bims-heshmo Biomed News
on Trauma hemorrhagic shock — molecular basis
Issue of 2021‒10‒24
seven papers selected by
Andreia Luís
Ludwig Boltzmann Institute
  1. Therapeutic Potential of Mesenchymal Stromal Cell-Derived Extracellular Vesicles in the Prevention of Organ Injuries Induced by Traumatic Hemorrhagic Shock.
  2. The Pathophysiology and Management of Hemorrhagic Shock in the Polytrauma Patient.
  3. An Estrogen (17α-ethinyl estradiol-3-sulfate) Reduces Mortality in a Swine Model of Poly Trauma and Hemorrhagic Shock.
  4. Protease-Activated Receptor-1 Antagonist Protects Against Lung Ischemia/Reperfusion Injury.
  5. CD226 deficiency promotes glutaminolysis and alleviates mitochondria damage in vascular endothelial cells under hemorrhagic shock.
  6. Inhibition of Prolyl Oligopeptidase Prevents Consequences of Reperfusion following Intestinal Ischemia.
  7. Histochrome Attenuates Myocardial Ischemia-Reperfusion Injury by Inhibiting Ferroptosis-Induced Cardiomyocyte Death.
  1. Front Immunol. 2021 ;12 749659
    Therapeutic Potential of Mesenchymal Stromal Cell-Derived Extracellular Vesicles in the Prevention of Organ Injuries Induced by Traumatic Hemorrhagic Shock.
    Guillaume Valade, Nicolas Libert, Christophe Martinaud, Eric Vicaut, Sébastien Banzet, Juliette Peltzer.
      Severe trauma is the principal cause of death among young people worldwide. Hemorrhagic shock is the leading cause of death after severe trauma. Traumatic hemorrhagic shock (THS) is a complex phenomenon associating an absolute hypovolemia secondary to a sudden and significant extravascular blood loss, tissue injury, and, eventually, hypoxemia. These phenomena are responsible of secondary injuries such as coagulopathy, endotheliopathy, microcirculation failure, inflammation, and immune activation. Collectively, these dysfunctions lead to secondary organ failures and multi-organ failure (MOF). The development of MOF after severe trauma is one of the leading causes of morbidity and mortality, where immunological dysfunction plays a central role. Damage-associated molecular patterns induce an early and exaggerated activation of innate immunity and a suppression of adaptive immunity. Severe complications are associated with a prolonged and dysregulated immune-inflammatory state. The current challenge in the management of THS patients is preventing organ injury, which currently has no etiological treatment available. Modulating the immune response is a potential therapeutic strategy for preventing the complications of THS. Mesenchymal stromal cells (MSCs) are multipotent cells found in a large number of adult tissues and used in clinical practice as therapeutic agents for immunomodulation and tissue repair. There is growing evidence that their efficiency is mainly attributed to the secretion of a wide range of bioactive molecules and extracellular vesicles (EVs). Indeed, different experimental studies revealed that MSC-derived EVs (MSC-EVs) could modulate local and systemic deleterious immune response. Therefore, these new cell-free therapeutic products, easily stored and available immediately, represent a tremendous opportunity in the emergency context of shock. In this review, the pathophysiological environment of THS and, in particular, the crosstalk between the immune system and organ function are described. The potential therapeutic benefits of MSCs or their EVs in treating THS are discussed based on the current knowledge. Understanding the key mechanisms of immune deregulation leading to organ damage is a crucial element in order to optimize the preparation of EVs and potentiate their therapeutic effect.
    Keywords:  acute injury; extracellular vesicles; inflammation; mesenchymal stromal cell; multi-organ failure; traumatic hemorrhagic shock
    DOI:  https://doi.org/10.3389/fimmu.2021.749659
  2. J Clin Med. 2021 Oct 19. pii: 4793. [Epub ahead of print]10(20):
    The Pathophysiology and Management of Hemorrhagic Shock in the Polytrauma Patient.
    Alison Fecher, Anthony Stimpson, Lisa Ferrigno, Timothy H Pohlman.
