Ethyl pyruvate ameliorates hepatic injury following blunt chest trauma and hemorrhagic shock by reducing local inflammation, NF-kappaB activation and HMGB1 release

Wagner, Nils; Dieteren, Scott; Franz, Niklas; Köhler, Kernt; Mörs, Katharina; Nicin, Luka; Schmidt, Julia; Perl, Mario; Marzi, Ingo; Relja, Borna

doi:10.1371/journal.pone.0192171

Cited by 17 publications

(20 citation statements)

References 57 publications

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“…In the present study, resuscitation with EtP reduced the expression of CD11b on circulating neutrophils, indicating at an anti-inflammatory effect via inhibition of systemic activation of leukocytes. Intriguing data have been found after resuscitation with EtP which further reduced caspase-3/7 activity in circulating granulocytes, effects that can be associated with diminished tissue damage in liver and lung as shown in our previous studies ( 32 , 37 ). This is in contrast to above described findings, where tissue-protective effects were demonstrated by restoring apoptotic capacity in neutrophils.…”

Section: Discussionsupporting

confidence: 78%

“…No tissue damage or necrosis were observed in the sham group. The representative and detailed analyses of the local effects of a EtP-reperfusion on lungs and liver in the underlying model of TxT and H/R are shown in our referred studies ( 32 , 37 ).…”

Section: Resultsmentioning

confidence: 99%

“…Then, the samples were embedded in paraffin and subsequently sectioned and stained with hematoxylin-eosin (H&E). The histological examination of the tissue morphology in both organs was performed by an independent pathologist who allocated the H&E-stained sections to the different experimental groups in a blinded manner as described before ( 32 , 37 ).…”

Section: Methodsmentioning

confidence: 99%

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Ethyl Pyruvate Reduces Systemic Leukocyte Activation via Caspase-1 and NF-κB After Blunt Chest Trauma and Haemorrhagic Shock

et al. 2020

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Background: Blunt chest (thoracic) trauma (TxT) and haemorrhagic shock with subsequent resuscitation (H/R) induce strong systemic and local inflammatory response, which is closely associated with apoptotic cell loss and subsequently impaired organ function. The underlying mechanisms are not completely understood, therefore, the treatment of patients suffering from TxT+H/R is challenging. In our recent studies, we have demonstrated local anti-inflammatory effects of ethyl pyruvate (EtP) in lung and liver after TxT+H/R. Here, the therapeutic potential of a reperfusion regime with EtP on the early post-traumatic systemic inflammatory response and apoptotic changes after TxT followed by H/R were investigated. Methods: Female Lewis rats underwent TxT followed by haemorrhagic shock (60 min). Resuscitation was performed with own blood transfusion and either lactated Ringers solution (LR) or LR supplemented with EtP (50 mg/kg). Sham group underwent the surgical procedures. After 2 h blood as well as lung and liver tissues were obtained for analyses. Systemic activation of neutrophils (expression of CD11b and CD62L), leukocyte phagocytosis, apoptosis (caspase-3/7 activation), pyroptosis (caspase-1 activation) and NF-κB p65 activity were assessed. p < 0.05 was considered significant. Results: TxT+H/R-induced systemic activation of neutrophils (increased CD11b and reduced CD62L expression) was significantly reduced by EtP. Trauma-induced delayed neutrophil apoptosis was further reduced by EtP reperfusion but remained unaltered in monocytes. Reperfusion with EtP significantly increased the phagocytizing capacity of granulocytes. Trauma-induced inflammasome activation, which was observed in monocytes and not in neutrophils, was significantly reduced by EtP in both cell entities. NF-κB p65 activation, which was increased in neutrophils and monocytes was significantly decreased in monocytes. Conclusion: TxT+H/R-induced systemic activation of both neutrophils and monocytes concomitant with increased systemic inflammation was reduced by a reperfusion with EtP and was associated with a down-regulation of NF-κB p65 activation.

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Section: Discussionsupporting

confidence: 78%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Ethyl Pyruvate Reduces Systemic Leukocyte Activation via Caspase-1 and NF-κB After Blunt Chest Trauma and Haemorrhagic Shock

et al. 2020

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“…Therefore, a reliable in vivo model is necessary to investigate the physiological response pattern to polytrauma. The most common in vivo trauma models imply mainly two insults, with major focus on hemorrhagic shock in combination with blunt chest trauma or fracture 9–14 . This so-called double-hit trauma model of a thoracic injury with hemorrhage/resuscitation is often applied to combine the posttraumatic systemic and local inflammatory response and organ damage 9,10 .…”

Section: Introductionmentioning

confidence: 99%

Traumatic injury pattern is of equal relevance as injury severity for experimental (poly)trauma modeling

