bims-heshmo 2021-08-22 papers

bims-heshmo

Biomed News

on Trauma hemorrhagic shock — molecular basis

Issue of 2021–08–22
eightteen papers selected by
Andreia Luís, Ludwig Boltzmann Institute

Prehospital evaluation and detection of induced coagulopathy in trauma: The PREDICT study.
The Story of Blood for Shock Resuscitation: How the Pendulum Swings.
WHOLE BLOOD RESUSCITATION RESTORES INTESTINAL PERFUSION AND INFLUENCES GUT MICROBIOME DIVERSITY.
Critical traumatic brain injury is associated with worse coagulopathy.
Safety and efficacy of thromboelastography guidance of antifibrinolytic therapy in trauma patients: An observational cohort analysis.
Trauma-induced pulmonary thromboembolism: What's update?
Therapeutic Potential of B-1a Cells in Intestinal Ischemia-reperfusion Injury.
Profiling the Expression of Circulating Acute-Phase Proteins, Cytokines, and Checkpoint Proteins in Patients with Severe Trauma: A Pilot Study.
The Influence of Macrophage-Activating Lipopeptide-2 in Regard to Liver-Specific Changes Within a Murine Two-Hit Model.
In vitro flow-based assay: From simple toward more sophisticated models for mimicking hemostasis and thrombosis.
miRNA-27a Transcription Activated by c-Fos Regulates Myocardial Ischemia-Reperfusion Injury by Targeting ATAD3a.
Hypoxic preconditioning protects against ischemic kidney injury through the IDO1/kynurenine pathway.
UBE2D3 contributes to myocardial ischemia-reperfusion injury by regulating autophagy in dependence of p62/SQSTM1.
Calcineurin-nuclear factor for activated T cells (NFAT) signaling in pathophysiology of wound healing.
Uridine treatment prevents myocardial injury in rat models of acute ischemia and ischemia/reperfusion by activating the mitochondrial ATP-dependent potassium channel.
Cx43 mediates changes in myofibroblast contraction and collagen release in human amniotic membrane defects after trauma.
The Doppler shock index measured by a wearable ultrasound patch accurately detects moderate-to-severe central hypovolemia during lower body negative pressure.
Extracellular vesicles from in vivo liver tissue accelerate recovery of liver necrosis induced by carbon tetrachloride.

J Trauma Acute Care Surg. 2021 Aug 01. 91(2): 344-351

Prehospital evaluation and detection of induced coagulopathy in trauma: The PREDICT study.

Holger Gaessler, Matthias Helm, Martin Kulla, Bjoern Hossfeld, Uta Schmid, Juergen Kerschowski, Ingeborg Bretschneider.

BACKGROUND: Hemorrhage with trauma-induced coagulopathy (TIC) and hyperfibrinolysis (HF) increases the mortality risk after severe trauma. While TIC at hospital admission is well studied, little is known about coagulopathy at the incident site. The aim of the study was to investigate coagulation disorders already present on scene.
METHODS: In a prospective single-center observational study, blood samples of trauma patients obtained before and at hospital admission were analyzed. Data on rotational thromboelastometry, blood gas analysis, prehospital treatment, injury severity, in-hospital blood transfusions, and mortality were investigated according to the presence of coagulation disorders at the incident site. The patients were divided into three groups according to the presence of coagulation disorders (no coagulopathy, TIC, TIC with HF). In a subgroup analysis, patients with a Trauma-Induced Coagulopathy Clinical Score (TICCS) of ≥10 were investigated.
RESULTS: Between August 2015 and February 2018, 148 patients were enrolled in the study. The mean Injury Severity Score was 22.1, and overall mortality was 7.4%. Trauma-induced coagulopathy and HF were already detectable at the incident site in 18.2% and 6.1%, respectively. Patients with HF had significantly altered circulation parameters with significant changes in pH, hemoglobin, lactate, and base excess at the incident site. In patients with TICCS of ≥10 (14.2%), TIC was detected in 47.6% of the cases and HF in 28.6%. Furthermore, in these patients, blood gas parameters significantly changed and the need for blood transfusion and mortality.
CONCLUSION: Trauma-induced coagulopathy and HF can be detected in severely injured patients even before medical treatment is started. Furthermore, in patients with HF and TICCS of ≥10, blood gas parameters were significantly changed at the incident site.
LEVEL OF EVIDENCE: Prognostic study, level III.

