bims-heshmo 2022-01-16 papers

bims-heshmo

Biomed News

on Trauma hemorrhagic shock — molecular basis

Issue of 2022–01–16
thirteen papers selected by
Andreia Luís, Ludwig Boltzmann Institute

Tranexamic acid for major trauma patients in Ireland.
Down-regulation of TRPM2 attenuates hepatic ischemia/reperfusion injury through activation of autophagy and inhibition of NLRP3 inflammasome pathway.
Impaired Glucocorticoid Receptor Signaling Aggravates Lung Injury after Hemorrhagic Shock.
TNF-α Induces Neutrophil Apoptosis Delay and Promotes Intestinal Ischemia-Reperfusion-Induced Lung Injury through Activating JNK/FoxO3a Pathway.
Multi-omic analysis in injured humans: Patterns align with outcomes and treatment responses.
Changes and significance of serum troponin in trauma patients: A retrospective study in a level I trauma center.
PAR1, a therapeutic target for remote lung injury associated with hind limb ischemia/reperfusion: ERK5/KLF2-dependent lung capillary barrier preservation.
Management of Coagulopathy in Bleeding Patients.
Preparation and characterization of tranexamic acid modified porous starch and its application as a hemostatic agent.
Pathophysiology of Hemorrhage as It Relates to the Warfighter.
Temporal Roles of Platelet and Coagulation Pathways in Collagen- and Tissue Factor-Induced Thrombus Formation.
Adaptive differentiation promotes intestinal villus recovery.
The transcription factor HIF-1α mediates plasticity of NKp46+ innate lymphoid cells in the gut.

World J Emerg Med. 2022 ;13(1): 11-17

Tranexamic acid for major trauma patients in Ireland.

Kieran Walsh, Francis O'Keeffe, Louise Brent, Biswadev Mitra.

   BACKGROUND: The Clinical Randomisation of an Anti-fibrinolytic in Significant Hemorrhage-2 (CRASH-2) is the largest randomized control trial (RCT) examining circulatory resuscitation for trauma patients to date and concluded a statistically significant reduction in all-cause mortality in patients administered tranexamic acid (TXA) within 3 hours of injury. Since the publication of CRASH-2, significant geographical variance in the use of TXA for trauma patients exists. This study aims to assess TXA use for major trauma patients with hemorrhagic shock in Ireland after the publication of CRASH-2.
METHODS: A retrospective cohort study was conducted using data derived from the Trauma Audit and Research Network (TARN). All injured patients in Ireland between January 2013 and December 2018 who had evidence of hemorrhagic shock on presentation (as defined by systolic blood pressure [SBP] <100 mmHg [1 mmHg=0.133 kPa] and administration of blood products) were eligible for inclusion. Death at hospital discharge was the primary outcome.
RESULTS: During the study period, a total of 234 patients met the inclusion criteria. Among injured patients presenting with hemorrhagic shock, 133 (56.8%; 95% confidence interval [CI] 50.2%-63.3%) received TXA. Of patients that received TXA, a higher proportion of patients presented with shock index >1 (70.68% vs.57.43%) and higher Injury Severity Score (ISS >25; 49.62% vs. 23.76%). Administration of TXA was not associated with mortality at hospital discharge (odds ratio [OR] 0.86, 95% CI 0.31-2.38).
CONCLUSIONS: Among injured Irish patients presenting with hemorrhagic shock, TXA was administered to 56.8% of patients. Patients administered with TXA were on average more severely injured. However, a mortality benefit could not be demonstrated.

Keywords:  Hemorrhage; Ireland; Shock; Tranexamic acid

DOI:  https://doi.org/10.5847/wjem.j.1920-8642.2022.003
Int Immunopharmacol. 2022 Jan 10. pii: S1567-5769(21)01079-1. [Epub ahead of print]104 108443

Down-regulation of TRPM2 attenuates hepatic ischemia/reperfusion injury through activation of autophagy and inhibition of NLRP3 inflammasome pathway.

Tao Zhang, Wenqi Huang, Yi Ma.

