Molecular Mechanisms and Therapeutics in Hemorrhagic Shock

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: closed (10 November 2024) | Viewed by 12165

Special Issue Editor

1. Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA
2. Department of Molecular Medicine, Zucker School of Medicine, Hempstead, NY 11549, USA
3. Elmezzi Graduate School of Molecular Medicine at Northwell Health, Manhasset, NY 11030, USA
Interests: hemorrhagic shock; ischemia-reperfusion injury; acute inflammation; shock therapeutics; therapeutic mechanisms

Special Issue Information

Dear Colleagues,

Hemorrhagic shock, a severe form of hypovolemic shock resulting from significant blood loss, poses a substantial global health burden with high mortality rates. Despite well-established medical interventions, trauma-related hemorrhagic shock has resulted in the loss of more than 75 million lives globally among young individuals. Beyond the cessation of bleeding, hemorrhagic shock progressed into a state of hypoperfusion-induced hypoxia, exacerbating tissue damage and systemic ischemia-reperfusion injury upon subsequent fluid resuscitation. This cascade of events triggers the release of inflammatory cytokines, initiating an inflammatory response that contributes to multi-organ dysfunction or even failure. Consequently, survivors of trauma-induced hemorrhage often face diminished functional outcomes and increased long-term mortality due to the lingering effects of this inflammatory response. Despite significant efforts to understand the pathogenesis of hemorrhagic shock, precise molecular mechanisms and effective treatments remain elusive. This Special Issue titled “Molecular Mechanisms and Therapeutics in Hemorrhagic Shock”, curated by Dr. Jacob, aims to shed light on the intricate molecular mechanism underlying the pathogenesis of hemorrhagic shock and explore potential therapeutic interventions. The scope of research covered in this Special Issue encompasses various organs affected by hemorrhagic shock, including the heart, lungs, liver, and kidneys. By collating contributions from diverse researchers, this Special Issue aims to foster a deeper understanding of hemorrhagic shock pathophysiology and facilitate the development of targeted therapeutic approaches to mitigate its devastating effects.

Dr. Asha Jacob
Guest Editor

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Keywords

  • hemorrhagic shock
  • trauma-induced hemorrhage
  • ischemia-reperfusion injury
  • immune response
  • shock therapeutics and their mechanisms
  • systemic inflammatory response
  • multi-organ dysfunction
  • tissue damage
  • organ injury
  • mitochondrial dysfunction

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Published Papers (6 papers)