DOI: https://doi.org/10.1097/TA.0000000000003246
J Am Coll Surg. 2021 Aug 11. pii: S1072-7515(21)01236-9. [Epub ahead of print]

The Story of Blood for Shock Resuscitation: How the Pendulum Swings.

Samuel P Carmichael, Nicholas Lin, Meagan E Evangelista, John B Holcomb.

  Whole blood transfusion (WBT) began in 1667 as a treatment for mental illness with predictably poor results. Its therapeutic utility and widespread use were initially limited by deficiencies in transfusion science and antisepsis. James Blundell, a British obstetrician, was recognized for the first allotransfusion in 1825. However, WBT did not become safe and therapeutic until the early 20th century with the advent of reliable equipment, sterilization and blood typing. The discovery of citrate preservation in World War I allowed a separation of donor from recipient and introduced the practice of blood banking. During World War II, Elliott and Strumia were the first to separate whole blood into blood component therapy (BCT), producing dried plasma as a resuscitative product for "traumatic shock". During the 1970s, infectious disease, blood fractionation and financial opportunities further drove the change from WBT to BCT with little supporting data. Following a period of high-volume crystalloid and BCT resuscitation well into the early 2000's, measures to avoid the resulting iatrogenic resuscitation injury were developed under the concept of damage control resuscitation. Modern transfusion strategies for hemorrhagic shock target balanced BCT to reapproximate whole blood. Contemporary research has expanded the role of WBT to therapy for the acute coagulopathy of trauma and the damaged endothelium. Many US trauma centers are now using WBT as a front-line treatment in tandem with BCT for patients suffering hemorrhagic shock. Looking ahead, it is likely that WBT will once again be the resuscitative fluid of choice for patients in hemorrhagic shock.

Keywords:  hemorrhagic shock; history; trauma; whole blood

DOI:  https://doi.org/10.1016/j.jamcollsurg.2021.08.001
J Trauma Acute Care Surg. 2021 Aug 16.

WHOLE BLOOD RESUSCITATION RESTORES INTESTINAL PERFUSION AND INFLUENCES GUT MICROBIOME DIVERSITY.

Jaclyn Yracheta, Wayne Muraoka, Xiaowu Wu, David Burmeister, Daniel Darlington, David Zhao, Zhao Lai, Shannon Scroggins, Andrew P Cap, James Bynum, Susannah E Nicholson.

