89 results on '"McCook O"'
Search Results
2. Effects of the anti-diabetic imeglimin in hyperglycemic mice with septic shock
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Wagner, F, Vogt, J, Wachter, U, Weber, S, Stahl, B, Groeger, M, McCook, O, Georgieff, M, Fouqueray, P, Kuhn, T, Calzia, E, Radermacher, P, Fontaine, E, and Wagner, K
- Published
- 2012
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3. Pre-emptive hypothermia during resuscitated porcine hemorrhagic shock
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Matallo, J, Stahl, W, Gröger, M, Seifritz, A, Mccook, O, Georgieff, M, Asfar, P, Matejovic, M, Calzia, E, Radermacher, P, and Simon, F
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- 2012
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4. Reduced expression of PPAR-β/δ limits the potential beneficial effects of GW0742 during septic shock in atherosclerotic swine
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Bracht, H, Simon, F, Matallo, J, Gröger, M, McCook, O, Seifritz, A, Georgieff, M, Calzia, E, Radermacher, P, Kapoor, A, and Thiemermann, C
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- 2012
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5. Sulfide-inhibition of mitochondrial respiration at very low oxygen concentrations
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Matallo, J., primary, Vogt, J., additional, McCook, O., additional, Wachter, U., additional, Tillmans, F., additional, Groeger, M., additional, Szabo, C., additional, Georgieff, M., additional, Radermacher, P., additional, and Calzia, E., additional
- Published
- 2014
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6. H2S-induzierte Organprotektion nach Langzeithämorrhagie im Schweinemodell
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Simon, F, Scheuerle, A, Hauser, B, Matallo, J, Gröger, M, McCook, O, Szabo, C, Georgieff, M, Rdermacher, P, Calzia, E, Bracht, H, Simon, F, Scheuerle, A, Hauser, B, Matallo, J, Gröger, M, McCook, O, Szabo, C, Georgieff, M, Rdermacher, P, Calzia, E, and Bracht, H
- Published
- 2012
7. Adrenomedullin blockade improves catecholamine responsiveness and kidney function in resuscitated murine septic shock
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Wagner, K, primary, Wachter, U, additional, Vogt, J, additional, Weber, S, additional, Groeger, M, additional, McCook, O, additional, Georgieff, M, additional, Bergmann, A, additional, Luettgen, H, additional, Calzia, E, additional, Radermacher, P, additional, and Wagner, F, additional
- Published
- 2012
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8. Time-dependent effects of intravenous H2S during long-term, resuscitated porcine hemorrhagic shock
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Bracht, H, primary, Simon, F, additional, Hauser, B, additional, Groeger, M, additional, Soell, A, additional, McCook, O, additional, Georgieff, M, additional, Radermacher, P, additional, Szabo, C, additional, and Calzia, E, additional
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- 2010
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9. Comparison of carbamylated versus recombinant erythropoietin during spinal cord ischemia/reperfusion injury
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Simon, F, primary, Scheuerle, A, additional, Soell, A, additional, Groeger, M, additional, McCook, O, additional, Radermacher, P, additional, Georgieff, M, additional, Calzia, E, additional, and Schelzig, H, additional
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- 2010
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10. Effect of intravenous H2S on porcine aortic occlusion-induced systemic inflammation and kidney ischemia/reperfusion injury
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Wagner, F, primary, Simon, F, additional, Scheuerle, A, additional, Groeger, M, additional, Calzia, E, additional, Soell, A, additional, McCook, O, additional, Stahl, B, additional, Speit, G, additional, Georgieff, M, additional, Radermacher, P, additional, Szabo, C, additional, and Schelzig, H, additional
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- 2010
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11. Effects of intravenous sulfide during resuscitated porcine hemorrhagic shock*.
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Bracht H, Scheuerle A, Gröger M, Hauser B, Matallo J, McCook O, Seifritz A, Wachter U, Vogt JA, Asfar P, Matejovic M, Möller P, Calzia E, Szabó C, Stahl W, Hoppe K, Stahl B, Lampl L, Georgieff M, and Wagner F
- Published
- 2012
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12. Cardiopulmonary, histologic, and inflammatory effects of intravenous Na2S after blunt chest trauma-induced lung contusion in mice.
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Wagner F, Scheuerle A, Weber S, Stahl B, McCook O, Knöferl MW, Huber-Lang M, Seitz DH, Thomas J, Asfar P, Szabó C, Möller P, Gebhard F, Georgieff M, Calzia E, Radermacher P, and Wagner K
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- 2011
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13. INTERLEUKIN-6 - POTENTIAL ROLE IN ACCELERATED TRANSPLANT CORONARY-ARTERY DISEASE
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Valantine, H., Mccook, O., Fausto J. Pinto, Hunt, S., Schroeder, Js, and Stinson, Eb
14. Correlation of morphologic diagnosis of Pneumocystis carinii with the presence of pneumocystis DNA amplified by the polymerase chain reaction
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Blumenfeld, W., Mccook, O., Mark Holodniy, and Katzenstein, D. A.
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Staining and Labeling ,Pneumocystis ,Pneumonia, Pneumocystis ,Humans ,DNA, Fungal ,Methenamine ,Bronchoalveolar Lavage Fluid ,Polymerase Chain Reaction - Abstract
We compared the presence of P. carinii in clinical specimens as detected by standard cytomorphologic techniques with amplification of P. carinii-specific DNA by the polymerase chain reaction (PCR). Results correlated in 33 of 37 instances (89%): nine specimens were positive by both PCR and morphology; 24 specimens were negative by both techniques. Two specimens from one patient were obtained 3 days apart. The first specimen was both cytologically and PCR negative, while the second specimen was both cytologically and PCR positive for P. carinii. At least in some instances, therefore, PCR is no more sensitive than morphology, and other factors such as specimen adequacy are more important. Twelve of the 24 negative specimens were from patients with prior histories of P. carinii pneumonia, suggesting that recurrent disease may be from reacquisition of organisms in previously exposed individuals, rather than reactivation of latent organisms. Discrepant results included three morphologically negative specimens that were positive by PCR. It remains to be determined whether the increased sensitivity of PCR in these cases is real or artifactual. One morphologically positive specimen was negative by PCR. Polymerase chain reaction correlates well with cytomorphologic diagnosis of P. carinii pneumonia and may be a valuable diagnostic and epidemiologic tool.
15. Globus Lucidus: A porcine study of an intracranial implant designed to deliver closed, repetitive photodynamic and photochemical therapy in glioblastoma.
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Bader N, Peschmann C, Kast RE, Heiland T, Merz T, McCook O, Alfieri A, Karpel-Massler G, Capanni F, and Halatsch ME
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- Animals, Swine, Brain Neoplasms drug therapy, Brain Neoplasms therapy, Female, Glioblastoma drug therapy, Glioblastoma therapy, Photochemotherapy methods, Photosensitizing Agents pharmacology, Photosensitizing Agents therapeutic use, Aminolevulinic Acid therapeutic use, Aminolevulinic Acid pharmacology
- Abstract
Objective: Herein we describe initial results in a porcine model of a fully implantable device designed to allow closed, repetitive photodynamic treatment of glioblastoma (GBM)., Methods: This implant, Globus Lucidus, is a transparent quartz glass sphere with light-emitting diodes releasing wavelengths of 630 nm (19.5 mW/cm
2 ), 405 nm (5.0 mW/cm2 ) or 275 nm (0.9 mW/cm2 ). 5-aminolevulinic acid was the photosensitizing prodrug chosen for use with Globus Lucidus, hence the implants illuminated at 630 nm or 405 nm. An additional 275 nm wavelength-emittance was included to explore the effects of photochemical therapy (PCT) by ultraviolet (UV) light. Twenty healthy domestic pigs underwent right-frontal craniotomies. The Globus Lucidus device was inserted into a surgically created right-frontal lobe cavity. After postoperative recovery, irradiation for up to 30 min daily for up to 14 d, or continuous irradiation for up to 14.6 h was conducted., Results: Surgery, implants, and repeated irradiations using the different wavelengths were generally well tolerated. Social behavior, wound healing, body weight, and temperature remained unaffected. Histopathological analyses revealed consistent leukocyte infiltration around the intracerebral implant sites with no significant differences between experimental and control groups., Conclusion: This Globus Lucidus porcine study prepares the groundwork for adjuvant, long-term, repeated PDT of the GBM infiltration zone. This is the first report of a fully implantable PDT/PCT device for the potential treatment of GBM. A preclinical effectivity study of Globus Lucidus PDT/PCT is warranted and in advanced stages of planning., Competing Interests: Declaration of competing interest The funders had no role in the study design, analyses, data interpretation, writing, or decision to publish., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)- Published
- 2024
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16. 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.