   AIM: Hepatic ischemia/reperfusion (I/R) injury is a significant pathological process that contributes to high morbidity and mortality rates, although the underlying mechanism is unknown. Recent studies have shown that transient receptor potential melastatin 2 (TRPM2) plays a critical role in organ I/R injury, but the exact mechanism is elusive. This study investigates the role and mechanism of TPRM2 in hepatic I/R injury and oxygen-glucosedeprivation/reoxygenation (OGD/R) induced hepatocyte injury.
METHODS: We evaluated the effects of TRPM2 on hepatic I/R injury using a knockout mouse model of hepatic I/R. In a model of OGD/R in hepatocytes, we investigated the mechanism of TPRM2 in it using the autophagy agonist and inhibitor and an NLRP3 inhibitor.
RESULTS: We discovered that knockout of TRPM2 protected against hepatic I/R accompanied by autophagy activation and NLRP3 inflammasome pathway inhibition. Furthermore, increasing autophagy attenuated OGD/R-induced cell injury and knockdown of TRPM2 alleviated the injury by activating autophagy. Additionally, we detected the expression of NLRP3 inflammasome pathway in the OGD/R-induced hepatocytes which had been treated with the autophagy agonist and inhibitor, and found that autophagy negatively regulated the NLRP3 inflammasome pathway. Moreover, we discovered that the administration of NLRP3-inhibitor INF39 increased cell viability and caused a decline in cell death in the OGD/R-treated hepatocytes.
CONCLUSIONS: Downregulation of TRPM2 protected the liver against I/R injury and OGD/R induced injury, mediated by autophagy activation and inhibition of the NLRP3 inflammasome pathway, whereas autophagy negatively regulated the NLRP3 inflammasome pathway in this process.

Keywords:  Autophagy; Hepatic ischemia/reperfusion injury; NLRP3 inflammasome; Transient receptor potential melastatin 2

DOI:  https://doi.org/10.1016/j.intimp.2021.108443
Cells. 2021 Dec 30. pii: 112. [Epub ahead of print]11(1):

Impaired Glucocorticoid Receptor Signaling Aggravates Lung Injury after Hemorrhagic Shock.

Jonathan M Preuss, Ute Burret, Michael Gröger, Sandra Kress, Angelika Scheuerle, Peter Möller, Jan P Tuckermann, Martin Wepler, Sabine Vettorazzi.

  We previously showed that attenuated lung injury after hemorrhagic shock (HS) coincided with enhanced levels of the glucocorticoid (GC) receptor (GR) in lung tissue of swine. Here, we investigated the effects of impaired GR signaling on the lung during resuscitated HS using a dysfunctional GR mouse model (GRdim/dim). In a mouse intensive care unit, HS led to impaired lung mechanics and aggravated lung inflammation in GRdim/dim mice compared to wildtype mice (GR+/+). After HS, high levels of the pro-inflammatory and pro-apoptotic transcription factor STAT1/pSTAT1 were found in lung samples from GRdim/dim mice. Lungs of GRdim/dim mice revealed apoptosis, most likely as consequence of reduced expression of the lung-protective Angpt1 compared to GR+/+ after HS. RNA-sequencing revealed increased expression of pro-apoptotic and cytokine-signaling associated genes in lung tissue of GRdim/dim mice. Furthermore, high levels of pro-inflammatory cytokines and iNOS were found in lungs of GRdim/dim mice. Our results indicate impaired repression of STAT1/pSTAT1 due to dysfunctional GR signaling in GRdim/dim mice, which leads to increased inflammation and apoptosis in the lungs. These data highlight the crucial role of functional GR signaling to attenuate HS-induced lung damage.

Keywords:  glucocorticoid receptor; hemorrhagic shock; homodimer; resuscitation

DOI:  https://doi.org/10.3390/cells11010112
Oxid Med Cell Longev. 2021 ;2021 8302831

TNF-α Induces Neutrophil Apoptosis Delay and Promotes Intestinal Ischemia-Reperfusion-Induced Lung Injury through Activating JNK/FoxO3a Pathway.

Daili Chen, Chaojin Chen, Xue Xiao, Ziyan Huang, Xiaolei Huang, Weifeng Yao.