OBJECTIVE: Gut dysbiosis, an imbalance in the gut microbiome, occurs after trauma which may be ameliorated with transfusion. We hypothesized that gut hypoperfusion following trauma causes dysbiosis and that whole blood (WB) resuscitation mitigates these effects.
METHODS: Anesthetized rats underwent sham (S; laparotomy only, n = 6), polytrauma (T; laparotomy, liver and skeletal muscle crush injuries and femur fracture, n = 5), polytrauma and 40% hemorrhage (H; n = 7) and polytrauma, hemorrhage and WB resuscitation (R; n = 7) which was given as 20% estimated blood volume from donor rats 1 hr post-trauma. Baseline cecal mesenteric tissue oxygen (O2) concentration was measured following laparotomy and at 1- and 2 hrs post-trauma. Fecal samples were collected pre-injury and at euthanasia (2 hrs). 16 s rRNA sequencing was performed on purified DNA, and diversity and phylogeny analyzed with QIIME using the Greengenes 16S rRNA database (OTUs; 97% similarity). Alpha- and β-diversity were estimated using observed species metrics. Permutational analysis of variance was performed for overall significance.
RESULTS: In H rats, an average decline of 36% ±3.6 was seen in the mesenteric O2 concentration at 1 hr without improvement by 2 hrs post-injury, which was reversed following resuscitation at 2 hrs post-injury (4.1% ±3.1 difference from baseline). There was no change in tissue O2 concentration in the S or T rats. β-diversity differed amongst groups for all measured indices except Bray-Curtis, with the spatial median of the S and R rats more similar compared to S and H rats (p < 0.05). While there was no difference in α-diversity found amongst the groups, indices were significantly correlated with mesenteric O2 concentration. Members of the family Enterobacteriaceae were significantly enriched in only 2 hrs.
CONCLUSIONS: Mesenteric perfusion after trauma and hemorrhage is restored with WB resuscitation, which influences β-diversity of the gut microbiome. WB resuscitation may also mitigate the effects of hemorrhage on intestinal dysbiosis, thereby influencing outcomes.
LEVEL OF EVIDENCE: N/A - Basic ScienceStudy TypeOriginal Article.

DOI: https://doi.org/10.1097/TA.0000000000003381
J Trauma Acute Care Surg. 2021 Aug 01. 91(2): 331-335

Critical traumatic brain injury is associated with worse coagulopathy.

Daniel Cucher, Laura Harmon, Brian Myer, Andrew Ngyuen, Timothy Rankin, Alan Cook, Charles Hu, Ronald Tesoriero, Thomas Scalea, Deborah Stein.

OBJECTIVES: As thromboelastography (TEG) becomes the standard of care in patients with hemorrhagic shock (HS), an association between concomitant traumatic brain injury (TBI) and coagulopathy by TEG parameters is not well understood and is thus investigated.
METHODS: Retrospective analysis of trauma registry data at a single level 1 trauma center of 772 patients admitted with head Abbreviated Injury Scale (AIS) score of 3 and TEG studies between 2014 and 2017. Patients were stratified to moderate-severe TBI by head AIS scores of 3 and 4 (435 patients) and critical TBI by head AIS score of 5 (328 patients). Hemorrhagic shock was defined by base deficit of 4 or shock index of 0.9. Statistical analysis with unpaired t tests compared patients with critical TBI with patients with moderate-severe TBI, and patients were grouped by presence or absence of HS. A comparison of TBI data with conventional coagulation studies was also evaluated.
RESULTS: In the setting of HS, critical TBI versus moderate-severe TBI was associated with longer R time (p = 0.004), longer K time (p < 0.05), less acute angle (p = 0.001), and lower clot strength and stability (maximum amplitude [MA]) (p = 0.01). Worse TBI did not correlate with increased fibrinolysis by clot lysis measured by the percentage decrease in amplitude at 30 minutes after MA (p = 0.3). Prothrombin time and international normalized ratio failed to demonstrate more severe coagulopathy, while partial thromboplastin time was found to correlate with severity of TBI (p = 0.01). In patients with critical TBI, the presence of HS correlated with a statistically significant worsening of all parameters (p < 0.05) except for clot lysis measured by the percentage decrease in amplitude at 30 minutes after MA (LY-30).
CONCLUSION: Thromboelastography demonstrates that, with and without hemorrhagic shock, critical TBI correlates with a significant worsening of traumatic coagulopathy in comparison with moderate/severe TBI. In HS, critical TBI correlates with impaired clot initiation, impaired clot kinetics, and impaired platelet-associated clot strength and stability versus parameters found in moderate-severe TBI. Hemorrhagic shock correlates with worse traumatic coagulopathy in all evaluated patient groups with TBI. Conventional coagulation studies underestimate TBI-associated coagulopathy. Traumatic brain injury-associated coagulopathy is not associated with fibrinolysis.
LEVEL OF EVIDENCE: Prognostic/epidemiological, level IV; prognostic/epidemiological, level III.