      The recognition and management of life-threatening hemorrhage in the polytrauma patient poses several challenges to prehospital rescue personnel and hospital providers. First, identification of acute blood loss and the magnitude of lost volume after torso injury may not be readily apparent in the field. Because of the expression of highly effective physiological mechanisms that compensate for a sudden decrease in circulatory volume, a polytrauma patient with a significant blood loss may appear normal during examination by first responders. Consequently, for every polytrauma victim with a significant mechanism of injury we assume substantial blood loss has occurred and life-threatening hemorrhage is progressing until we can prove the contrary. Second, a decision to begin damage control resuscitation (DCR), a costly, highly complex, and potentially dangerous intervention must often be reached with little time and without sufficient clinical information about the intended recipient. Whether to begin DCR in the prehospital phase remains controversial. Furthermore, DCR executed imperfectly has the potential to worsen serious derangements including acidosis, coagulopathy, and profound homeostatic imbalances that DCR is designed to correct. Additionally, transfusion of large amounts of homologous blood during DCR potentially disrupts immune and inflammatory systems, which may induce severe systemic autoinflammatory disease in the aftermath of DCR. Third, controversy remains over the composition of components that are transfused during DCR. For practical reasons, unmatched liquid plasma or freeze-dried plasma is transfused now more commonly than ABO-matched fresh frozen plasma. Low-titer type O whole blood may prove safer than red cell components, although maintaining an inventory of whole blood for possible massive transfusion during DCR creates significant challenges for blood banks. Lastly, as the primary principle of management of life-threatening hemorrhage is surgical or angiographic control of bleeding, DCR must not eclipse these definitive interventions.
    Keywords:  coagulopathy; endotheliopathy; hemorrhage; macrocirculation; microcirculation; oxygen transport; polytrauma; resuscitation; shock
    DOI:  https://doi.org/10.3390/jcm10204793
  3. J Trauma Acute Care Surg. 2021 Oct 19.
    An Estrogen (17α-ethinyl estradiol-3-sulfate) Reduces Mortality in a Swine Model of Poly Trauma and Hemorrhagic Shock.
    Hossam Abdou, Jonathan J Morrison, Joseph Edwards, Neerav Patel, Eric Lang, Michael J Richmond, Noha Elansary, Mathangi Gopalakrishnan, Jonathan Berman, William J Hubbard, Thomas M Scalea, Irshad H Chaudry.
      BACKGROUND: Although 17α-ethinyl estradiol-3-sulfate (EES) reduces mortality in animal models of controlled hemorrhage, its role in a clinically relevant injury model is unknown. We assessed the impact of EES in a swine model of poly trauma and hemorrhage.METHODS: The study was performed under Good Laboratory Practice, with 30 male uncastrated swine (25-50 kg) subjected to tibial fracture, pulmonary contusion, and 30% controlled hemorrhage over an hour. Animals were randomized to one of five EES doses: 0 (control), 0.3, 1, 3 and 5 mg/kg, administered post-injury. Subjects received no resuscitation and were observed for 6 hours or until death. Survival data were analyzed using Cox-proportional hazard regression. Left ventricular pressure-volume loops were used to derive preload recruitable stroke work (PRSW) as a measure of cardiac inotropy. Immediate post-injury PRSW values were compared to values at one hour (T60) post drug administration.
    RESULTS: 6-hr survival for the 0, 0.3, 1, 3 and 5 mg/kg groups was 0%, 50%, 33.3%, 16.7% and 0%, respectively. Following Cox regression, the hazard [95% confidence interval] of death was significantly reduced in the 0.3 (0.22 [0.05-0.93]) and 1 (0.24 [0.06-0.89]) mg/kg groups but not the 3 and 5 mg/kg groups: 0.49 [0.15-1.64] and 0.46 [0.14-1.47]. Mean survival time was significantly extended in the 1 mg/kg group (246 min) vs. the 0 mg/kg group (96 min) [p = 0.04, t-test]. T60 inotropy was significantly higher than post-injury values in the 0.3 and 1 mg/kg groups (p = 0.003 and p < 0.001, respectively). Inotropy was unchanged in the 3 and 5 mg/kg groups but significantly depressed in the control (p = 0.022).
    CONCLUSIONS: Administration of EES even in the absence of fluid resuscitation reduces mortality and improves cardiac inotropy in a clinically relevant swine model of poly trauma and hemorrhage. These findings support the need for a clinical trial in human trauma patients.
    DOI:  https://doi.org/10.1097/TA.0000000000003434
  4. Front Pharmacol. 2021 ;12 752507
    Protease-Activated Receptor-1 Antagonist Protects Against Lung Ischemia/Reperfusion Injury.
    Shi-Jye Chu, Shih-En Tang, Hsin-Ping Pao, Shu-Yu Wu, Wen-I Liao.
