author

Denk, Stephanie, Weckbach, Sebastian, Eisele, Philipp, Braun, Christian K., Wiegner, Rebecca, Ohmann, Julia J., Wrba, Lisa, Hoenes, Felix M., Kellermann, Philipp, Radermacher, Peter, Wachter, Ulrich, Hafner, Sebastian, McCook, Oscar, Schultze, Anke, Palmer, Annette, Braumüller, Sonja, Gebhard, Florian, and Huber-Lang, Markus

Published
2018
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22. The effect of targeted hyperoxemia in a randomized controlled trial employing a long-term resuscitated, model of combined acute subdural hematoma and hemorrhagic shock in swine with coronary artery disease: An exploratory, hypothesis-generating study

Author

Datzmann, Thomas, primary, Messerer, David Alexander Christian, additional, Münz, Franziska, additional, Hoffmann, Andrea, additional, Gröger, Michael, additional, Mathieu, René, additional, Mayer, Simon, additional, Gässler, Holger, additional, Zink, Fabian, additional, McCook, Oscar, additional, Merz, Tamara, additional, Scheuerle, Angelika, additional, Wolfschmitt, Eva-Maria, additional, Thebrath, Timo, additional, Zuech, Stefan, additional, Calzia, Enrico, additional, Asfar, Pierre, additional, Radermacher, Peter, additional, and Kapapa, Thomas, additional

Published
2022
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23. Effects of Hyperoxia During Resuscitation From Hemorrhagic Shock in Swine With Preexisting Coronary Artery Disease

Author

Hartmann, Clair, Loconte, Maurizio, Antonucci, Elena, Holzhauser, Michael, Hölle, Tobias, Katzsch, David, Merz, Tamara, McCook, Oscar, Wachter, Ulrich, Vogt, Josef A., Hoffmann, Andrea, Wepler, Martin, Gröger, Michael, Matejovic, Martin, Calzia, Enrico, Georgieff, Michael, Asfar, Pierre, Radermacher, Peter, and Nussbaum, Benedikt L.

Published
2017
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26. Brain Histology and Immunohistochemistry After Resuscitation From Hemorrhagic Shock in Swine With Pre-Existing Atherosclerosis and Sodium Thiosulfate (Na2S2O3) Treatment

Author

Denoix, Nicole, primary, McCook, Oscar, additional, Scheuerle, Angelika, additional, Kapapa, Thomas, additional, Hoffmann, Andrea, additional, Gündel, Harald, additional, Waller, Christiane, additional, Szabo, Csaba, additional, Radermacher, Peter, additional, and Merz, Tamara, additional

Published
2022
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27. Effects of Sodium Thiosulfate During Resuscitation From Trauma-and-Hemorrhage in Cystathionine-γ-Lyase Knockout Mice With Diabetes Type 1

Author

Gröger, Michael, primary, Hogg, Melanie, additional, Abdelsalam, Essam, additional, Kress, Sandra, additional, Hoffmann, Andrea, additional, Stahl, Bettina, additional, Calzia, Enrico, additional, Wachter, Ulrich, additional, Vogt, Josef A., additional, Wang, Rui, additional, Merz, Tamara, additional, Radermacher, Peter, additional, and McCook, Oscar, additional

Published
2022
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29. Human Placental Tissue Contains A Placental Lactogen–Derived Vasoinhibin

Author

Markl-Hahn, Hülya, primary, Neugebauer, Leon, additional, Lenke, Livia, additional, Ecker, Sarah, additional, Merz, Tamara, additional, McCook, Oscar, additional, Khoder, Noura, additional, Brucker, Cosima, additional, Radermacher, Peter, additional, Waller, Christiane, additional, Clapp, Carmen, additional, Bertsch, Thomas, additional, and Triebel, Jakob, additional

Published
2022
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31. Carbamylated erythropoietin-FC fusion protein and recombinant human erythropoietin during porcine kidney ischemia/reperfusion injury

Author

Matejková, Sárka, Scheuerle, Angelika, Wagner, Florian, McCook, Oscar, Matallo, José, Gröger, Michael, and Seifritz, Andrea