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Datzmann T, Messerer DAC, Münz F, Hoffmann A, Gröger M, Mathieu R, Mayer S, Gässler H, Zink F, McCook O, Merz T, Scheuerle A, Wolfschmitt EM, Thebrath T, Zuech S, Calzia E, Asfar P, Radermacher P, and Kapapa T
- Abstract
Controversial evidence is available regarding suitable targets for the arterial O
2 tension (Pa O2 ) after traumatic brain injury and/or hemorrhagic shock (HS). We previously demonstrated that hyperoxia during resuscitation from hemorrhagic shock attenuated cardiac injury and renal dysfunction in swine with coronary artery disease. Therefore, this study investigated the impact of targeted hyperoxemia in a long-term, resuscitated model of combined acute subdural hematoma (ASDH)-induced brain injury and HS. The prospective randomized, controlled, resuscitated animal investigation consisted of 15 adult pigs. Combined ASDH plus HS was induced by injection of 0.1 ml/kg autologous blood into the subdural space followed by controlled passive removal of blood. Two hours later, resuscitation was initiated comprising re-transfusion of shed blood, fluids, continuous i.v. noradrenaline, and either hyperoxemia (target Pa O2 200 - 250 mmHg) or normoxemia (target Pa O2 80 - 120 mmHg) during the first 24 h of the total of 54 h of intensive care. Systemic hemodynamics, intracranial and cerebral perfusion pressures, parameters of brain microdialysis and blood biomarkers of brain injury did not significantly differ between the two groups. According to the experimental protocol, Pa O2 was significantly higher in the hyperoxemia group at the end of the intervention period, i.e., at 24 h of resuscitation, which coincided with a higher brain tissue PO2 . The latter persisted until the end of observation period. While neurological function as assessed using the veterinary Modified Glasgow Coma Score progressively deteriorated in the control group, it remained unaffected in the hyperoxemia animals, however, without significant intergroup difference. Survival times did not significantly differ in the hyperoxemia and control groups either. Despite being associated with higher brain tissue PO2 levels, which were sustained beyond the intervention period, targeted hyperoxemia exerted neither significantly beneficial nor deleterious effects after combined ASDH and HS in swine with pre-existing coronary artery disease. The unavailability of a power calculation and, thus, the limited number of animals included, are the limitations of the study., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Datzmann, Messerer, Münz, Hoffmann, Gröger, Mathieu, Mayer, Gässler, Zink, McCook, Merz, Scheuerle, Wolfschmitt, Thebrath, Zuech, Calzia, Asfar, Radermacher and Kapapa.)- Published
- 2022
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17. Brain Histology and Immunohistochemistry After Resuscitation From Hemorrhagic Shock in Swine With Pre-Existing Atherosclerosis and Sodium Thiosulfate (Na 2 S 2 O 3 ) Treatment.
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Denoix N, McCook O, Scheuerle A, Kapapa T, Hoffmann A, Gündel H, Waller C, Szabo C, Radermacher P, and Merz T
- Abstract
Background: The hydrogen sulfide (H
2 S) and the oxytocin/oxytocin receptor (OT/OTR) systems interact in the central nervous and cardiovascular system. As a consequence of osmotic balance stress, H2 S stimulates OT release from the paraventricular nuclei (PVN) in the hypothalamic regulation of blood volume and pressure. Hemorrhagic shock (HS) represents one of the most pronounced acute changes in blood volume, which, moreover, may cause at least transient brain tissue hypoxia. Atherosclerosis is associated with reduced vascular expression of the main endogenous H2 S producing enzyme cystathionine-γ-lyase (CSE), and, hence, exogenous H2 S administration could be beneficial in these patients, in particular after HS. However, so far cerebral effects of systemic H2 S administration are poorly understood. Having previously shown lung-protective effects of therapeutic Na2 S2 O3 administration in a clinically relevant, long-term, porcine model of HS and resuscitation we evaluated if these protective effects were extended to the brain., Methods: In this study, available unanalyzed paraffin embedded brain sections (Na2 S2 O3 N = 8 or vehicle N = 5) of our recently published HS study were analyzed via neuro-histopathology and immunohistochemistry for the endogenous H2 S producing enzymes, OT, OTR, and markers for brain injury and oxidative stress (glial fibrillary acidic protein (GFAP) and nitrotyrosine)., Results: Neuro-histopathological analysis revealed uninjured brain tissue with minor white matter edema. Protein quantification in the hypothalamic PVN showed no significant inter-group differences between vehicle or Na2 S2 O3 treatment., Conclusions: The endogenous H2 S enzymes, OT/OTR co-localized in magnocellular neurons in the hypothalamus, which may reflect their interaction in response to HS-induced hypovolemia. The preserved blood brain barrier (BBB) may have resulted in impermeability for Na2 S2 O3 and no inter-group differences in the PVN. Nonetheless, our results do not preclude that Na2 S2 O3 could have a therapeutic benefit in the brain in an injury that disrupts the BBB, e.g., traumatic brain injury (TBI) or acute subdural hematoma (ASDH)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Denoix, McCook, Scheuerle, Kapapa, Hoffmann, Gündel, Waller, Szabo, Radermacher and Merz.)- Published
- 2022
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18. Effects of Sodium Thiosulfate During Resuscitation From Trauma-and-Hemorrhage in Cystathionine-γ-Lyase Knockout Mice With Diabetes Type 1.
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Gröger M, Hogg M, Abdelsalam E, Kress S, Hoffmann A, Stahl B, Calzia E, Wachter U, Vogt JA, Wang R, Merz T, Radermacher P, and McCook O
- Abstract
Background: Sodium thiosulfate (STS) is a recognized drug with antioxidant and H
2 S releasing properties. We recently showed that STS attenuated organ dysfunction and injury during resuscitation from trauma-and-hemorrhage in CSE-ko mice, confirming its previously described organ-protective and anti-inflammatory properties. The role of H2 S in diabetes mellitus type 1 (DMT1) is controversial: genetic DMT1 impairs H2 S biosynthesis, which has been referred to contribute to endothelial dysfunction and cardiomyopathy. In contrast, development and severity of hyperglycemia in streptozotocin(STZ)-induced DMT1 was attenuated in CSE-ko mice. Therefore, we tested the hypothesis whether STS would also exert organ-protective effects in CSE-ko mice with STZ-induced DMT1, similar to our findings in animals without underlying co-morbidity., Methods: Under short-term anesthesia with sevoflurane and analgesia with buprenorphine CSE-ko mice underwent DMT1-induction by single STZ injection (100 μg⋅g-1 ). Seven days later, animals underwent blast wave-induced blunt chest trauma and surgical instrumentation followed by 1 h of hemorrhagic shock (MAP 35 ± 5 mmHg). Resuscitation comprised re-transfusion of shed blood, lung-protective mechanical ventilation, fluid resuscitation and continuous i.v. norepinephrine together with either i.v. STS (0.45 mg⋅g-1 ) or vehicle ( n = 9 in each group). Lung mechanics, hemodynamics, gas exchange, acid-base status, stable isotope-based metabolism, and visceral organ function were assessed. Blood and organs were collected for analysis of cytokines, chemokines, and immunoblotting., Results: Diabetes mellitus type 1 was associated with more severe circulatory shock when compared to our previous study using the same experimental design in CSE-ko mice without co-morbidity. STS did not exert any beneficial therapeutic effect. Most of the parameters measured of the inflammatory response nor the tissue expression of marker proteins of the stress response were affected either., Conclusion: In contrast to our previous findings in CSE-ko mice without underlying co-morbidity, STS did not exert any beneficial therapeutic effect in mice with STZ-induced DMT1, possibly due to DMT1-related more severe circulatory shock. This result highlights the translational importance of both integrating standard ICU procedures and investigating underlying co-morbidity in animal models of shock research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gröger, Hogg, Abdelsalam, Kress, Hoffmann, Stahl, Calzia, Wachter, Vogt, Wang, Merz, Radermacher and McCook.)- Published
- 2022
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19. H 2 S in Critical Illness-A New Horizon for Sodium Thiosulfate?
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Merz T, McCook O, Brucker C, Waller C, Calzia E, Radermacher P, and Datzmann T
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- Critical Illness, Humans, Thiosulfates pharmacology, Thiosulfates therapeutic use, Hydrogen Sulfide therapeutic use, COVID-19 Drug Treatment
- Abstract
Ever since the discovery of endogenous H
2 S and the identification of its cytoprotective properties, efforts have been made to develop strategies to use H2 S as a therapeutic agent. The ability of H2 S 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 H2 S, nor the administration of inorganic H2 S-releasing salts or slow-releasing H2 S-donors are feasible for clinical use. Na2 S2 O3 is a clinically approved compound with a good safety profile and is able to release H2 S, in particular under hypoxic conditions. Pre-clinical studies show promise for Na2 S2 O3 in the acute management of critical illness. A current clinical trial is investigating the therapeutic potential for Na2 S2 O3 in myocardial infarct. Pre-eclampsia and COVID-19 pneumonia might be relevant targets for future clinical trials.- Published
- 2022
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20. Human Placental Tissue Contains A Placental Lactogen-Derived Vasoinhibin.
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Markl-Hahn H, Neugebauer L, Lenke L, Ecker S, Merz T, McCook O, Khoder N, Brucker C, Radermacher P, Waller C, Clapp C, Bertsch T, and Triebel J
- Abstract
Hormonal factors affecting the vascular adaptions of the uteroplacental unit in noncomplicated and complicated pregnancies are of interest. Here, 4 human placentas from women with and without preeclampsia (PE) were investigated for the presence of placental lactogen (PL)-derived, antiangiogenic vasoinhibin. Western blotting and mass spectrometry of placental tissue revealed the presence of a 9-kDa PL-derived vasoinhibin, the normal 22-kDa full-length PL, and a 28-kDa immunoreactive protein of undetermined nature. The sequence of the 9-kDa vasoinhibin includes the antiangiogenic determinant of vasoinhibin and could constitute a relevant factor in normal pregnancy and PE., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)
- Published
- 2022
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21. Effects of Sodium Thiosulfate During Resuscitation From Trauma-and-Hemorrhage in Cystathionine Gamma Lyase (CSE) Knockout Mice.