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Research

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15 pages, 4108 KiB  
Article
Humanin-G Ameliorates Hemorrhage-Induced Acute Lung Injury in Mice Through AMPKα1-Dependent and -Independent Mechanisms
by Allison M. Amman, Vivian Wolfe, Giovanna Piraino, Assem Ziady and Basilia Zingarelli
Biomedicines 2024, 12(11), 2615; https://doi.org/10.3390/biomedicines12112615 - 15 Nov 2024
Viewed by 1038
Abstract
Background/Objectives: The severity of acute lung injury is significantly impacted by age and sex in patients with hemorrhagic shock. AMP-activated protein kinase (AMPK) is a crucial regulator of energy metabolism but its activity declines with aging. Humanin is a mitochondrial peptide that [...] Read more.
Background/Objectives: The severity of acute lung injury is significantly impacted by age and sex in patients with hemorrhagic shock. AMP-activated protein kinase (AMPK) is a crucial regulator of energy metabolism but its activity declines with aging. Humanin is a mitochondrial peptide that exerts cytoprotective effects in response to oxidative stressors and is associated with longevity. Using a mouse model of hemorrhagic shock that mimics the clinical condition of adult patients, we investigated whether treatment with a humanin analog, humanin-G, mitigates lung injury and whether its mechanisms of action are dependent on the catalytic AMPKα1 subunit activation. Methods: Male and female AMPKα1 wild-type (WT) and knock-out (KO) mice (8–13 months old) were subjected to hemorrhagic shock by blood withdrawal, followed by resuscitation with shed blood and lactated Ringer’s solution. The mice were treated with PEGylated humanin-G or vehicle and euthanized 3 h post-resuscitation. Results: Sex- and genotype-related differences were observed after hemorrhagic shock as lung neutrophil infiltration was more pronounced in the male AMPKα1 WT mice than the female WT mice; also, the male AMPKα1 KO mice experienced a significant decline in mean arterial blood pressure when compared to the male WT mice after resuscitation. The scores of histological lung injury were similarly elevated in all the male and female AMPKα1 WT and KO mice when compared to the control mice. At molecular analysis, acute lung injury was associated with the downregulation of AMPKα1/α2 catalytic subunits in the WT mice, whereas an increased activation of the signal transducer and activator of transcription-3 (STAT3) was observed in all the vehicle-treated groups. The in vivo administration of humanin-G ameliorated histological lung damage in all the groups of animals and ameliorated mean arterial blood pressure in the male AMPKα1 KO mice. The in vivo administration of humanin-G lowered lung neutrophil infiltration in the male and female AMPKα1 WT mice only but not in the KO mice. The beneficial results of humanin-G correlated with the lung cytosolic and nuclear activation of AMPKα in the male and female AMPKα1 WT groups, whereas STAT3 activation was not modified. Conclusions: In adult age, hemorrhage-induced acute lung injury manifests with sex-dependent characteristics. Humanin-G has therapeutic potential and the AMPKα1subunit is an important requisite for its inhibitory effects on lung leucosequestration, but not for the amelioration of lung alveolar structure or the hemodynamic effects of the peptide. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapeutics in Hemorrhagic Shock)
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15 pages, 1242 KiB  
Article
Metabolic Effects of Sodium Thiosulfate During Resuscitation from Trauma and Hemorrhage in Cigarette-Smoke-Exposed Cystathionine-γ-Lyase Knockout Mice
by Maximilian Feth, Felix Hezel, Michael Gröger, Melanie Hogg, Fabian Zink, Sandra Kress, Andrea Hoffmann, Enrico Calzia, Ulrich Wachter, Peter Radermacher and Tamara Merz
Biomedicines 2024, 12(11), 2581; https://doi.org/10.3390/biomedicines12112581 - 12 Nov 2024
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Abstract
Background: Acute and chronic pre-traumatic cigarette smoke exposure increases morbidity and mortality after trauma and hemorrhage. In mice with a genetic deletion of the H2S-producing enzyme cystathione-γ-lyase (CSE−/−), providing exogenous H2S using sodium thiosulfate (Na2S [...] Read more.