Subjects
Esmolol, Erythropoietin, Noradrenaline, Swine, Nitric oxide, Interleukins, Atherosclerosis, Health care industry
Abstract

Purpose To test the hypothesis that a carbamylated EPO-FC fusion protein (cEPO-FC) or recombinant human erythropoietin (rhEPO) would protect against kidney ischemia/reperfusion (I/R) injury in pigs with atherosclerosis. Methods Anesthetized and mechanically ventilated animals received cEPO-FC (50 [mu]g kg.sup.-1), rhEPO (5,000 IU kg.sup.-1), or vehicle (n = 9 per group) prior to 120 min of aortic occlusion and over 4 h of reperfusion. During aortic occlusion, mean arterial pressure (MAP) was maintained at 80-120 % of baseline values by esmolol, nitroglycerin, and ATP. During reperfusion, noradrenaline was titrated to keep MAP at pre-ischemic levels. Blood creatinine and neutrophil gelatinase-associated lipocalin (NGAL) levels, creatinine clearance, fractional Na.sup.+ excretion, and HE and PAS staining were used to assess kidney function and histological damage. Plasma interleukin-6, tumor necrosis factor-[alpha], nitrate + nitrite and 8-isoprostane levels were measured to assess systemic inflammation, and nitrosative and oxidative stress. Results I/R caused acute kidney injury with reduced creatinine clearance, increased fractional Na.sup.+ excretion and NGAL levels, moderate to severe glomerular and tubular damage and apoptosis, systemic inflammation and oxidative and nitrosative stress, but there were no differences between the treatment groups. Pre-ischemia nitrate + nitrite and 8-isoprostanes levels were lower and higher, respectively, than in healthy animals of a previous study, and immune histochemistry showed higher endothelial nitric oxide synthase and lower EPO receptor expression in pre-ischemia kidney biopsies than in biopsies from healthy animals. Conclusions In swine with atherosclerosis, rhEPO and cEPO-FC failed to attenuate prolonged ischemia-induced kidney injury within an 8-h reperfusion period, possibly due to reduced EPO receptor expression resulting from pre-existing oxidative stress and/or reduced NO release., Author(s): Sárka Matejková [sup.1], Angelika Scheuerle [sup.2], Florian Wagner [sup.1], Oscar McCook [sup.1], José Matallo [sup.1], Michael Gröger [sup.1], Andrea Seifritz [sup.1], Bettina Stahl [sup.1], Brigitta Vcelar [sup.3], Enrico Calzia [...]

Published
2013
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33. Effects of the PPAR-β/δ agonist GW0742 during resuscitated porcine septic shock

Author

Wepler, Martin, Hafner, Sebastian, Scheuerle, Angelika, Reize, Matthias, Gröger, Michael, Wagner, Florian, Simon, Florian, Matallo, José, Gottschalch, Frank, Seifritz, Andrea, Stahl, Bettina, Matejovic, Martin, Kapoor, Amar, Möller, Peter, Calzia, Enrico, Georgieff, Michael, Wachter, Ulrich, Vogt, Josef A, Thiemermann, Christoph, Radermacher, Peter, and McCook, Oscar

Published
2013
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36. Effects of Sodium Thiosulfate During Resuscitation From Trauma-and-Hemorrhage in Cystathionine Gamma Lyase (CSE) Knockout Mice

Author

Gröger, Michael, primary, Hogg, Melanie, additional, Abdelsalam, Essam, additional, Kress, Sandra, additional, Hoffmann, Andrea, additional, Stahl, Bettina, additional, Saub, Veronique, additional, Denoix, Nicole, additional, McCook, Oscar, additional, Calzia, Enrico, additional, Wolfschmitt, Eva-Maria, additional, Wachter, Ulrich, additional, Vogt, Josef A., additional, Wang, Rui, additional, Radermacher, Peter, additional, Merz, Tamara, additional, and Nussbaum, Benedikt L., additional

Published
2021
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37. Microcirculation vs. Mitochondria—What to Target?