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Gröger M, Hogg M, Abdelsalam E, Kress S, Hoffmann A, Stahl B, Saub V, Denoix N, McCook O, Calzia E, Wolfschmitt EM, Wachter U, Vogt JA, Wang R, Radermacher P, Merz T, and Nussbaum BL
- Subjects
- Animals, Chemokine CCL2 metabolism, Cystathionine gamma-Lyase genetics, Glucose metabolism, Heme Oxygenase-1 metabolism, Interleukin-6 metabolism, Kidney metabolism, Lung metabolism, Mice, Knockout, NF-KappaB Inhibitor alpha metabolism, Norepinephrine administration & dosage, Oxygen blood, Receptors, Glucocorticoid metabolism, Shock, Hemorrhagic therapy, Thoracic Injuries therapy, Urine, Vasoconstrictor Agents administration & dosage, Mice, Antioxidants pharmacology, Resuscitation, Thiosulfates pharmacology
- Abstract
Background: Sodium thiosulfate (Na2S2O3) is a clinically established drug with antioxidant and sulphide-releasing properties. Na2S2O3 mediated neuro- and cardioprotective effects in ischemia/reperfusion models and anti-inflammatory effects in LPS-induced acute lung injury. Moreover, Na2S2O3 improved lung function during resuscitation from hemorrhagic shock in swine with pre-existing atherosclerosis, characterized by decreased expression of cystathionine γ-lyase (CSE), a major source of hydrogen sulfide (H2S) synthesis in the vasculature. Based on these findings, we investigated the effects of Na2S2O3 administration during resuscitation from trauma-and-hemorrhage in mice under conditions of whole body CSE deficit., Methods: After blast wave-induced blunt chest trauma and surgical instrumentation, CSE knockout (CSE-/-) mice underwent 1 h of hemorrhagic shock (MAP 35 ± 5 mm Hg). At the beginning of resuscitation comprising retransfusion, norepinephrine support and lung-protective mechanical ventilation, animals received either i.v. Na2S2O3 (0.45 mg g-1, n = 12) or vehicle (saline, n = 13). Hemodynamics, acid-base status, metabolism using stable isotopes, and visceral organ function were assessed. Blood and organs were collected for analysis of cytokines, mitochondrial respiratory capacity, and immunoblotting., Results: Na2S2O3 treatment improved arterial paO2 (P = 0.03) coinciding with higher lung tissue glucocorticoid receptor expression. Norepinephrine requirements were lower in the Na2S2O3 group (P < 0.05), which was associated with lower endogenous glucose production and higher urine output. Na2S2O3 significantly increased renal tissue IκBα and heme oxygenase-1 expression, whereas it lowered kidney IL-6 and MCP-1 levels., Conclusion: Na2S2O3 exerted beneficial effects during resuscitation of murine trauma-and-hemorrhage in CSE-/- mice, confirming and extending the previously described organ-protective and anti-inflammatory properties of Na2S2O3. The findings make Na2S2O3 a potentially promising therapeutic option in the context of impaired CSE activity and/or reduced endogenous H2S availability., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 by the Shock Society.)
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- 2022
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22. Localization of the hydrogen sulfide and oxytocin systems at the depth of the sulci in a porcine model of acute subdural hematoma.
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McCook O, Scheuerle A, Denoix N, Kapapa T, Radermacher P, and Merz T
- Abstract
In the porcine model discussed in this review, the acute subdural hematoma was induced by subdural injection of autologous blood over the left parietal cortex, which led to a transient elevation of the intracerebral pressure, measured by bilateral neuromonitoring. The hematoma-induced brain injury was associated with albumin extravasation, oxidative stress, reactive astrogliosis and microglial activation in the ipsilateral hemisphere. Further proteins and injury markers were validated to be used for immunohistochemistry of porcine brain tissue. The cerebral expression patterns of oxytocin, oxytocin receptor, cystathionine-γ-lyase and cystathionine-β-synthase were particularly interesting: these four proteins all co-localized at the base of the sulci, where pressure-induced brain injury elicits maximum stress. In this context, the pig is a very relevant translational model in contrast to the rodent brain. The structure of the porcine brain is very similar to the human: the presence of gyri and sulci (gyrencephalic brain), white matter to grey matter proportion and tentorium cerebelli. Thus, pressure-induced injury in the porcine brain, unlike in the rodent brain, is reflective of the human pathophysiology., Competing Interests: None
- Published
- 2021
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23. H2S as a Therapeutic Adjuvant Against COVID-19: Why and How?
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Datzmann T, Merz T, McCook O, Szabo C, and Radermacher P
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- Humans, SARS-CoV-2, Signal Transduction, COVID-19, Hydrogen Sulfide
- Abstract
Competing Interests: The authors report no conflicts of interest.
- Published
- 2021
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24. Biological Connection of Psychological Stress and Polytrauma under Intensive Care: The Role of Oxytocin and Hydrogen Sulfide.
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Merz T, McCook O, Denoix N, Radermacher P, Waller C, and Kapapa T
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- Animals, Brain Injuries psychology, Brain Injuries therapy, Humans, Multiple Trauma psychology, Multiple Trauma therapy, Stress Disorders, Post-Traumatic epidemiology, Stress Disorders, Post-Traumatic etiology, Brain Injuries metabolism, Critical Care methods, Multiple Trauma metabolism, Oxytocin metabolism, Stress Disorders, Post-Traumatic metabolism, Sulfites metabolism
- Abstract
This paper explored the potential mediating role of hydrogen sulfide (H
2 S) and the oxytocin (OT) systems in hemorrhagic shock (HS) and/or traumatic brain injury (TBI). Morbidity and mortality after trauma mainly depend on the presence of HS and/or TBI. Rapid "repayment of the O2 debt" and prevention of brain tissue hypoxia are cornerstones of the management of both HS and TBI. Restoring tissue perfusion, however, generates an ischemia/reperfusion (I/R) injury due to the formation of reactive oxygen (ROS) and nitrogen (RNS) species. Moreover, pre-existing-medical-conditions (PEMC's) can aggravate the occurrence and severity of complications after trauma. In addition to the "classic" chronic diseases (of cardiovascular or metabolic origin), there is growing awareness of psychological PEMC's, e.g., early life stress (ELS) increases the predisposition to develop post-traumatic-stress-disorder (PTSD) and trauma patients with TBI show a significantly higher incidence of PTSD than patients without TBI. In fact, ELS is known to contribute to the developmental origins of cardiovascular disease. The neurotransmitter H2 S is not only essential for the neuroendocrine stress response, but is also a promising therapeutic target in the prevention of chronic diseases induced by ELS. The neuroendocrine hormone OT has fundamental importance for brain development and social behavior, and, thus, is implicated in resilience or vulnerability to traumatic events. OT and H2 S have been shown to interact in physical and psychological trauma and could, thus, be therapeutic targets to mitigate the acute post-traumatic effects of chronic PEMC's. OT and H2 S both share anti-inflammatory, anti-oxidant, and vasoactive properties; through the reperfusion injury salvage kinase (RISK) pathway, where their signaling mechanisms converge, they act via the regulation of nitric oxide (NO).- Published
- 2021
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25. H 2 S and Oxytocin Systems in Early Life Stress and Cardiovascular Disease.
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McCook O, Denoix N, Radermacher P, Waller C, and Merz T
- Abstract
Today it is well established that early life stress leads to cardiovascular programming that manifests in cardiovascular disease, but the mechanisms by which this occurs, are not fully understood. This perspective review examines the relevant literature that implicates the dysregulation of the gasomediator hydrogen sulfide and the neuroendocrine oxytocin systems in heart disease and their putative mechanistic role in the early life stress developmental origins of cardiovascular disease. Furthermore, interesting hints towards the mutual interaction of the hydrogen sulfide and OT systems are identified, especially with regards to the connection between the central nervous and the cardiovascular system, which support the role of the vagus nerve as a communication link between the brain and the heart in stress-mediated cardiovascular disease.
- Published
- 2021
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26. ΔMST and the Regulation of Cardiac CSE and OTR Expression in Trauma and Hemorrhage.
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Trautwein B, Merz T, Denoix N, Szabo C, Calzia E, Radermacher P, and McCook O
- Abstract
Genetic deletion of 3-mercaptopyruvate sulfurtransferase (MST) is known to result in hypertension and cardiac hypertrophy in older mice, and is associated with increased anxiety-like behaviors. Endogenous hydrogen sulfide (H
2 S) produced by MST in the mitochondria is also known to be involved in physiological and cellular bioenergetics, and its dysfunction associated with depressive behavior and increased cardiovascular morbidity. Interestingly, early life stress has been shown to lead to a significant loss of cystathionine-γ-lyase (CSE) and oxytocin receptor (OTR) expression in the heart. Thus, we were interested in testing the hypothesis of whether genetic MST mutation (ΔMST) would affect cardiac CSE and OTR expression and affect the mitochondrial respiration in a clinically relevant, resuscitated, mouse model of trauma and hemorrhagic shock. In ΔMST mice, we found a reduction of CSE and OTR in both the naive as well as injured state, in contrast to the wild type (wt) controls. Interestingly, the ΔMST showed a different complex IV response to injury than the wt controls, although our claims are based on the non-demonstrated assumption that naive wt and naive ΔMST mice have comparable complex IV activity. Finally, hemorrhagic shock led to a reduction of CSE and OTR, confirming previous results in the injured mouse heart. To date, the exact mechanisms of the cardiac interaction between H2 S and OT are not clear, but they point the way to potential cardioprotective therapies.- Published
- 2021
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27. To the Editor.
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Radermacher P, Calzia E, McCook O, Wachter U, and Szabo C
- Abstract
Competing Interests: The authors report no conflicts of interest.