      Protease-activated receptor (PAR)-1 is a thrombin-activated receptor that plays an essential role in ischemia/reperfusion (IR)-induced acute inflammation. PAR-1 antagonists have been shown to alleviate injuries in various IR models. However, the effect of PAR-1 antagonists on IR-induced acute lung injury (ALI) has not yet been elucidated. This study aimed to investigate whether PAR-1 inhibition could attenuate lung IR injury. Lung IR was induced in an isolated perfused rat lung model. Male rats were treated with the specific PAR-1 antagonist SCH530348 (vorapaxar) or vehicle, followed by ischemia for 40 min and reperfusion for 60 min. To examine the role of PAR-1 and the mechanism of SCH530348 in lung IR injury, western blotting and immunohistochemical analysis of lung tissue were performed. In vitro, mouse lung epithelial cells (MLE-12) were treated with SCH530348 or vehicle and subjected to hypoxia-reoxygenation (HR). We found that SCH530348 decreased lung edema and neutrophil infiltration, attenuated thrombin production, reduced inflammatory factors, including cytokine-induced neutrophil chemoattractant-1, interleukin-6 and tumor necrosis factor-α, mitigated lung cell apoptosis, and downregulated the phosphoinositide 3-kinase (PI3K), nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways in IR-injured lungs. In addition, SCH530348 prevented HR-induced NF-κB activation and inflammatory chemokine production in MLE12 cells. Our results demonstrate that SCH530348 exerts protective effects by blocking PAR-1 expression and modulating the downstream PI3K, NF-κB and MAPK pathways. These findings indicate that the PAR-1 antagonist protects against IR-induced ALI and is a potential therapeutic candidate for lung protection following IR injury.
    Keywords:  SCH530348; acute lung injury; ischemia-reperfusion; protease-activated receptor 1; thrombin
    DOI:  https://doi.org/10.3389/fphar.2021.752507
  5. FASEB J. 2021 Nov;35(11): e21998
    CD226 deficiency promotes glutaminolysis and alleviates mitochondria damage in vascular endothelial cells under hemorrhagic shock.
    Shangxun Zhou, Jiangang Xie, Chaoping Yu, Zhusheng Feng, Kun Cheng, Jingchang Ma, Yuling Wang, Chujun Duan, Yuan Zhang, Boquan Jin, Wen Yin, Ran Zhuang.
      Hemorrhagic shock (HS) is common in clinical emergencies, leading to millions of deaths each year globally. CD226 is a costimulatory adhesion molecule expressed on both immune cells and endothelial cells (ECs) to regulate their metabolic activity and function. As endothelial dysfunction occurs after HS, the roles CD226 plays in vascular EC metabolism were investigated. CD226fl/fl Tekcre mice were adopted to achieve vascular EC-specific knockout of CD226, and subjected to HS modelling. Serum levels of crucial intermediate metabolites were evaluated through liquid chromatography-mass spectrometry analysis. Human umbilical vein ECs (HUVECs) were used to study the effects of CD226 under hypoxia in vitro. Seahorse analysis evaluated the cellular glycolysis and mitochondria bioenergetics. Results showed that CD226 deficiency in vascular ECs alleviated HS-induced intestinal damage and inflammatory response in mice. Animal studies indicated an improved energy metabolism when CD226 was knocked out in ECs after HS, as evidenced by enhanced glutamine-glutamate metabolism and decreased lactic acid levels. Glut-1 was upregulated in mouse vascular ECs after HS and HUVECs under hypoxia, combined with decreased CD226. Moreover, HUVECs with CD226 knockdown exhibited relieved mitochondrial damage and early apoptosis under hypoxia, whereas CD226 overexpression showed opposite effects. Seahorse analysis showed that downregulated CD226 significantly increased mitochondrial ATP production and glucose uptake in HUVECs under hypoxia. Additionally, Erk/PHD2 signaling-mediated HIF-1α/Glut-1 and HIF-2α/ASCT2 pathways were involved in CD226 regulation on HUVEC glutaminolysis after hypoxia. Hence, CD226 deficiency promotes bypass energy supply to vascular ECs under ischemic or hypoxic stress, to ameliorate the stress-mediated metabolic disturbance.
    Keywords:  CD226; HUVEC; energy metabolism; hemorrhagic shock; hypoxia
    DOI:  https://doi.org/10.1096/fj.202101134R
  6. Biomedicines. 2021 Sep 29. pii: 1354. [Epub ahead of print]9(10):
    Inhibition of Prolyl Oligopeptidase Prevents Consequences of Reperfusion following Intestinal Ischemia.