Author

Merz, Tamara, Denoix, Nicole, Huber-Lang, Markus, Singer, Mervyn, Radermacher, Peter, and McCook, Oscar

Subjects
Inflammation, lcsh:R5-920, Kreislaufversagen, hypoxia, Hypoxie, inflammation, Circulatory shock, Oxidative stress, Organversagen, Schock, Oxidativer Stress, Perspective, Medicine, oxidative stress, Organ failure, organ failure, ddc:610, circulatory shock, lcsh:Medicine (General), Hypoxia, DDC 610 / Medicine & health
Abstract

Circulatory shock is associated with marked disturbances of the macro- and microcirculation and flow heterogeneities. Furthermore, a lack of tissue adenosine trisphosphate (ATP) and mitochondrial dysfunction are directly associated with organ failure and poor patient outcome. While it remains unclear if microcirculation-targeted resuscitation strategies can even abolish shock-induced flow heterogeneity, mitochondrial dysfunction and subsequently diminished ATP production could still lead to organ dysfunction and failure even if microcirculatory function is restored or maintained. Preserved mitochondrial function is clearly associated with better patient outcome. This review elucidates the role of the microcirculation and mitochondria during circulatory shock and patient management and will give a viewpoint on the advantages and disadvantages of tailoring resuscitation to microvascular or mitochondrial targets., publishedVersion

Published
2020

38. The role of glucocorticoid receptor and oxytocin receptor in the septic heart in a clinically relevant, resuscitated porcine model with underlying atherosclerosis

Author

Merz, Tamara, Denoix, Nicole, Wigger, Daniela, Waller, Christiane, Wepler, Martin, Vettorazzi, Sabine, Tuckermann, Jan Peter Gottfried, Radermacher, Peter, and McCook, Oscar

Subjects
Inflammation, Receptors, Glucocorticoid, Glucocorticosteroidrezeptor, Receptors, Oxytocin, Oxidative stress, Sepsis, Oxidativer Stress, Entzündung, Cystathionine gamma-Lyase, Heart, ddc:610, %22">Cystathioninlyase
Published
2020

40. In-depth characterization of a long-term, resuscitated model of acute subdural hematoma–induced brain injury

Author

Datzmann, Thomas, primary, Kapapa, Thomas, additional, Scheuerle, Angelika, additional, McCook, Oscar, additional, Merz, Tamara, additional, Unmuth, Sarah, additional, Hoffmann, Andrea, additional, Mathieu, René, additional, Mayer, Simon, additional, Mauer, Uwe Max, additional, Röhrer, Stefan, additional, Yilmazer-Hanke, Deniz, additional, Möller, Peter, additional, Nussbaum, Benedikt Lukas, additional, Calzia, Enrico, additional, Gröger, Michael, additional, Hartmann, Clair, additional, Radermacher, Peter, additional, and Wepler, Martin, additional

Published
2021
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45. Cerebral Immunohistochemical Characterization of the H2S and the Oxytocin Systems in a Porcine Model of Acute Subdural Hematoma

Author

Denoix, Nicole, primary, Merz, Tamara, additional, Unmuth, Sarah, additional, Hoffmann, Andrea, additional, Nespoli, Ester, additional, Scheuerle, Angelika, additional, Huber-Lang, Markus, additional, Gündel, Harald, additional, Waller, Christiane, additional, Radermacher, Peter, additional, and McCook, Oscar, additional

Published
2020
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46. To the Editor

Author

Radermacher, Peter, primary, Calzia, Enrico, additional, McCook, Oscar, additional, Wachter, Ulrich, additional, and Szabo, Csaba, additional

Published
2020
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48. H 2 S in Critical Illness—A New Horizon for Sodium Thiosulfate?

Author

Merz, Tamara, McCook, Oscar, Brucker, Cosima, Waller, Christiane, Calzia, Enrico, Radermacher, Peter, and Datzmann, Thomas

Subjects
*CRITICALLY ill, *SODIUM, *OXIDATIVE stress, *MYOCARDIAL infarction, *CLINICAL trials, *PREECLAMPSIA
Abstract