- Published
- 2021
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28. Mouse Intensive Care Unit (MICU).
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Merz T, Kress S, Gröger M, Radermacher P, and McCook O
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- Animals, Hemodynamics physiology, Intensive Care Units, Lung physiopathology, Respiration, Artificial methods, Resuscitation methods, Sepsis physiopathology, Translational Research, Biomedical methods, Clinical Studies as Topic methods, Mice physiology
- Abstract
The translation of preclinical results into successful clinical therapies remains a challenge in sepsis research. One reason for this lack of translation might be the discrepancy between preclinical models and the clinical reality: nonresuscitated young healthy rodents in contrast to elderly comorbid patients in an intensive care unit. We introduce the mouse intensive care unit (MICU) as a concept to address the lack of resuscitation in preclinical studies as one of the limiting issues in translational research. The MICU reflects standard procedures of the clinical intensive care unit: fluid resuscitation, lung-protective mechanical ventilation, and hemodynamic monitoring and management, all tailored to organ- and function-specific targets. Thus, the MICU gives an experimental animal the intermediate possibility of recovery and survival due to "patient" management, which is not reflected in less complex experimental scenarios, which either result in acute survival or death.
- Published
- 2021
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29. H 2 S in acute lung injury: a therapeutic dead end(?).
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Merz T, Denoix N, Wepler M, Gäßler H, Messerer DAC, Hartmann C, Datzmann T, Radermacher P, and McCook O
- Abstract
This review addresses the plausibility of hydrogen sulfide (H
2 S) therapy for acute lung injury (ALI) and circulatory shock, by contrasting the promising preclinical results to the present clinical reality. The review discusses how the narrow therapeutic window and width, and potentially toxic effects, the route, dosing, and timing of administration all have to be balanced out very carefully. The development of standardized methods to determine in vitro and in vivo H2 S concentrations, and the pharmacokinetics and pharmacodynamics of H2 S-releasing compounds is a necessity to facilitate the safety of H2 S-based therapies. We suggest the potential of exploiting already clinically approved compounds, which are known or unknown H2 S donors, as a surrogate strategy.- Published
- 2020
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30. Impact of downstream effects of glucocorticoid receptor dysfunction on organ function in critical illness-associated systemic inflammation.
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Wepler M, Preuss JM, Merz T, McCook O, Radermacher P, Tuckermann JP, and Vettorazzi S
- Abstract
Glucocorticoids (GCs) are stress hormones that regulate developmental and physiological processes and are among the most potent anti-inflammatory drugs to suppress chronic and acute inflammation. GCs act through the glucocorticoid receptor (GR), a ubiquitously expressed ligand-activated transcription factor, which translocates into the nucleus and can act via two different modes, as a GR monomer or as a GR dimer. These two modes of action are not clearly differentiated in practice and may lead to completely different therapeutic outcomes. Detailed aspects of GR mechanisms are often not taken into account when GCs are used in different clinical scenarios. Patients, with critical illness-related corticosteroid insufficiency, treated with natural or synthetic GCs are still missing a clearly defined therapeutic strategy. This review discusses the different modes of GR function and its importance on organ function in vivo.
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- 2020
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31. The Interaction of the Endogenous Hydrogen Sulfide and Oxytocin Systems in Fluid Regulation and the Cardiovascular System.
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Denoix N, McCook O, Ecker S, Wang R, Waller C, Radermacher P, and Merz T
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The purpose of this review is to explore the parallel roles and interaction of hydrogen sulfide (H
2 S) and oxytocin (OT) in cardiovascular regulation and fluid homeostasis. Their interaction has been recently reported to be relevant during physical and psychological trauma. However, literature reports on H2 S in physical trauma and OT in psychological trauma are abundant, whereas available information regarding H2 S in psychological trauma and OT in physical trauma is much more limited. This review summarizes recent direct and indirect evidence of the interaction of the two systems and their convergence in downstream nitric oxide-dependent signaling pathways during various types of trauma, in an effort to better understand biological correlates of psychosomatic interdependencies.- Published
- 2020
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32. Microcirculation vs. Mitochondria-What to Target?
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Merz T, Denoix N, Huber-Lang M, Singer M, Radermacher P, and McCook O
- 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., (Copyright © 2020 Merz, Denoix, Huber-Lang, Singer, Radermacher and McCook.)
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- 2020
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33. Cerebral Immunohistochemical Characterization of the H 2 S and the Oxytocin Systems in a Porcine Model of Acute Subdural Hematoma.
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Denoix N, Merz T, Unmuth S, Hoffmann A, Nespoli E, Scheuerle A, Huber-Lang M, Gündel H, Waller C, Radermacher P, and McCook O
- Abstract
The hydrogen sulfide (H
2 S) and the oxytocin/oxytocin receptor (OT/OTR) systems interact in trauma and are implicated in vascular protection and regulation of fluid homeostasis. Acute brain injury is associated with pressure-induced edema formation, blood brain barrier disruption, and neuro-inflammation. The similarities in brain anatomy: size, gyrencephalic organization, skull structure, may render the pig a highly relevant model for translational medicine. Cerebral biomarkers for pigs for pathophysiological changes and neuro-inflammation are limited. The current study aims to characterize the localization of OT/OTR and the endogenous H2 S producing enzymes together with relevant neuro-inflammatory markers on available porcine brain tissue from an acute subdural hematoma (ASDH) model. In a recent pilot study, anesthetized pigs underwent ASDH by injection of 20 mL of autologous blood above the left parietal cortex and were resuscitated with neuro-intensive care measures. After 54 h of intensive care, the animals were sacrificed, the brain was removed and analyzed via immunohistochemistry. The endogenous H2 S producing enzymes cystathionine-ɤ-lyase (CSE) and cystathionine-β-synthase (CBS), the OTR, and OT were localized in neurons, vasculature and parenchyma at the base of sulci, where pressure-induced injury leads to maximal stress in the gyrencephalic brain. The pathophysiological changes in response to brain injury in humans and pigs, we show here, are comparable. We additionally identified modulators of brain injury to further characterize the pathophysiology of ASDH and which may indicate future therapeutic approaches., (Copyright © 2020 Denoix, Merz, Unmuth, Hoffmann, Nespoli, Scheuerle, Huber-Lang, Gündel, Waller, Radermacher and McCook.)- Published
- 2020
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34. The Role of Glucocorticoid Receptor and Oxytocin Receptor in the Septic Heart in a Clinically Relevant, Resuscitated Porcine Model With Underlying Atherosclerosis.
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Merz T, Denoix N, Wigger D, Waller C, Wepler M, Vettorazzi S, Tuckermann J, Radermacher P, and McCook O
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- Animals, Cystathionine gamma-Lyase genetics, Disease Models, Animal, Heart Diseases etiology, Heart Diseases metabolism, Hydrogen Sulfide metabolism, Male, Oxidative Stress, Receptors, Glucocorticoid genetics, Receptors, Oxytocin genetics, Signal Transduction, Swine, Atherosclerosis physiopathology, Cystathionine gamma-Lyase metabolism, Gene Expression Regulation, Heart Diseases pathology, Hypercholesterolemia physiopathology, Receptors, Glucocorticoid metabolism, Receptors, Oxytocin metabolism, Shock, Septic complications
- Abstract
The pathophysiology of sepsis-induced myocardial dysfunction is not resolved to date and comprises inflammation, barrier dysfunction and oxidative stress. Disease-associated reduction of tissue cystathionine-γ-lyase (CSE) expression, an endogenous H
2 S-producing enzyme, is associated with oxidative stress, barrier dysfunction and organ injury. CSE-mediated cardio-protection has been suggested to be related the upregulation of oxytocin receptor (OTR). CSE can also mediate glucocorticoid receptor (GR) signaling, which is important for normal heart function. A sepsis-related loss of cardiac CSE expression associated with impaired organ function has been reported previously. The aim of this current post hoc study was to investigate the role of cardiac GR and OTR after polymicrobial sepsis in a clinically relevant, resuscitated, atherosclerotic porcine model. Anesthetized and instrumented FBM (Familial Hypercholesterolemia Bretoncelles Meishan) pigs with high fat diet-induced atherosclerosis underwent poly-microbial septic shock ( n = 8) or sham procedure ( n = 5), and subsequently received intensive care therapy with fluid and noradrenaline administration for 24 h. Cardiac protein expression and mRNA levels were analyzed. Systemic troponin, a marker of cardiac injury, was significantly increased in septic animals in contrast to sham, whereas OTR and GR expression in septic hearts were reduced, along with a down-regulation of anti-inflammatory GR target genes and the antioxidant transcription factor NRF2. These results suggest a potential interplay between GR, CSE, and OTR in sepsis-mediated oxidative stress, inflammation and cardiac dysfunction., (Copyright © 2020 Merz, Denoix, Wigger, Waller, Wepler, Vettorazzi, Tuckermann, Radermacher and McCook.)- Published
- 2020
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35. Maternal Separation Induces Long-Term Alterations in the Cardiac Oxytocin Receptor and Cystathionine γ -Lyase Expression in Mice.
