Effects of Hyperoxia During Resuscitation From Hemorrhagic Shock in Swine With Preexisting Coronary Artery Disease

Hartmann, Clair; Loconte, Maurizio; Antonucci, Elena; Holzhauser, Michael; Hölle, Tobias; Katzsch, David; Merz, Tamara; McCook, Oscar; Wachter, Ulrich; Vogt, J.; Hoffmann, Andrea; Wepler, Martin; Gröger, Michael; Matějovič, Martin; Calzia, Enrico; Georgieff, Michael; Asfar, Pierre; Radermacher, Peter; Nußbaum, Benedikt

doi:10.1097/ccm.0000000000002767

Cited by 23 publications

(23 citation statements)

References 43 publications

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“…In contrast to young healthy pigs, the FBM pigs display a similar reduction of cardiac output as patients with CAD in response to sepsis (10). Moreover, during resuscitation from hemorrhagic shock, this pig strain requires significantly higher noradrenaline doses to achieve similar hemodynamic targets (27,28). Aggravated septic cardiomyopathy can be related to atherosclerosis, chronic kidney disease and cardiac dysfunction, all of which are associated with reduced tissue CSE expression [coronary artery (10), kidney (7), heart (9)].…”

Section: Discussionmentioning

confidence: 99%

The Role of Glucocorticoid Receptor and Oxytocin Receptor in the Septic Heart in a Clinically Relevant, Resuscitated Porcine Model With Underlying Atherosclerosis

et al. 2020

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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.

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Section: Discussionmentioning

confidence: 99%

The Role of Glucocorticoid Receptor and Oxytocin Receptor in the Septic Heart in a Clinically Relevant, Resuscitated Porcine Model With Underlying Atherosclerosis

et al. 2020

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“…Mitochondrial respiratory activity was determined via high-resolution respirometry with a Clark-electrode-based system (Oxygraph 2k, OROBOROS Instruments Corp., Innsbruck, Austria) as described previously [ 34 , 35 ]. Fresh postmortem kidney samples were collected in Custodiol (Franz Köhler Chemie) and mechanically homogenized in respiration medium (MIR05; 0.5 mM EGTA, 3 mM MgCl 2 ·6H 2 O, 60 mM lactobionic acid, 20 mM taurine, 10 mM KH 2 PO 4 , 20 mM HEPES, 110 mM sucrose, and 1 g/L bovine serum albumin), and 2 mg of tissue was added to the Oxygraph chamber.…”

Section: Methodsmentioning

confidence: 99%

Cystathionine-γ-lyase expression is associated with mitochondrial respiration during sepsis-induced acute kidney injury in swine with atherosclerosis

Merz

Wepler

Nußbaum

et al. 2018

ICMx

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BackgroundSepsis 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 H2S 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.MethodsThis 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 blood 13C6-glucose and expiratory 13CO2/12CO2 isotope enrichment during 13C6-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.ResultsSepsis 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.ConclusionsSepsis-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.Electronic supplementary materialThe online version of this article (10.1186/s40635-018-0208-z) contains supplementary material, which is available to authorized users.

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“…It is well established that age, sex and, in particular, chronic comorbidities markedly influence the outcome after sepsis and/or circulatory shock. This notion is also true for preclinical animal experiments, for which the importance of age, sex [56, 57] and/or underlying chronic diseases, including chronic obstructive pulmonary disease (COPD) [30, 58, 59] or cystic fibrosis [60], atherosclerosis [61], cancer [62], diabetes [63, 64] or even “psychological stress” [65], has been demonstrated. Indeed, preexisting coronary artery disease even completely abolished [66, 67] the otherwise promising results obtained in comparable experimental settings in young and healthy animals [68, 69].…”

Section: Advanced Animal Models Comprising Full-scale Icu Treatmentmentioning

confidence: 99%

Preclinical septic shock research: why we need an animal ICU

Guillon¹,

Preau²,

Aboab³

et al. 2019

Ann. Intensive Care

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Animal experiments are widely used in preclinical medical research with the goal of disease modeling and exploration of novel therapeutic approaches. In the context of sepsis and septic shock, the translation into clinical practice has been disappointing. Classical animal models of septic shock usually involve one-sex-one-age animal models, mostly in mice or rats, contrasting with the heterogeneous population of septic shock patients. Many other factors limit the reliability of preclinical models and may contribute to preclinical research failure in critical care, including the host specificity of several pathogens, the fact that laboratory animals are raised in pathogen-free facilities and that organ support techniques are either absent or minimal. Advanced animal models have been developed with the aim of improving the clinical translatability of experimental findings. So-called animal ICUs refer to the preclinical investigation of adult or even aged animals of either sex, using—in case of rats and mice—miniaturized equipment allowing for reproducing an ICU environment at a small animal scale and integrating chronic comorbidities to more closely reflect the clinical conditions studied. Strength and limitations of preclinical animal models designed to decipher the mechanisms involved in septic cardiomyopathy are discussed. This article reviews the current status and the challenges of setting up an animal ICU.

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Effects of Hyperoxia During Resuscitation From Hemorrhagic Shock in Swine With Preexisting Coronary Artery Disease

Cited by 23 publications

References 43 publications

The Role of Glucocorticoid Receptor and Oxytocin Receptor in the Septic Heart in a Clinically Relevant, Resuscitated Porcine Model With Underlying Atherosclerosis

The Role of Glucocorticoid Receptor and Oxytocin Receptor in the Septic Heart in a Clinically Relevant, Resuscitated Porcine Model With Underlying Atherosclerosis

Cystathionine-γ-lyase expression is associated with mitochondrial respiration during sepsis-induced acute kidney injury in swine with atherosclerosis

Preclinical septic shock research: why we need an animal ICU

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