Background: Intestinal ischemia is a common clinical critical illness. Intestinal ischemia-reperfusion (IIR) leads to acute lung injury (ALI), but the causative factors of ALI are unknown. The aim of this study was to reveal the causative factors and mechanisms of IIR-induced lung injury.
Methods: A mouse model of IIR was developed using C57BL/6 mice, followed by detection of lung injury status and plasma levels of inflammatory factors in sham-operated mice and model mice. Some model mice were treated with a tumor necrosis factor-α (TNF-α) inhibitor lenalidomide (10 mg/kg), followed by observation of lung injury status through hematoxylin and eosin staining and detection of neutrophil infiltration levels through naphthol esterase and Ly6G immunohistochemical staining. Additionally, peripheral blood polymorphonuclear neutrophils (PMNs) were cultured in vitro and then stimulated by TNF-α to mimic in vivo inflammatory stimuli; this TNF-α stimulation was also performed on PMNs after knockdown of FoxO3a or treatment with the c-Jun N-terminal kinase (JNK) inhibitor SP600125. PMN apoptosis after stimulation was detected using flow cytometry. Finally, the role of PMN apoptosis in IIR-induced lung injury was evaluated in vivo by detecting the ALI status in the model mice administered with ABT-199, a Bcl-2 inhibitor.
Results: IIR led to pulmonary histopathological injury and increased lung water content, which were accompanied by increased plasma levels of inflammatory factors, with the TNF-α plasma level showing the most pronounced increase. Inhibition of TNF-α led to effective reduction of lung tissue injury, especially that of the damaging infiltration of PMNs in the lung. In vitro knockdown of FoxO3a or inhibition of JNK activity could inhibit TNF-α-induced PMN apoptosis. Further in vivo experiments revealed that ABT-199 effectively alleviated lung injury and decreased inflammation levels by promoting PMN apoptosis during IIR-induced lung injury.
Conclusion: TNF-α activates the JNK/FoxO3a pathway to induce a delay in PMN apoptosis, which promotes IIR-induced lung injury.

DOI: https://doi.org/10.1155/2021/8302831
Cell Rep Med. 2021 Dec 21. 2(12): 100478

Multi-omic analysis in injured humans: Patterns align with outcomes and treatment responses.

PAMPer study group

  Trauma is a leading cause of death and morbidity worldwide. Here, we present the analysis of a longitudinal multi-omic dataset comprising clinical, cytokine, endotheliopathy biomarker, lipidome, metabolome, and proteome data from severely injured humans. A "systemic storm" pattern with release of 1,061 markers, together with a pattern suggestive of the "massive consumption" of 892 constitutive circulating markers, is identified in the acute phase post-trauma. Data integration reveals two human injury response endotypes, which align with clinical trajectory. Prehospital thawed plasma rescues only endotype 2 patients with traumatic brain injury (30-day mortality: 30.3 versus 75.0%; p = 0.0015). Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) was identified as the most predictive circulating biomarker to identify endotype 2-traumatic brain injury (TBI) patients. These response patterns refine the paradigm for human injury, while the datasets provide a resource for the study of critical illness, trauma, and human stress responses.

Keywords:  PAMPer trial; endotype; host response; metabolomics; multi-omics; outcome; proteomics; systemic storm; thawed plasma; trauma

DOI:  https://doi.org/10.1016/j.xcrm.2021.100478
World J Emerg Med. 2022 ;13(1): 27-31

Changes and significance of serum troponin in trauma patients: A retrospective study in a level I trauma center.

Li-Wen Dou, Zhe Du, Ji-Hong Zhu, Tian-Bing Wang.