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Wigger DC, Gröger N, Lesse A, Krause S, Merz T, Gündel H, Braun K, McCook O, Radermacher P, Bock J, and Waller C
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- Animals, Female, Heterozygote, Homozygote, Male, Maternal Deprivation, Mice, Mice, Inbred C57BL, Mice, Knockout, Myocytes, Cardiac metabolism, Oxytocin metabolism, Up-Regulation, Cystathionine gamma-Lyase metabolism, Oxytocin blood, Receptors, Oxytocin metabolism
- Abstract
We recently showed that blunt chest trauma reduced the expression of the myocardial oxytocin receptor (Oxtr), which was further aggravated by genetic deletion of the H
2 S-producing enzyme cystathionine γ -lyase (CSE). Exogenous H2 S supplementation restored myocardial Oxtr expression under these conditions. Early life stress (ELS) is a risk factor for cardiovascular disease by affecting vascular and heart structures. Therefore, we tested the hypotheses that (i) ELS affects cardiac Oxtr and CSE expressions and (ii) Oxtr and CSE expression patterns depend on the duration of stress exposure. Thus, two stress paradigms were compared: long- and short-term separation stress (LTSS and STSS, respectively). Cardiac Oxtr expression was differentially affected by the two stress paradigms with a significant reduction after LTSS and a significant increase after STSS. CSE expression, which was significantly reduced in Oxtr-/- knockout hearts, was downregulated and directly related to Oxtr expression in LTSS hearts ( r = 0.657, p = 0.012). In contrast, CSE expression was not related to Oxtr upregulation in STSS. Plasma Oxt levels were not affected by either ELS paradigm. The coincidence of LTSS-induced reduction of cardiac Oxtr and reduced CSE expression may suggest a novel pathophysiological link between early life adversities and increased risk for the development of cardiovascular disorders in adulthood., Competing Interests: The authors declare no competing interests., (Copyright © 2020 Daniela C. Wigger et al.)- Published
- 2020
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36. Impaired Glucocorticoid Receptor Dimerization Aggravates LPS-Induced Circulatory and Pulmonary Dysfunction.
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Wepler M, Preuss JM, Merz T, Hartmann C, Wachter U, McCook O, Vogt J, Kress S, Gröger M, Fink M, Scheuerle A, Möller P, Calzia E, Burret U, Radermacher P, Tuckermann JP, and Vettorazzi S
- Subjects
- Acute Lung Injury etiology, Acute Lung Injury metabolism, Animals, Dimerization, Mice, Protein Multimerization, Shock, Septic complications, Lipopolysaccharides toxicity, Receptors, Glucocorticoid chemistry, Receptors, Glucocorticoid metabolism, Shock, Septic metabolism, Shock, Septic physiopathology
- 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 (GR
dim/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., (Copyright © 2020 Wepler, Preuss, Merz, Hartmann, Wachter, McCook, Vogt, Kress, Gröger, Fink, Scheuerle, Möller, Calzia, Burret, Radermacher, Tuckermann and Vettorazzi.)- Published
- 2020
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37. Effects of sodium thiosulfate (Na 2 S 2 O 3 ) during resuscitation from hemorrhagic shock in swine with preexisting atherosclerosis.
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Datzmann T, Hoffmann A, McCook O, Merz T, Wachter U, Preuss J, Vettorazzi S, Calzia E, Gröger M, Kohn F, Schmid A, Denoix N, Radermacher P, and Wepler M
- Subjects
- Animals, Antioxidants administration & dosage, Atherosclerosis pathology, Coronary Artery Disease complications, Coronary Artery Disease pathology, Female, Male, Random Allocation, Resuscitation, Shock, Hemorrhagic pathology, Swine, Thiosulfates administration & dosage, Antioxidants therapeutic use, Atherosclerosis complications, Shock, Hemorrhagic complications, Shock, Hemorrhagic drug therapy, Thiosulfates therapeutic use
- Abstract
Controversial data are available on hydrogen sulfide (H
2 S) during hemorrhage and resuscitation, depending on timing, dosing, mode of application, and the H2 S donor used. Sodium thiosulfate (Na2 S2 O3 ) is a recognized drug devoid of major side effects, which attenuated murine acute lung injury and cerebral ischemia/reperfusion injury. Therefore, we tested the hypothesis whether Na2 S2 O3 would mitigate organ dysfunction in porcine hemorrhage-and-resuscitation. We studied animals with pre-existing coronary artery disease because of the reduced coronary arterial expression of the H2 S producing enzyme cystathionine-γ-lyase (CSE) in this prospective, randomized, controlled, blinded experimental study. 20 anesthetized and instrumented pigs underwent 3 h of hemorrhage (removal of 30 % of the blood volume and subsequent titration of mean arterial pressure to 40 mmHg). Resuscitation (72 h) comprised re-transfusion of shed blood, crystalloids, and continuous i.v. norepinephrine. Animals randomly received vehicle or Na2 S2 O3 (0.1 g·kg-1 h-1 ) for 24 h. Before, at the end of and every 24 h after shock, hemodynamics, metabolism, blood gases, lung, heart, kidney, and liver function and injury were evaluated together with cytokines and parameters of oxidative and nitrosative stress. Immediate post mortem lung, kidney, heart, and liver specimen were analyzed for marker proteins of inflammation and oxidative and nitrosative stress and mitochondrial respiratory activity in the heart, kidney, and liver. Immuno-histochemical analysis comprised lung extra-vascular albumin accumulation, nitrotyrosine formation, and CSE and glucocorticoid receptor (GCR) expression. Na2 S2 O3 significantly attenuated shock-induced impairment of lung mechanics and gas exchange (plateau and positive end-expiratory pressure at 72 h p = 0.0006/p = 0.0264; Horovitz index at 48 h p = 0.0261), which coincided with a higher tissue GCR expression (p = 0.0415). During resuscitation from hemorrhagic shock Na2 S2 O3 attenuated shock-induced acute lung injury in co-morbid swine, most likely due to a GCR expression related mechanism., (Copyright © 2019 Elsevier Ltd. All rights reserved.)- Published
- 2020
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38. In-depth characterization of a long-term, resuscitated model of acute subdural hematoma-induced brain injury.
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Datzmann T, Kapapa T, Scheuerle A, McCook O, Merz T, Unmuth S, Hoffmann A, Mathieu R, Mayer S, Mauer UM, Röhrer S, Yilmazer-Hanke D, Möller P, Nussbaum BL, Calzia E, Gröger M, Hartmann C, Radermacher P, and Wepler M
- Abstract
Objective: Acute subdural hematoma (ASDH) is a leading entity in brain injury. Rodent models mostly lack standard intensive care, while large animal models frequently are only short term. Therefore, the authors developed a long-term, resuscitated porcine model of ASDH-induced brain injury and report their findings., Methods: Anesthetized, mechanically ventilated, and instrumented pigs with human-like coagulation underwent subdural injection of 20 mL of autologous blood and subsequent observation for 54 hours. Continuous bilateral multimodal brain monitoring (intracranial pressure [ICP], cerebral perfusion pressure [CPP], partial pressure of oxygen in brain tissue [PbtO2], and brain temperature) was combined with intermittent neurological assessment (veterinary modified Glasgow Coma Scale [MGCS]), microdialysis, and measurement of plasma protein S100β, GFAP, neuron-specific enolase [NSE], nitrite+nitrate, and isoprostanes. Fluid resuscitation and continuous intravenous norepinephrine were targeted to maintain CPP at pre-ASDH levels. Immediately postmortem, the brains were taken for macroscopic and histological evaluation, immunohistochemical analysis for nitrotyrosine formation, albumin extravasation, NADPH oxidase 2 (NOX2) and GFAP expression, and quantification of tissue mitochondrial respiration., Results: Nine of 11 pigs survived the complete observation period. While ICP significantly increased after ASDH induction, CPP, PbtO2, and the MGCS score remained unaffected. Blood S100β levels significantly fell over time, whereas GFAP, NSE, nitrite+nitrate, and isoprostane concentrations were unaltered. Immunohistochemistry showed nitrotyrosine formation, albumin extravasation, NOX2 expression, fibrillary astrogliosis, and microglial activation., Conclusions: The authors describe a clinically relevant, long-term, resuscitated porcine model of ASDH-induced brain injury. Despite the morphological injury, maintaining CPP and PbtO2 prevented serious neurological dysfunction. This model is suitable for studying therapeutic interventions during hemorrhage-induced acute brain injury with standard brain-targeted intensive care.
- Published
- 2019
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39. Cardiac Effects of Hyperoxia During Resuscitation From Hemorrhagic Shock in Swine.
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Datzmann T, Wepler M, Wachter U, Vogt JA, McCook O, Merz T, Calzia E, Gröger M, Hartmann C, Asfar P, Radermacher P, and Nussbaum BL
- Subjects
- Animals, Gene Expression Regulation, Enzymologic, Nitric Oxide Synthase Type II biosynthesis, Swine, Tyrosine analogs & derivatives, Tyrosine metabolism, Ventricular Function, Left, Hyperoxia blood, Hyperoxia etiology, Hyperoxia physiopathology, Myocardium metabolism, Myocardium pathology, Resuscitation, Shock, Hemorrhagic blood, Shock, Hemorrhagic pathology, Shock, Hemorrhagic physiopathology, Shock, Hemorrhagic therapy
- Abstract
Hyperoxia (ventilation with FIO2 = 1.0) has vasoconstrictor properties, in particular in the coronary vascular bed, and, hence, may promote cardiac dysfunction. However, we previously showed that hyperoxia attenuated myocardial injury during resuscitation from hemorrhage in swine with coronary artery disease. Therefore, we tested the hypothesis whether hyperoxia would also mitigate myocardial injury and improve heart function in the absence of chronic cardiovascular comorbidity.After 3 h of hemorrhage (removal of 30% of the calculated blood volume and subsequent titration of mean arterial pressure to 40 mm Hg) 19 anesthetized, mechanically ventilated, and instrumented pigs received FIO2 = 0.3(control) or hyperoxia(FIO2 = 1.0) during the first 24 h. Before, at the end of and every 12 h after shock, hemodynamics, blood gases, metabolism, cytokines, and cardiac function (pulmonary artery thermodilution, left ventricular pressure-conductance catheterization) were recorded. At 48 h, cardiac tissue was harvested for western blotting, immunohistochemistry, and mitochondrial respiration.Except for higher left ventricular end-diastolic pressures at 24 h (hyperoxia 21 (17;24), control 17 (15;18) mm Hg; P = 0.046), hyperoxia affected neither left ventricular function cardiac injury (max. Troponin I at 12 h: hyperoxia:9 (6;23), control:17 (11;24) ng mL; P = 0.395), nor plasma cytokines (except for interleukin-1β: hyperoxia 10 (10;10) and 10 (10;10)/control 14 (10;22), 12 (10;15) pg mL, P = 0.023 and 0.021 at 12 and 24 h, respectively), oxidation and nitrosative stress, and mitochondrial respiration. However, hyperoxia decreased cardiac tissue three-nitrotyrosine formation (P < 0.001) and inducible nitric oxide synthase expression (P = 0.016). Ultimately, survival did not differ significantly either.In conclusion, in contrast to our previous study in swine with coronary artery disease, hyperoxia did not beneficially affect cardiac function or tissue injury in healthy swine, but was devoid of deleterious side effects.