Yang

Bundkirchen

Krettek

et al. 2019

Sci Rep

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This study aims to elaborate the relevance of trauma severity and traumatic injury pattern in different multiple and/or polytrauma models by comparing five singular trauma to two different polytrauma (PT) models with high and one multiple trauma (MT) model with low injury-severity score (ISS). The aim is to provide a baseline for reducing animal harm according to 3Rs by providing less injury as possible in polytrauma modeling. Mice were randomly assigned to 10 groups: controls (Ctrl; n = 15), Sham (n = 15); monotrauma groups: hemorrhagic shock (HS; n = 15), thoracic trauma (TxT; n = 18), osteotomy with external fixation (Fx; n = 16), bilateral soft tissue trauma (bSTT; n = 16) or laparotomy (Lap; n = 16); two PT groups: PT I (TxT + HS + Fx; ISS = 18; n = 18), PT II (TxT + HS + Fx + Lap; ISS = 22; n = 18), and a MT group (TxT + HS + bSTT + Lap, ISS = 13; n = 18). Activity and mortality were assessed. Blood gas analyses and organ damage markers were determined after 6 h. Significant mortality occurred in TxT, PT and MT (11.7%). Activity decreased significantly in TxT, HS, both polytrauma and MT vs . Ctrl/Sham. PT-groups and MT had significantly decreased activity vs . bsTT, Lap or Fx. MT had significantly lower pCO 2 vs . Ctrl/Sham, Lap or bsTT. Transaminases increased significantly in PT-groups and MT vs . Ctrl, Sham or monotrauma. Traumatic injury pattern is of comparable relevance as injury severity for experimental multiple or (poly)trauma modeling.

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“…HMGB1 is released from damaged tissue and circulates beyond the site of injury, engaging specific cell receptors, RAGE (receptor for advanced glycation end products), TLR-4 (toll-like receptor-4) and TLR-2 expressed on endothelial cells, and circulating mononuclear phagocytes. 116 , 117 HMGB1 serum levels increase in hemorrhagic shock and trauma, 118 , 119 suggesting plausibly that HMGB1 mediates in part pathophysiologic consequences of rapid reperfusion of ischemic tissue. Plasma levels of HMGB1 are increased within 30 min after severe trauma in humans and correlate with the severity of injury, extent of tissue hypoperfusion, early posttraumatic coagulofibrinolytic abnormalities, and auto-inflammatory responses.…”

Section: Coagulation and Inflammationmentioning

confidence: 99%

Optimizing transfusion strategies in damage control resuscitation: current insights

Pohlman

Fecher

Arreola-Garcia

2018

JBM

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From clinical and laboratory studies of specific coagulation defects induced by injury, damage control resuscitation (DCR) emerged as the most effective management strategy for hemorrhagic shock. DCR of the trauma patient who has sustained massive blood loss consists of 1) hemorrhage control; 2) permissive hypotension; and 3) the prevention and correction of trauma-induced coagulopathies, referred to collectively here as acute coagulopathy of trauma (ACOT). Trauma patients with ACOT have higher transfusion requirements, may eventually require massive transfusion, and are at higher risk of exsanguinating. Distinct impairments in the hemostatic system associated with trauma include acquired quantitative and qualitative platelet defects, hypocoagulable and hypercoagulable states, and dysregulation of the fibrinolytic system giving rise to hyperfibrinolysis or a phenomenon referred to as fibrinolytic shutdown. Furthermore, ACOT is a component of a systemic host defense dysregulation syndrome that bears several phenotypic features comparable with other acute systemic physiological insults such as sepsis, myocardial infarction, and postcardiac arrest syndrome. Progress in the science of resuscitation has been continuing at an accelerated rate, and clinicians who manage catastrophic blood loss may be incompletely informed of important advances that pertain to DCR. Therefore, we review recent findings that further characterize the pathophysiology of ACOT and describe the application of this new information to optimization of resuscitation strategies for the patient in hemorrhagic shock.

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Ethyl pyruvate ameliorates hepatic injury following blunt chest trauma and hemorrhagic shock by reducing local inflammation, NF-kappaB activation and HMGB1 release

Cited by 17 publications

References 57 publications

Ethyl Pyruvate Reduces Systemic Leukocyte Activation via Caspase-1 and NF-κB After Blunt Chest Trauma and Haemorrhagic Shock

Ethyl Pyruvate Reduces Systemic Leukocyte Activation via Caspase-1 and NF-κB After Blunt Chest Trauma and Haemorrhagic Shock

Traumatic injury pattern is of equal relevance as injury severity for experimental (poly)trauma modeling

Optimizing transfusion strategies in damage control resuscitation: current insights

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