   BACKGROUND: Elevated troponin I (TnI) is common among trauma patients. TnI is an indicator of myocardial injury, but clinical diagnosis of blunt cardiac injury cannot be based solely on an increase in TnI. Therefore, this study aims to explore the changes and clinical significance of serum TnI in trauma patients.
METHODS: The clinical data of consecutive trauma patients admitted to our trauma center between July 1, 2017 and July 31, 2020 were retrospectively analyzed. According to TnI levels within 24 hours of admission, patients were divided into the elevated and normal TnI groups. According to the TnI levels after 7 days of admission, a graph depicting a change in trend was drawn and then analyzed whether TnI was related to in-hospital mortality.
RESULTS: A total of 166 patients (69 and 97 cases with elevated and normal TnI, respectively) were included in this study. The average hospital stay, intensive care time, mechanical ventilation time, and in-hospital mortality were higher in the elevated TnI group than in the normal TnI group (P<0.05). The TnI level of trauma patients gradually increased after admission and peaked at 48 hours (7.804±1.537 ng/mL). Subsequently, it decreased, and then recovered to normal within 7 days. However, 13 patients did not recover. Logistic regression analysis revealed that abnormal TnI at 7 days was independently related to in-hospital mortality.
CONCLUSIONS: Trauma patients with elevated TnI levels may have a worse prognosis. Monitoring the changes in serum TnI is important, which can reflect the prognosis better than the TnI measured immediately after admission.

Keywords:  Blunt cardiac injury; Electrocardiography; Trauma; Troponin I

DOI:  https://doi.org/10.5847/wjem.j.1920-8642.2022.016
Chem Biol Interact. 2022 Jan 11. pii: S0009-2797(22)00014-X. [Epub ahead of print] 109809

PAR1, a therapeutic target for remote lung injury associated with hind limb ischemia/reperfusion: ERK5/KLF2-dependent lung capillary barrier preservation.

Nada M Kamel, Dalia M El-Tanbouly, Dalaal M Abdallah, Helmy M Sayed.

  Protease-activated receptor 1 (PAR1) is expressed in pneumocytes and endothelial cells of the alveolar barrier. Its activation by thrombin disrupts the barrier integrity dynamics and induces lung injury in in vitro and in vivo paradigms. Nonetheless, the role of PAR1, as a therapeutic target, in hind limb ischemia/reperfusion (I/R)-mediated remote lung injury has been unclear. Therefore, this study aimed to determine the potential benefit of PAR1 blockade using the selective antagonist SCH79797 in distant lung dysfunction following hind limb I/R injury with special emphasis on the extracellular signal-regulated kinase 5 (ERK5)/Krüppel-like factor 2 (KLF2) axis. Rats were subdivided into control, bilateral hind limb I/R, SCH79797, and SCH79797+BIX02189 (ERK5 inhibitor) groups. PAR1 blockade, ERK5-dependently, alleviated alveolar barrier disruption as evidenced by reductions in both pulmonary systemic leakage of surfactant protein-D and lung fluid accumulation with increase in pulmonary claudin 5, vascular endothelial cadherin, and connexin 37 levels. Such improvements are downstream targets of the ERK5/KLF2-mediated sphingosine-1-phosphate receptor 1 (S1PR1) upregulated expression and pS536-nuclear factor-κB (NF-κB) p65 inhibition. SCH79797 effectively impedes the evoked inflammatory response and oxidative burst by suppressing vascular endothelial growth factor, tumor necrosis factor-α, lipid peroxidation, and neutrophil infiltration while boosting the glutathione antioxidant defense. Accordingly, PAR1 could be a therapeutic target, where its blockade mitigated pulmonary-endothelial barrier disruption via mutual S1PR1 enhancement and NF-κB p65 inhibition following ERK5/KLF2 activation.

Keywords:  Claudin 5; Connexin 37; Permeability; SCH79797; TNF-α; VE-cadherin

DOI:  https://doi.org/10.1016/j.cbi.2022.109809
J Clin Med. 2021 Dec 21. pii: 1. [Epub ahead of print]11(1):

Management of Coagulopathy in Bleeding Patients.

Stefan Hofer, Christoph J Schlimp, Sebastian Casu, Elisavet Grouzi.

  Early recognition of coagulopathy is necessary for its prompt correction and successful management. Novel approaches, such as point-of-care testing (POC) and administration of coagulation factor concentrates (CFCs), aim to tailor the haemostatic therapy to each patient and thus reduce the risks of over- or under-transfusion. CFCs are an effective alternative to ratio-based transfusion therapies for the correction of different types of coagulopathies. In case of major bleeding or urgent surgery in patients treated with vitamin K antagonist anticoagulants, prothrombin complex concentrate (PCC) can effectively reverse the effects of the anticoagulant drug. Evidence for PCC effectiveness in the treatment of direct oral anticoagulants-associated bleeding is also increasing and PCC is recommended in guidelines as an alternative to specific reversal agents. In trauma-induced coagulopathy, fibrinogen concentrate is the preferred first-line treatment for hypofibrinogenaemia. Goal-directed coagulation management algorithms based on POC results provide guidance on how to adjust the treatment to the needs of the patient. When POC is not available, concentrate-based management can be guided by other parameters, such as blood gas analysis, thus providing an important alternative. Overall, tailored haemostatic therapies offer a more targeted approach to increase the concentration of coagulation factors in bleeding patients than traditional transfusion protocols.