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- 2019
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40. The Mitochondria-Targeted H2S-Donor AP39 in a Murine Model of Combined Hemorrhagic Shock and Blunt Chest Trauma.
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Wepler M, Merz T, Wachter U, Vogt J, Calzia E, Scheuerle A, Möller P, Gröger M, Kress S, Fink M, Lukaschewski B, Rumm G, Stahl B, Georgieff M, Huber-Lang M, Torregrossa R, Whiteman M, McCook O, Radermacher P, and Hartmann C
- Subjects
- Animals, Body Temperature, Chemokines metabolism, Cytokines metabolism, Disease Models, Animal, Hemodynamics drug effects, Immunoblotting, Immunohistochemistry, Male, Mice, Mice, Inbred C57BL, Wounds, Nonpenetrating drug therapy, Wounds, Nonpenetrating metabolism, Mitochondria metabolism, Organophosphorus Compounds therapeutic use, Shock, Hemorrhagic drug therapy, Shock, Hemorrhagic metabolism, Thiones therapeutic use, Thoracic Injuries drug therapy, Thoracic Injuries metabolism, Wounds and Injuries drug therapy, Wounds and Injuries metabolism
- Abstract
Hemorrhagic shock (HS) accounts for 30% to 40% of trauma-induced mortality, which is due to multi-organ-failure subsequent to systemic hyper-inflammation, triggered by hypoxemia and tissue ischemia. The slow-releasing, mitochondria-targeted H2S donor AP39 exerted beneficial effects in several models of ischemia-reperfusion injury and acute inflammation. Therefore, we tested the effects of AP39-treatment in a murine model of combined blunt chest trauma (TxT) and HS with subsequent resuscitation., Methods: After blast wave-induced TxT or sham procedure, anesthetized and instrumented mice underwent 1 h of hemorrhage followed by 4 h of resuscitation comprising an i.v. bolus injection of 100 or 10 nmol kg AP39 or vehicle, retransfusion of shed blood, fluid resuscitation, and norepinephrine. Lung mechanics and gas exchange were assessed together with hemodynamics, metabolism, and acid-base status. Blood and tissue samples were analyzed for cytokine and chemokine levels, western blot, immunohistochemistry, mitochondrial oxygen consumption (JO2), and histological changes., Results: High dose AP39 attenuated systemic inflammation and reduced the expression of inducible nitric oxide synthase (iNOS) and IκBα expression in lung tissue. In the combined trauma group (TxT + HS), animals treated with high dose AP39 presented with the lowest mean arterial pressure and thus highest norepinephrine requirements and higher mortality. Low dose AP39 had no effects on hemodynamics, leading to unchanged norepinephrine requirements and mortality rates., Conclusion: AP39 is a systemic anti-inflammatory agent. In our model of trauma with HS, there may be a narrow dosing and timing window due to its potent vasodilatory properties, which might result in or contribute to aggravation of circulatory shock-related hypotension.
- Published
- 2019
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41. Effects of Psychosocial Stress on Subsequent Hemorrhagic Shock and Resuscitation in Male Mice.
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Langgartner D, Wachter U, Hartmann C, Gröger M, Vogt J, Merz T, McCook O, Fink M, Kress S, Georgieff M, Kunze JF, Radermacher PL, Reber SO, and Wepler M
- Subjects
- Animals, Male, Mice, Multiple Organ Failure pathology, Multiple Organ Failure physiopathology, Multiple Organ Failure therapy, Resuscitation, Shock, Hemorrhagic pathology, Shock, Hemorrhagic physiopathology, Shock, Hemorrhagic therapy, Stress, Psychological pathology, Stress, Psychological physiopathology, Stress, Psychological therapy
- Abstract
Background: Hypoxemia and tissue ischemia during hemorrhage as well as formation of oxygen and nitrogen radicals during resuscitation promote hyperinflammation and, consequently, trigger severe multi-organ failure (MOF). Individuals diagnosed with stress-related disorders or reporting a life history of psychosocial stress are characterized by chronic low-grade inflammation and a reduced glucocorticoid (GC) signaling. We hypothesized that exposure to chronic psychosocial stress during adulthood prior to hemorrhagic shock increases oxidative/nitrosative stress and therefore the risk of developing MOF in mice., Methods and Findings: To induce chronic psychosocial stress linked to mild immune activation and reduced GC signaling in male mice, the chronic subordinate colony housing (CSC) paradigm was employed. Single-housed (SHC) mice were used as controls. Subsequently, CSC and SHC mice were exposed to hemorrhagic shock following resuscitation to investigate the effects of prior psychosocial stress load on survival, organ function, metabolism, oxidative/nitrosative stress, and inflammatory readouts. An increased adrenal weight in CSC mice indicates that the stress paradigm reliably worked. However, no effect of prior psychosocial stress on outcome after subsequent hemorrhage and resuscitation could be detected., Conclusions: Chronic psychosocial stress during adulthood is not sufficient to promote hemodynamic complications, organ dysfunction, metabolic disturbances and did not increase the risk of MOF after subsequent hemorrhage and resuscitation. Intravenous norepinephrine to keep target hemodynamics might have led to a certain level of oxidative stress in both groups and, therefore, disguised potential effects of chronic psychosocial stress on organ function after hemorrhagic shock in the present murine trauma model.
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- 2019
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42. The Effects of Genetic 3-Mercaptopyruvate Sulfurtransferase Deficiency in Murine Traumatic-Hemorrhagic Shock.
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Gröger M, Wepler M, Wachter U, Merz T, McCook O, Kress S, Lukaschewski B, Hafner S, Huber-Lang M, Calzia E, Georgieff M, Nagahara N, Szabó C, Radermacher P, and Hartmann C
- Subjects
- Animals, Cysteine metabolism, Disease Models, Animal, Female, Immunohistochemistry, Male, Mice, Mitochondria metabolism, Mutation genetics, Shock, Hemorrhagic genetics, Shock, Traumatic enzymology, Shock, Traumatic genetics, Shock, Traumatic metabolism, Cysteine analogs & derivatives, Shock, Hemorrhagic enzymology, Shock, Hemorrhagic metabolism, Sulfurtransferases genetics, Sulfurtransferases metabolism
- Abstract
Introduction: Hemorrhagic shock is a major cause of death after trauma. An additional blunt chest trauma independently contributes to mortality upon the development of an acute lung injury (ALI) by aggravating pathophysiological consequences of hemorrhagic shock. The maintenance of hydrogen sulfide availability is known to play an important role during hemorrhage and ALI. We therefore tested the impact of a genetic 3-mercaptopyruvate sulfurtransferase mutation (Δ3-MST) in a resuscitated murine model of traumatic-hemorrhagic shock., Methods: Anesthetized wild-type (WT) and Δ3-MST mice underwent hemorrhagic shock with/without blunt chest trauma. Hemorrhagic shock was implemented for 1 h followed by retransfusion of shed blood and intensive care therapy for 4 h, including lung-protective mechanical ventilation, fluid resuscitation, and noradrenaline titrated to maintain a mean arterial pressure at least 50 mmHg. Systemic hemodynamics, metabolism, and acid-base status were assessed together with lung mechanics and gas exchange. Postmortem tissue samples were analyzed for immunohistological protein expression and mitochondrial oxygen consumption., Results: 3-MST-deficient mice showed similar results in parameters of hemodynamics, gas exchange, metabolism, acid base status, and survival compared with the respective WT controls. Renal albumin extravasation was increased in Δ3-MST mice during hemorrhagic shock, together with a decrease of LEAK respiration in heart tissue. In contrast, mitochondrial oxygen consumption in the uncoupled state was increased in kidney and liver tissue of Δ3-MST mice subjected to the combined trauma., Conclusions: In summary, in a resuscitated murine model of traumatic-hemorrhagic shock, 3-MST deficiency had no physiologically relevant impact on hemodynamics and metabolism, which ultimately lead to unchanged mortality regardless of an additional blunt chest trauma.
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- 2019
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43. In-Depth Characterization of the Effects of Cigarette Smoke Exposure on the Acute Trauma Response and Hemorrhage in Mice.