Background: Acute and chronic pre-traumatic cigarette smoke exposure increases morbidity and mortality after trauma and hemorrhage. In mice with a genetic deletion of the H2S-producing enzyme cystathione-γ-lyase (CSE−/−), providing exogenous H2S using sodium thiosulfate (Na2S2O3) improved organ function after chest trauma and hemorrhagic shock. Therefore, we evaluated the effect of Na2S2O3 during resuscitation from blunt chest trauma and hemorrhagic shock on CSE−/− mice with pre-traumatic cigarette smoke (CS) exposure. Since H2S is well established as being able to modify energy metabolism, a specific focus was placed on whole-body metabolic pathways and mitochondrial respiratory activity. Methods: Following CS exposure, the CSE−/− mice underwent anesthesia, surgical instrumentation, blunt chest trauma, hemorrhagic shock for over 1 h (target mean arterial pressure (MAP) ≈ 35 ± 5 mmHg), and resuscitation for up to 8 h comprising lung-protective mechanical ventilation, the re-transfusion of shed blood, fluid resuscitation, and continuous i.v. noradrenaline (NoA) to maintain an MAP ≥ 55 mmHg. At the start of the resuscitation, the mice randomly received either i.v. Na2S2O3 (0.45 mg/gbodyweight; n = 14) or the vehicle (NaCl 0.9%; n = 11). In addition to the hemodynamics, lung mechanics, gas exchange, acid–base status, and organ function, we quantified the parameters of carbohydrate, lipid, and protein metabolism using a primed continuous infusion of stable, non-radioactive, isotope-labeled substrates (gas chromatography/mass spectrometry) and the post-mortem tissue mitochondrial respiratory activity (“high-resolution respirometry”). Results: While the hemodynamics and NoA infusion rates did not differ, Na2S2O3 was associated with a trend towards lower static lung compliance (p = 0.071) and arterial PO2 (p = 0.089) at the end of the experiment. The direct, aerobic glucose oxidation rate was higher (p = 0.041) in the Na2S2O3-treated mice, which resulted in lower glycemia levels (p = 0.050) and a higher whole-body CO2 production rate (p = 0.065). The mitochondrial respiration in the heart, kidney, and liver tissue did not differ. While the kidney function was comparable, the Na2S2O3-treated mice showed a trend towards a shorter survival time (p = 0.068). Conclusions: During resuscitation from blunt chest trauma and hemorrhagic shock in CSE−/− mice with pre-traumatic CS exposure, Na2S2O3 was associated with increased direct, aerobic glucose oxidation, suggesting a switch in energy metabolism towards preferential carbohydrate utilization. Nevertheless, treatment with Na2S2O3 coincided with a trend towards worsened lung mechanics and gas exchange, and, ultimately, shorter survival. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapeutics in Hemorrhagic Shock)
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12 pages, 1428 KiB  
Communication
β-Adrenoceptor Agonists Attenuate Thrombin-Induced Impairment of Human Lung Endothelial Cell Barrier Function and Protect the Lung Vascular Barrier during Resuscitation from Hemorrhagic Shock
by Michelle Y. McGee, Ololade Ogunsina, Sadia N. Boshra, Xianlong Gao and Matthias Majetschak
Biomedicines 2024, 12(8), 1813; https://doi.org/10.3390/biomedicines12081813 - 9 Aug 2024
Viewed by 1300
Abstract
β-adrenoceptor (β-AR) agonists are known to antagonize thrombin-induced impairment (TII) of bovine and ovine lung endothelial barrier function. The effects of adrenoceptor agonists and other vasoactive agents on human lung microvascular endothelial cell (HULEC-5a) barrier function upon thrombin exposure have not been studied. [...] Read more.
β-adrenoceptor (β-AR) agonists are known to antagonize thrombin-induced impairment (TII) of bovine and ovine lung endothelial barrier function. The effects of adrenoceptor agonists and other vasoactive agents on human lung microvascular endothelial cell (HULEC-5a) barrier function upon thrombin exposure have not been studied. Furthermore, it is unknown whether the in vitro effects of adrenoceptor agonists translate to lung protective effects in vivo. We observed that epinephrine, norepinephrine, and phenylephrine enhanced normal and prevented TII of HULEC-5a barrier function. Arginine vasopressin and angiotensin II were ineffective. α1B-, α2A/B-, and β1/2-ARs were detectable in HULEC-5a by RT-PCR. Propranolol but not doxazosin blocked the effects of all adrenoceptor agonists. Phenylephrine stimulated β2-AR-mediated Gαs activation with 13-fold lower potency than epinephrine. The EC50 to inhibit TII of HULEC-5a barrier function was 1.8 ± 1.9 nM for epinephrine and >100 nM for phenylephrine. After hemorrhagic shock and fluid resuscitation in rats, Evans blue extravasation into the lung increased threefold (p < 0.01 vs. sham). Single low-dose (1.8 μg/kg) epinephrine administration at the beginning of resuscitation had no effects on blood pressure and reduced Evans blue extravasation by 60% (p < 0.05 vs. vehicle). Our findings confirm the effects of β-adrenoceptor agonists in HULEC-5a and suggest that low-dose β-adrenoceptor agonist treatment protects lung vascular barrier function after traumatic hemorrhagic shock. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapeutics in Hemorrhagic Shock)
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Review