Ever since the discovery of endogenous H2S and the identification of its cytoprotective properties, efforts have been made to develop strategies to use H2S as a therapeutic agent. The ability of H2S to regulate vascular tone, inflammation, oxidative stress, and apoptosis might be particularly useful in the therapeutic management of critical illness. However, neither the inhalation of gaseous H2S, nor the administration of inorganic H2S-releasing salts or slow-releasing H2S-donors are feasible for clinical use. Na2S2O3 is a clinically approved compound with a good safety profile and is able to release H2S, in particular under hypoxic conditions. Pre-clinical studies show promise for Na2S2O3 in the acute management of critical illness. A current clinical trial is investigating the therapeutic potential for Na2S2O3 in myocardial infarct. Pre-eclampsia and COVID-19 pneumonia might be relevant targets for future clinical trials. [ABSTRACT FROM AUTHOR]

Published
2022
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49. Impaired Glucocorticoid Receptor Dimerization Aggravates LPS-Induced Circulatory and Pulmonary Dysfunction

Author

Wepler, Martin, Preuss, Jonathan M., Merz, Tamara, Hartmann, Clair, Wachter, Ulrich, McCook, Oscar, Vogt, Josef, Kress, Sandra, Gröger, Michael, Fink, Marina, Scheuerle, Angelika, Möller, Peter, Calzia, Enrico, Burret, Ute, Radermacher, Peter, Tuckermann, Jan P., and Vettorazzi, Sabine

Subjects
Inflammation, Lipopolysaccharides, Entzündung, Acute Lung Injury, Immunology, Shock, Septic, Lung function, Mice, DDC 570 / Life sciences, Lungenfunktion, Receptors, Glucocorticoid, ddc:570, glucocorticoid receptor, Acute lung injury, Transfusionsassoziiertes akutes Lungenversagen, Animals, Immunology and Allergy, Osteopontin, ddc:610, Endotoxic shock, Protein Multimerization, DDC 610 / Medicine & health, Dimerization, Original Research
Abstract

Background: Sepsis, that can be modeled by LPS injections, as an acute systemic inflammation syndrome is the most common cause for acute lung injury (ALI). ALI induces acute respiratory failure leading to hypoxemia, which is often associated with multiple organ failure (MOF). During systemic inflammation, the hypothalamus-pituitary-adrenal axis (HPA) is activated and anti-inflammatory acting glucocorticoids (GCs) are released to overcome the inflammation. GCs activate the GC receptor (GR), which mediates its effects via a GR monomer or GR dimer. The detailed molecular mechanism of the GR in different inflammatory models and target genes that might be crucial for resolving inflammation is not completely identified. We previously observed that mice with attenuated GR dimerization (GRdim/dim) had a higher mortality in a non-resuscitated lipopolysaccharide (LPS)- and cecal ligation and puncture (CLP)-induced inflammation model and are refractory to exogenous GCs to ameliorate ALI during inflammation. Therefore, we hypothesized that impaired murine GR dimerization (GRdim/dim) would further impair organ function in LPS-induced systemic inflammation under human like intensive care management and investigated genes that are crucial for lung function in this setup. Methods: Anesthetized GRdim/dim and wildtype (GR+/+) mice were challenged with LPS (10 mg·kg−1, intraperitoneal) and underwent intensive care management (“lung-protective” mechanical ventilation, crystalloids, and norepinephrine) for 6 h. Lung mechanics and gas exchange were assessed together with systemic hemodynamics, acid-base status, and mitochondrial oxygen consumption (JO2). Western blots, immunohistochemistry, and real time quantitative polymerase chain reaction were performed to analyze lung tissue and inflammatory mediators were analyzed in plasma and lung tissue. Results: When animals were challenged with LPS and subsequently resuscitated under intensive care treatment, GRdim/dim mice had a higher mortality compared to GR+/+ mice, induced by an increased need of norepinephrine to achieve hemodynamic targets. After challenge with LPS, GRdim/dim mice also displayed an aggravated ALI shown by a more pronounced impairment of gas exchange, lung mechanics and increased osteopontin (Opn) expression in lung tissue. Conclusion: Impairment of GR dimerization aggravates systemic hypotension and impairs lung function during LPS-induced endotoxic shock in mice. We demonstrate that the GR dimer is an important mediator of hemodynamic stability and lung function, possibly through regulation of Opn, during LPS-induced systemic inflammation., publishedVersion

Published
2020
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