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Hartmann C, Gröger M, Noirhomme JP, Scheuerle A, Möller P, Wachter U, Huber-Lang M, Nussbaum B, Jung B, Merz T, McCook O, Kress S, Stahl B, Calzia E, Georgieff M, Radermacher P, and Wepler M
- Subjects
- Acute Disease, Animals, Disease Models, Animal, Inflammation blood, Male, Mice, Acute Kidney Injury blood, Acute Lung Injury blood, Cigarette Smoking adverse effects, Cigarette Smoking blood, Shock, Hemorrhagic blood, Sulfides blood, Wounds, Nonpenetrating blood
- Abstract
Introduction: Hemorrhagic shock accounts for a large amount of trauma-related mortality. The severity of trauma can be further aggravated by an additional blunt chest trauma (TxT), which independently contributes to mortality upon the development of an acute lung injury (ALI). Besides, cigarette smoke (CS) exposure before TxT enhanced posttraumatic inflammation, thereby aggravating ALI. We therefore aimed to characterize the impact of an acute and/or chronic lung injury on organ dysfunction in a murine model of traumatic hemorrhagic shock (HS)., Methods: After 3 weeks of CS exposure, anesthetized mice underwent HS with/without TxT. Hemorrhagic shock was implemented for 1 h followed by retransfusion of shed blood and intensive care therapy for 4 h including lung-protective mechanical ventilation, fluid resuscitation, and noradrenaline titrated to maintain mean arterial pressure ≥50 mmHg. Lung mechanics and gas exchange were assessed together with systemic hemodynamics, metabolism, and acid-base status. Postmortem blood and tissue samples were analyzed for cytokine and chemokine levels, protein expression, mitochondrial respiration, and histological changes., Results: CS exposure and HS alone coincided with increased inflammation, decreased whole blood sulfide concentrations, and decreased diaphragmatic mitochondrial respiration. CS-exposed mice, which were subjected to TxT and subsequent HS, showed hemodynamic instability, acute kidney injury, and high mortality., Conclusions: Chronic CS exposure per se had the strongest impact on inflammatory responses. The degree of inflammation was similar upon an additional TxT, however, mice presented with organ dysfunction and increased mortality rates. Hence, in mice the degree of inflammation may be dissociated from the severity of organ dysfunction or injury.
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- 2019
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44. Effects of the Humanized Anti-Adrenomedullin Antibody Adrecizumab (HAM8101) on Vascular Barrier Function and Survival in Rodent Models of Systemic Inflammation and Sepsis.
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Geven C, Peters E, Schroedter M, Struck J, Bergmann A, McCook O, Radermacher P, Kox M, and Pickkers P
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- Animals, Cecum injuries, Inflammation immunology, Kidney drug effects, Kidney metabolism, Ligation adverse effects, Male, Mice, Punctures adverse effects, Rats, Rats, Wistar, Sepsis immunology, Adrenomedullin antagonists & inhibitors, Adrenomedullin immunology, Antibodies therapeutic use, Antibodies, Monoclonal, Humanized therapeutic use, Inflammation drug therapy, Sepsis drug therapy
- Abstract
Purpose: Adrenomedullin (ADM) is an important regulator of endothelial barrier function during sepsis. Administration of a murine antibody targeted against the N-terminus of ADM (HAM1101) resulted in improved outcome in models of murine sepsis. We studied the effects of a humanized form of this antibody (HAM8101, also known as Adrecizumab) on vascular barrier dysfunction and survival in rodent models of systemic inflammation and sepsis., Methods: Rats (n=48) received different dosages of HAM8101 or placebo (n = 8 per group), directly followed by administration of lipopolysaccharide (5 mg/kg). Twenty-four hours later, Evans Blue dye was administered to assess vascular leakage in kidney and liver tissue. Furthermore, mice (n = 24) were administered different dosages of HAM8101 or placebo (n = 6 per group), immediately followed by cecal ligation and puncture (CLP). Eighteen hours later, albumin, vascular endothelial growth factor (VEGF), and angiopoietin-1 were analyzed in the kidney. Finally, effects of single and repeated dose administration of HAM1101, HAM8101 and placebo on survival were assessed in CLP-induced murine sepsis (n = 60, n = 10 per group)., Results: Dosages of 0.1 and 2.5 mg/kg HAM8101 attenuated renal albumin leakage in endotoxemic rats. Dosages of 0.1, 2.0, and 20 mg/kg HAM8101 reduced renal concentrations of albumin and the detrimental protein VEGF in septic mice, whereas concentrations of the protective protein angiopoietin-1 were augmented. Both single and repeated administration of both HAM1101 and HAM8101 resulted in improved survival during murine sepsis., Conclusions: Pretreatment with the humanized anti-ADM antibody HAM8101 improved vascular barrier function and survival in rodent models of systemic inflammation and sepsis.
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- 2018
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45. Intravenous hydrogen sulfide does not induce neuroprotection after aortic balloon occlusion-induced spinal cord ischemia/reperfusion injury in a human-like porcine model of ubiquitous arteriosclerosis.
- Author
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Bredthauer A, Lehle K, Scheuerle A, Schelzig H, McCook O, Radermacher P, Szabo C, Wepler M, and Simon F
- Abstract
Objective: In rodents, intravenous sulfide protected against spinal cord ischemia/reperfusion (I/R) injury during aortic balloon occlusion. We investigated the effect of intravenous sulfide on aortic occlusion-induced porcine spinal cord I/R injury., Methods: Anesthetized and mechanically ventilated "familial hypercholesterolemia Bretoncelles Meishan" (FBM) pigs with high-fat-diet-induced hypercholesterolemia and atherosclerosis were randomized to receive either intravenous sodium sulfide 2 h (initial bolus, 0.2 mg kg body weight (bw)
-1 ; infusion, 2 mg kg bw-1 h-1 ; n = 4) or vehicle (sodium chloride, n = 4) prior to 45 min of thoracic aortic balloon occlusion and for 8 h during reperfusion (infusion, 1 mg kg bw-1 h-1 ). During reperfusion, noradrenaline was titrated to maintain blood pressure at above 80% of the baseline level. Spinal cord function was assessed by motor evoked potentials (MEPs) and lower limb reflexes using a modified Tarlov score. Spinal cord tissue damage was evaluated in tissue collected at the end of experiment using hematoxylin and eosin and Nissl staining., Results: A balloon occlusion time of 45 min resulted in marked ischemic neuron damage (mean of 16% damaged motoneurons in the anterior horn of all thoracic motor neurons) in the spinal cord. In the vehicle group, only one animal recovered partial neuronal function with regain of MEPs and link motions at each time point after deflating. All other animals completely lost neuronal functions. The intravenous application of sodium sulfide did not prevent neuronal cell injury and did not confer to functional recovery., Conclusion: In a porcine model of I/R injury of the spinal cord, treatment with intravenous sodium sulfide had no protective effect in animals with a pre-existing arteriosclerosis.- Published
- 2018
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46. Cystathionine-γ-lyase expression is associated with mitochondrial respiration during sepsis-induced acute kidney injury in swine with atherosclerosis.
- Author
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Merz T, Wepler M, Nußbaum B, Vogt J, Calzia E, Wang R, Szabo C, Radermacher P, and McCook O
- Abstract
Background: Sepsis is associated with disturbed glucose metabolism and reduced mitochondrial activity and biogenesis, ultimately leading to multiple organ dysfunction, e.g., acute kidney injury (AKI). Cystathionine-γ-lyase (CSE), the major cardiovascular source of endogenous H
2 S release, is implicated in the regulation of glucose metabolism and mitochondrial activity through a PGC1α-dependent mechanism, and critical for kidney function. Atherosclerosis is associated with mitochondrial dysfunction and reduced CSE expression. Thus, the aim of this post hoc study was to test the hypothesis whether there is an interplay between CSE expression and kidney dysfunction, mitochondrial activity, and oxidative/nitrosative stress in porcine septic AKI with underlying coronary artery disease., Methods: This study is a post hoc analysis of material from anesthetized and instrumented swine with a high fat diet-induced hypercholesterolemia and atherosclerosis undergoing faecal peritonitis-induced septic shock or sham procedure and intensive care (comprising fluid resuscitation and continuous i.v. noradrenaline (NoA) infusion) for 24 h. Glucose metabolism was quantified from blood13 C6 -glucose and expiratory13 CO2 /12 CO2 isotope enrichment during13 C6 -glucose infusion. Mitochondrial activity was determined by high-resolution respirometry. CSE and PGC1α expression, as well as nitrotyrosine formation and albumin extravasation, were quantified by immunohistochemistry of formalin-fixed kidney paraffin sections., Results: Sepsis was associated with lactic acidosis (p = 0.004) and AKI (50% fall of creatinine clearance (CrCl), p = 0.019). While both whole-body glucose production (p = 0.004) and oxidation (p = 0.006) were increased, kidney tissue mitochondrial respiration was reduced (p = 0.028), coinciding with decreased CSE (p = 0.003) and PGC1α (p = 0.003) expression. Albumin extravasation (p = 0.011) and nitrotyrosine formation (p = 0.008) were increased in septic kidneys., Conclusions: Sepsis-induced AKI is associated with disturbed mitochondrial respiration and biogenesis, which may be aggravated by oxidative and nitrosative stress. Our results confirm previous data in murine septic shock and porcine hemorrhage and resuscitation on the crucial role of CSE for barrier integrity and kidney function.- Published
- 2018
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47. Interaction of the hydrogen sulfide system with the oxytocin system in the injured mouse heart.