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19 pages, 995 KiB  
Review
Extracellular Cold-Inducible RNA-Binding Protein and Hemorrhagic Shock: Mechanisms and Therapeutics
by Naureen Rashid, Zhijian Hu, Asha Jacob and Ping Wang
Biomedicines 2025, 13(1), 12; https://doi.org/10.3390/biomedicines13010012 - 25 Dec 2024
Cited by 1 | Viewed by 882
Abstract
Hemorrhagic shock is a type of hypovolemic shock and a significant cause of trauma-related death worldwide. The innate immune system has been implicated as a key mediator in developing severe complications after shock. Inflammation from the innate immune system begins at the time [...] Read more.
Hemorrhagic shock is a type of hypovolemic shock and a significant cause of trauma-related death worldwide. The innate immune system has been implicated as a key mediator in developing severe complications after shock. Inflammation from the innate immune system begins at the time of initial insult; however, its activation is exaggerated, resulting in early and late-stage complications. Hypoxia and hypoperfusion lead to the release of molecules that act as danger signals known as damage-associated molecular patterns (DAMPs). DAMPs continue to circulate after shock, resulting in excess inflammation and tissue damage. We recently discovered that cold-inducible RNA-binding protein released into the extracellular space acts as a DAMP. During hemorrhagic shock, hypoperfusion leads to cell necrosis and the release of CIRP into circulation, triggering both systemic inflammation and local tissue damage. In this review, we discuss extracellular cold-inducible RNA-binding protein (eCIRP)’s role in sterile inflammation, as well as its various mechanisms of action. We also share our more newly developed anti-eCIRP agents with the eventual goal of producing drug therapies to mitigate organ damage, reduce mortality, and improve patient outcomes related to hemorrhagic shock. Finally, we suggest that future preclinical studies are required to develop the listed therapeutics for hemorrhagic shock and related conditions. In addition, we emphasize on the challenges to the translational phase and caution that the therapy should allow the immune system to continue to function well against secondary infections during hospitalization. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapeutics in Hemorrhagic Shock)
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11 pages, 879 KiB  
Review
The Intersection of Trauma and Immunity: Immune Dysfunction Following Hemorrhage
by Nicholas Salvo, Angel M. Charles and Alicia M. Mohr
Biomedicines 2024, 12(12), 2889; https://doi.org/10.3390/biomedicines12122889 - 19 Dec 2024
Cited by 1 | Viewed by 1364
Abstract
Hemorrhagic shock is caused by rapid loss of a significant blood volume, which leads to insufficient blood flow and oxygen delivery to organs and tissues, resulting in severe physiological derangements, organ failure, and death. Physiologic derangements after hemorrhage are due in a large [...] Read more.
Hemorrhagic shock is caused by rapid loss of a significant blood volume, which leads to insufficient blood flow and oxygen delivery to organs and tissues, resulting in severe physiological derangements, organ failure, and death. Physiologic derangements after hemorrhage are due in a large part to the body’s strong inflammatory response, which leads to severe immune dysfunction, and secondary complications such as chronic immunosuppression, increased susceptibility to infection, coagulopathy, multiple organ failure, and unregulated inflammation. Immediate management of hemorrhagic shock includes timely control of the source of bleeding, restoring intravascular volume, preferably with whole blood, and prevention of ischemia and organ failure by optimizing tissue oxygenation. However, currently, there are no clinically effective treatments available that can stabilize the immune response to hemorrhage and reinstate homeostatic conditions. In this review, we will discuss what is known about immunologic dysfunction following hemorrhage and potential therapeutic strategies. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapeutics in Hemorrhagic Shock)
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26 pages, 2291 KiB  
Review
Navigating Hemorrhagic Shock: Biomarkers, Therapies, and Challenges in Clinical Care
by Kenneth Meza Monge, Caleb Rosa, Christopher Sublette, Akshay Pratap, Elizabeth J. Kovacs and Juan-Pablo Idrovo
Biomedicines 2024, 12(12), 2864; https://doi.org/10.3390/biomedicines12122864 - 17 Dec 2024
Cited by 2 | Viewed by 5345
Abstract
Hemorrhagic shock remains a leading cause of preventable death worldwide, with mortality patterns varying significantly based on injury mechanisms and severity. This comprehensive review examines the complex pathophysiology of hemorrhagic shock, focusing on the temporal evolution of inflammatory responses, biomarker utility, and evidence-based [...] Read more.
Hemorrhagic shock remains a leading cause of preventable death worldwide, with mortality patterns varying significantly based on injury mechanisms and severity. This comprehensive review examines the complex pathophysiology of hemorrhagic shock, focusing on the temporal evolution of inflammatory responses, biomarker utility, and evidence-based therapeutic interventions. The inflammatory cascade progresses through distinct phases, beginning with tissue injury and endothelial activation, followed by a systemic inflammatory response that can transition to devastating immunosuppression. Recent advances have revealed pattern-specific responses between penetrating and blunt trauma, necessitating tailored therapeutic approaches. While damage control resuscitation principles and balanced blood product administration have improved outcomes, many molecular targeted therapies remain investigational. Current evidence supports early hemorrhage control, appropriate blood product ratios, and time-sensitive interventions like tranexamic acid administration. However, challenges persist in biomarker validation, therapeutic timing, and implementation of personalized treatment strategies. Future directions include developing precision medicine approaches, real-time monitoring systems, and novel therapeutic modalities while addressing practical implementation barriers across different healthcare settings. Success in hemorrhagic shock management increasingly depends on integrating multiple interventions across different time points while maintaining focus on patient-centered outcomes. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapeutics in Hemorrhagic Shock)
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