    Alessia Filippone, Giovanna Casili, Alessio Ardizzone, Marika Lanza, Deborah Mannino, Irene Paterniti, Emanuela Esposito, Michela Campolo.
      BACKGROUND: Intestinal ischemia/reperfusion injury (IRI) remains a clinical event that contributes to high morbidity and mortality rates. Intestinal epithelium is exposed to histological and vascular changes following tissue ischemia. Prolyl endopeptidase (PREP), involved in inflammatory responses, could be targeted for recovery from the permanent consequences following intestinal ischemia. Our aim was to investigate the role of PREP inhibitor KYP-2047 in tissue damage, angiogenesis, and endothelial barrier permeability after intestinal IRI in mice.METHODS: KYP-2047 treatments were performed 5 min prior to intestinal damage. Intestinal IRI was induced in mice by clamping the superior mesenteric artery and the celiac trunk for 30 min, followed by 1 h of reperfusion.
    RESULTS: PREP inhibition by KYP-2047 treatment reduced intestinal IR-induced histological damage and neutrophil accumulation, limiting inflammation through decrease of NF-ĸB nuclear translocation and fibrotic processes. KYP-2047 treatment restored barrier permeability and structural alteration following intestinal IRI, attenuating neovascular processes compromised by ischemia/reperfusion. Additionally, loss of epithelial cells during intestinal ischemia occurring by apoptosis was limited by KYP-2047 treatment, which showed strong effects counteracting apoptosis and DNA damage.
    CONCLUSIONS: These findings provide the first evidence that PREP inhibition through KYP-2047 inhibitor use could be a validate strategy for resolving alterations of intestinal epithelium the pathophysiology of intestinal disease.
    Keywords:  angiogenesis; apoptosis; inflammation; intestinal barrier permeability; intestinal ischemia/reperfusion injury
    DOI:  https://doi.org/10.3390/biomedicines9101354
  7. Antioxidants (Basel). 2021 Oct 15. pii: 1624. [Epub ahead of print]10(10):
    Histochrome Attenuates Myocardial Ischemia-Reperfusion Injury by Inhibiting Ferroptosis-Induced Cardiomyocyte Death.
    Ji-Won Hwang, Jae-Hyun Park, Bong-Woo Park, Hyeok Kim, Jin-Ju Kim, Woo-Sup Sim, Natalia P Mishchenko, Sergey A Fedoreyev, Elena A Vasileva, Kiwon Ban, Hun-Jun Park, Sang-Hong Baek.
      Reactive oxygen species (ROS) and intracellular iron levels are critical modulators of lipid peroxidation that trigger iron-dependent non-apoptotic ferroptosis in myocardial ischemia-reperfusion (I/R) injury. Histochrome (HC), with a potent antioxidant moiety and iron-chelating capacity, is now available in clinical practice. However, limited data are available about the protective effects of HC on ferroptotic cell death in myocardial I/R injury. In this study, we investigated whether the intravenous administration of HC (1 mg/kg) prior to reperfusion could decrease myocardial damage by reducing ferroptosis. Rats undergoing 60 min of ischemia and reperfusion were randomly divided into three groups as follows: (1) Sham, (2) I/R control, and (3) I/R + HC. Serial echocardiography up to four weeks after I/R injury showed that intravenous injection of HC significantly improved cardiac function compared to the I/R controls. In addition, the hearts of rats who received intravenous injection of HC exhibited significantly lower cardiac fibrosis and higher capillary density. HC treatment decreased intracellular and mitochondrial ROS levels by upregulating the expression of nuclear factor erythroid 2-related factor (Nrf2) and its downstream genes. HC also inhibited erastin- and RSL3-induced ferroptosis in rat neonatal cardiomyocytes by maintaining the intracellular glutathione level and through upregulated activity of glutathione peroxidase 4. These findings suggest that early intervention with HC before reperfusion rescued myocardium from I/R injury by preventing ferroptotic cell death. Therefore, HC is a promising therapeutic option to provide secondary cardioprotection in patients who undergo coronary reperfusion therapy.
    Keywords:  anti-ferroptosis; cardioprotection; histochrome; iron-chelating; ischemia-reperfusion injury
    DOI:  https://doi.org/10.3390/antiox10101624
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