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Merz T, Lukaschewski B, Wigger D, Rupprecht A, Wepler M, Gröger M, Hartmann C, Whiteman M, Szabo C, Wang R, Waller C, Radermacher P, and McCook O
- Abstract
Background: Both the hydrogen sulfide/cystathionine-γ-lyase (H
2 S/CSE) and oxytocin/oxytocin receptor (OT/OTR) systems have been reported to be cardioprotective. H2 S can stimulate OT release, thereby affecting blood volume and pressure regulation. Systemic hyper-inflammation after blunt chest trauma is enhanced in cigarette smoke (CS)-exposed CSE-/- mice compared to wildtype (WT). CS increases myometrial OTR expression, but to this point, no data are available on the effects CS exposure on the cardiac OT/OTR system. Since a contusion of the thorax (Txt) can cause myocardial injury, the aim of this post hoc study was to investigate the effects of CSE-/- and exogenous administration of GYY4137 (a slow release H2 S releasing compound) on OTR expression in the heart, after acute on chronic disease, of CS exposed mice undergoing Txt., Methods: This study is a post hoc analysis of material obtained in wild type (WT) homozygous CSE-/- mice after 2-3 weeks of CS exposure and subsequent anesthesia, blast wave-induced TxT, and surgical instrumentation for mechanical ventilation (MV) and hemodynamic monitoring. CSE-/- animals received a 50 μg/g GYY4137-bolus after TxT. After 4h of MV, animals were exsanguinated and organs were harvested. The heart was cut transversally, formalin-fixed, and paraffin-embedded. Immunohistochemistry for OTR, arginine-vasopressin-receptor (AVPR), and vascular endothelial growth factor (VEGF) was performed with naïve animals as native controls., Results: CSE-/- was associated with hypertension and lower blood glucose levels, partially and significantly restored by GYY4137 treatment, respectively. Myocardial OTR expression was reduced upon injury, and this was aggravated in CSE-/- . Exogenous H2 S administration restored myocardial protein expression to WT levels., Conclusions: This study suggests that cardiac CSE regulates cardiac OTR expression, and this effect might play a role in the regulation of cardiovascular function.- Published
- 2018
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48. Role of Hemorrhagic Shock in Experimental Polytrauma.
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Denk S, Weckbach S, Eisele P, Braun CK, Wiegner R, Ohmann JJ, Wrba L, Hoenes FM, Kellermann P, Radermacher P, Wachter U, Hafner S, McCook O, Schultze A, Palmer A, Braumüller S, Gebhard F, and Huber-Lang M
- Subjects
- Animals, Bronchoalveolar Lavage, Creatinine blood, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, HMGB1 Protein metabolism, Interleukin-6 blood, Kidney metabolism, Mice, Mice, Inbred C57BL, Multiple Trauma metabolism, Peroxidase metabolism, Random Allocation, Shock, Hemorrhagic metabolism, Multiple Trauma blood, Multiple Trauma physiopathology, Shock, Hemorrhagic blood, Shock, Hemorrhagic physiopathology
- Abstract
Hemorrhagic shock (HS) after tissue trauma increases the complication and mortality rate of polytrauma (PT) patients. Although several murine trauma models have been introduced, there is a lack of knowledge about the exact impact of an additional HS. We hypothesized that HS significantly contributes to organ injury, which can be reliably monitored by detection of specific organ damage markers. Therefore we established a novel clinically relevant PT plus HS model in C57BL/6 mice which were randomly assigned to control, HS, PT, or PT+HS procedure (n = 8 per group). For induction of PT, anesthetized animals received a blunt chest trauma, head injury, femur fracture, and soft tissue injury. HS was induced by pressure-controlled blood drawing (mean arterial blood pressure of 30 mmHg for 60 min) and mice then resuscitated with ionosterile (4 × volume drawn), monitored, and killed for blood and organ harvesting 4 h after injury. After HS and resuscitation, PT+HS mice required earlier and overall more catecholamine support than HS animals to keep their mean arterial blood pressure. HS significantly contributed to the systemic release of interleukin-6 and high mobility group box 1 protein. Furthermore, the histological lung injury score, pulmonary edema, neutrophil influx, and plasma clara cell protein 16 were all significantly enhanced in PT animals in the presence of an additional HS. Although early morphological changes were minor, HS also contributed functionally to remote acute kidney injury but not to early liver damage. Moreover, PT-induced systemic endothelial injury, as determined by plasma syndecan-1 levels, was significantly aggravated by an additional HS. These results indicate that HS adds to the systemic inflammatory reaction early after PT. Within hours after PT, HS seems to aggravate pulmonary damage and to worsen renal and endothelial function which might overall contribute to the development of early multiple organ dysfunction.
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- 2018
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49. Effects of Hyperoxia During Resuscitation From Hemorrhagic Shock in Swine With Preexisting Coronary Artery Disease.
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Hartmann C, Loconte M, Antonucci E, Holzhauser M, Hölle T, Katzsch D, Merz T, McCook O, Wachter U, Vogt JA, Hoffmann A, Wepler M, Gröger M, Matejovic M, Calzia E, Georgieff M, Asfar P, Radermacher P, and Nussbaum BL
- Subjects
- Animals, Blood Gas Analysis, Blood Pressure, Cytokines metabolism, Heart Function Tests, Hemodynamics, Kidney Function Tests, Prospective Studies, Random Allocation, Shock, Hemorrhagic mortality, Shock, Hemorrhagic therapy, Swine, Coronary Artery Disease epidemiology, Hypercholesterolemia epidemiology, Hyperoxia physiopathology, Resuscitation methods, Shock, Hemorrhagic epidemiology, Shock, Hemorrhagic physiopathology
- Abstract
Objectives: Investigation of the effects of hyperoxia during resuscitation from hemorrhagic shock in swine with preexisting coronary artery disease., Design: Prospective, controlled, randomized trial., Setting: University animal research laboratory., Subjects: Nineteen hypercholesterolemic pigs with preexisting coronary artery disease., Interventions: Anesthetized, mechanically ventilated, and surgically instrumented pigs underwent 3 hours of hemorrhagic shock (removal of 30% of the calculated blood volume and subsequent titration of mean arterial blood pressure ≈40 mm Hg). Postshock resuscitation (48 hr) comprised retransfusion of shed blood, crystalloids (balanced electrolyte solution), and norepinephrine support. Pigs were randomly assigned to "control" (FIO2 0.3, adjusted for arterial oxygen saturation ≥ 90%) and "hyperoxia" (FIO2 1.0 for 24 hr) groups., Measurements and Main Results: Before, at the end of shock and every 12 hours of resuscitation, datasets comprising hemodynamics, calorimetry, blood gases, cytokines, and cardiac and renal function were recorded. Postmortem, organs were sampled for immunohistochemistry, western blotting, and mitochondrial high-resolution respirometry. Survival rates were 50% and 89% in the control and hyperoxia groups, respectively (p = 0.077). Apart from higher relaxation constant τ at 24 hours, hyperoxia did not affect cardiac function. However, troponin values were lower (2.2 [0.9-6.2] vs 6.9 [4.8-9.8] ng/mL; p < 0.05) at the end of the experiment. Furthermore, hyperoxia decreased cardiac 3-nitrotyrosine formation and increased inducible nitric oxide synthase expression. Plasma creatinine values were lower in the hyperoxia group during resuscitation coinciding with significantly improved renal mitochondrial respiratory capacity and lower 3-nitrotyrosine formation., Conclusions: Hyperoxia during resuscitation from hemorrhagic shock in swine with preexisting coronary artery disease reduced renal dysfunction and cardiac injury, potentially resulting in improved survival, most likely due to increased mitochondrial respiratory capacity and decreased oxidative and nitrosative stress. Compared with our previous study, the present results suggest a higher benefit of hyperoxia in comorbid swine due to an increased susceptibility to hemorrhagic shock.
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- 2017
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50. Impact of hyperglycemia on cystathionine-γ-lyase expression during resuscitated murine septic shock.
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Merz T, Vogt JA, Wachter U, Calzia E, Szabo C, Wang R, Radermacher P, and McCook O
- Abstract
Background: Cystathionine-γ-lyase (CSE) was shown to have a regulatory role in glucose metabolism. Circulatory shock can induce metabolic stress, thereby leading to hyperglycemia and mitochondrial dysfunction. In vitro data suggest an effect of high glucose on CSE expression. Therefore, the aim of this study was to investigate the effects of hyperglycemia on CSE expression in resuscitated murine septic shock., Methods: Normo- (80-150 mg/dl) and hyperglycemic (>200 mg/dl) male C57/BL6J mice (n = 5-6 per group) underwent cecal ligation and puncture (CLP)-induced polymicrobial sepsis or sham procedure (n = 6 per group) and, 15 h afterwards, were anesthetized again, surgically instrumented and received intensive care treatment, including antibiotics, lung protective mechanical ventilation, circulatory support, and intravenous (i.v.) glucose infusion (50% as stable-isotope labeled 1,2,3,4,5,6-
13 C6 glucose). Blood and breath gas were sampled hourly to quantify parameters of glucose metabolism. 5 h later, mice were sacrificed and organs were harvested. The liver mitochondrial respiratory activity was determined via high resolution respirometry; CSE, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), and adipocyte differentiation-related protein (ADRP) expression was immunohistochemically investigated., Results: In sepsis combined with hyperglycemia the least CSE and PGC1α expression could be detected, along with reduced mitochondrial respiratory activity, and enhanced ADRP expression, a marker of lipid droplet formation, in the liver. A novel in vivo finding is the CSE translocation from the cytosol to the nucleus triggered by metabolic stress., Conclusions: A relationship between CSE and glucose metabolism was established, which, when dysregulated, may contribute to fatty liver disease and hepatic steatosis.- Published
- 2017
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