Keywords:  acquired coagulopathy; anticoagulation reversal; coagulation factor concentrate; goal-directed coagulation management; haemostasis; viscoelastic testing

DOI:  https://doi.org/10.3390/jcm11010001
Int J Biol Macromol. 2022 Jan 07. pii: S0141-8130(21)02824-5. [Epub ahead of print]200 273-284

Preparation and characterization of tranexamic acid modified porous starch and its application as a hemostatic agent.

Xinhong Zhao, Yunbo Sun, Zhiyun Meng, Zhiyuan Yang, Shan Fan, Tong Ye, Lei Yang, Tong Li, Ruolan Gu, Zhuona Wu, Hui Gan, Guifang Dou, Yongxiu Qi, Shuchen Liu.

  Effective bleeding control is essential for the reduction of traumatic deaths among civilians and military personnel, particularly for physical visceral and arteriovenous injuries. Materials with good hemostatic properties have recently attracted significant scientific attention. In this study, a novel material of tranexamic acid modified porous starch (TAMPS) was produced through esterification. The structure of the final product was characterized using Fourier-transform infrared spectroscopy, X-ray diffraction, scanning electron microscopy, and thermogravimetric analysis. The hemostatic effect of TAMPS was preliminarily analyzed via in vitro clotting time, mouse tail amputation model and liver injury model experiments. Hemostatic effect of TAMPS was found to be significantly better than that of the positive control Quickclean. Through the exploration of related hemostatic mechanisms, TAMPS can promote coagulation via rapid fluid absorption and high erythrocyte aggregation capacity. The in vitro cytotoxicity, acute toxicity, and hemolysis tests revealed that TAMPS is safe and nontoxic and has perfect blood compatibility. Therefore, the TAMPS has a great potential for future clinical application as a rapid and multitarget hemostatic material.

Keywords:  Esterification; Hemostasis; Starch

DOI:  https://doi.org/10.1016/j.ijbiomac.2021.12.180
Physiology (Bethesda). 2022 Jan 10.

Pathophysiology of Hemorrhage as It Relates to the Warfighter.

Carmen Hinojosa-Laborde, Ian L Hudson, Evan Ross, Lusha Xiang, Kathy L Ryan.

  Saving lives of wounded military Warfighters often depends on the ability to resolve or mitigate the pathophysiology of hemorrhage, specifically diminished oxygen delivery to vital organs that leads to multi-organ failure and death. However, caring for hemorrhaging patients on the battlefield presents unique challenges that extend beyond applying a tourniquet and giving a blood transfusion, especially when battlefield care must be provided for a prolonged period. This review will describe these challenges and potential strategies for treating hemorrhage on the battlefield in a prolonged casualty care situation.

Keywords:  battlefield; hemorrhage; prolonged casualty care; trauma

DOI:  https://doi.org/10.1152/physiol.00028.2021
Int J Mol Sci. 2021 Dec 29. pii: 358. [Epub ahead of print]23(1):

Temporal Roles of Platelet and Coagulation Pathways in Collagen- and Tissue Factor-Induced Thrombus Formation.

Stefano Navarro, David Stegner, Bernhard Nieswandt, Johan W M Heemskerk, Marijke J E Kuijpers.

  In hemostasis and thrombosis, the complex process of thrombus formation involves different molecular pathways of platelet and coagulation activation. These pathways are considered as operating together at the same time, but this has not been investigated. The objective of our study was to elucidate the time-dependency of key pathways of thrombus and clot formation, initiated by collagen and tissue factor surfaces, where coagulation is triggered via the extrinsic route. Therefore, we adapted a microfluidics whole-blood assay with the Maastricht flow chamber to acutely block molecular pathways by pharmacological intervention at desired time points. Application of the technique revealed crucial roles of glycoprotein VI (GPVI)-induced platelet signaling via Syk kinase as well as factor VIIa-induced thrombin generation, which were confined to the first minutes of thrombus buildup. A novel anti-GPVI Fab EMF-1 was used for this purpose. In addition, platelet activation with the protease-activating receptors 1/4 (PAR1/4) and integrin αIIbβ3 appeared to be prolongedly active and extended to later stages of thrombus and clot formation. This work thereby revealed a more persistent contribution of thrombin receptor-induced platelet activation than of collagen receptor-induced platelet activation to the thrombotic process.

Keywords:  coagulation; fibrin; glycoprotein VI; platelet receptors; spatiotemporal thrombus; thrombin

DOI:  https://doi.org/10.3390/ijms23010358
Dev Cell. 2022 Jan 03. pii: S1534-5807(21)01032-7. [Epub ahead of print]

Adaptive differentiation promotes intestinal villus recovery.

Takahiro E Ohara, Marco Colonna, Thaddeus S Stappenbeck.

  Loss of differentiated cells to tissue damage is a hallmark of many diseases. In slow-turnover tissues, long-lived differentiated cells can re-enter the cell cycle or transdifferentiate to another cell type to promote repair. Here, we show that in a high-turnover tissue, severe damage to the differentiated compartment induces progenitors to transiently acquire a unique transcriptional and morphological postmitotic state. We highlight this in an acute villus injury model in the mouse intestine, where we identified a population of progenitor-derived cells that covered injured villi. These atrophy-induced villus epithelial cells (aVECs) were enriched for fetal markers but were differentiated and lineage committed. We further established a role for aVECs in maintaining barrier integrity through the activation of yes-associated protein (YAP). Notably, loss of YAP activity led to impaired villus regeneration. Thus, we define a key repair mechanism involving the activation of a fetal-like program during injury-induced differentiation, a process we term "adaptive differentiation."

Keywords:  Hippo; YAP; adaptive differentiation; enteropathy; injury-repair; intestine; poly(I:C); regeneration; single-cell RNA sequencing; villus atrophy

DOI:  https://doi.org/10.1016/j.devcel.2021.12.012
J Exp Med. 2022 Feb 07. pii: e20210909. [Epub ahead of print]219(2):

The transcription factor HIF-1α mediates plasticity of NKp46+ innate lymphoid cells in the gut.

Ewelina Krzywinska, Michal Sobecki, Shunmugam Nagarajan, Julian Zacharjasz, Murtaza M Tambuwala, Abigaelle Pelletier, Eoin Cummins, Dagmar Gotthardt, Joachim Fandrey, Yann M Kerdiles, Carole Peyssonnaux, Cormac T Taylor, Veronika Sexl, Christian Stockmann.

Gut innate lymphoid cells (ILCs) show remarkable phenotypic diversity, yet microenvironmental factors that drive this plasticity are incompletely understood. The balance between NKp46+, IL-22-producing, group 3 ILCs (ILC3s) and interferon (IFN)-γ-producing group 1 ILCs (ILC1s) contributes to gut homeostasis. The gut mucosa is characterized by physiological hypoxia, and adaptation to low oxygen is mediated by hypoxia-inducible transcription factors (HIFs). However, the impact of HIFs on ILC phenotype and gut homeostasis is not well understood. Mice lacking the HIF-1α isoform in NKp46+ ILCs show a decrease in IFN-γ-expressing, T-bet+, NKp46+ ILC1s and a concomitant increase in IL-22-expressing, RORγt+, NKp46+ ILC3s in the gut mucosa. Single-cell RNA sequencing revealed HIF-1α as a driver of ILC phenotypes, where HIF-1α promotes the ILC1 phenotype by direct up-regulation of T-bet. Loss of HIF-1α in NKp46+ cells prevents ILC3-to-ILC1 conversion, increases the expression of IL-22-inducible genes, and confers protection against intestinal damage. Taken together, our results suggest that HIF-1α shapes the ILC phenotype in the gut.

DOI: https://doi.org/10.1084/jem.20210909