DOI: https://doi.org/10.1097/TA.0000000000003253
Int J Crit Illn Inj Sci. 2021 Apr-Jun;11(2):11(2): 67-72

Safety and efficacy of thromboelastography guidance of antifibrinolytic therapy in trauma patients: An observational cohort analysis.

Rachel N Heilbronner, Michelle Kincaid, Grant Walliser, Michelle Pershing, M Chance Spalding.

   Background: Tranexamic acid (TXA) is an antifibrinolytic therapy intended to decrease blood loss and improve hemostasis in traumatic hemorrhage. Viscoelastic assays, such as thromboelastography (TEG), allow for the identification of a patient's specific hemostasis. The purpose of this research study was to explore the safety and efficacy of TEG-guided antifibrinolytic therapy in trauma patients.
Methods: This study was a retrospective review of trauma patients meeting institution-specific inclusion criteria for TXA. Patients were assigned to fibrinolytic groups per TEG LY30 data. Safety outcomes (24-h mortality, overall in-hospital mortality, and thromboembolic events) were compared between patients who did or did not receive TXA and within fibrinolytic groups. Mortality outcomes were adjusted for baseline Injury Severity Score (ISS). Secondary aims included blood product utilization, length of hospital, and intensive care unit stay.
Results: Hypofibrinolysis was the most common fibrinolytic phenotype. Adjusting for ISS, there were no significant differences in mortality. A 30.7% thromboembolism incidence was identified in the TXA group compared to 16.6% not receiving TXA (P = 0.26), with 72.7% of these patients experiencing fibrinolytic shutdown.
Conclusions: There were no differences in 24-h mortality, all-cause mortality, or secondary outcomes. The difference in thromboembolic rates between patients receiving TXA and those who did not, while not statistically significant, poses clinical concern.

Keywords:  Antifibrinolytic agents; Injury Severity Score; thromboelastography; tranexamic acid; wounds and injuries

DOI:  https://doi.org/10.4103/IJCIIS.IJCIIS_79_20
Chin J Traumatol. 2021 Aug 05. pii: S1008-1275(21)00127-9. [Epub ahead of print]

Trauma-induced pulmonary thromboembolism: What's update?

Yu-Hong Mi, Ming-Ying Xu.

  Trauma-induced pulmonary thromboembolism is the second leading cause of death in severe trauma patients. Primary fibrinolytic hyperactivity combined with hemorrhage and consequential hypercoagulability in severe trauma patients create a huge challenge for clinicians. It is crucial to ensure a safe anticoagulant therapy for trauma patients, but a series of clinical issues need to be answered first, for example, what are the risk factors for traumatic venous thromboembolism? How to assess and determine the status of coagulation dysfunction of patients? When is the optimal timing to initiate pharmacologic prophylaxis for venous thromboembolism? What types of prophylactic agent should be used? How to manage the anticoagulation-related hemorrhage and to determine the optimal timing of restarting chemoprophylaxis? The present review attempts to answer the above questions.

Keywords:  Deep venous thrombosis; Etiology; Prevention; Pulmonary thromboembolism; Treatment; Venous thromboembolism; Wounds and injuries

DOI:  https://doi.org/10.1016/j.cjtee.2021.08.003
J Surg Res. 2021 Aug 13. pii: S0022-4804(21)00460-1. [Epub ahead of print]268 326-336

Therapeutic Potential of B-1a Cells in Intestinal Ischemia-reperfusion Injury.

William Royster, Mahendar Ochani, Monowar Aziz, Ping Wang.

   BACKGROUND: Acute mesenteric ischemia is a common surgical emergency. Restoration of blood flow is a critical objective of treating this pathology. However, many patients suffer from ischemia-reperfusion (I/R) injuries at the time of revascularization, requiring prolonged hospitalizations. B-1a cells are a subtype of B lymphocytes with roles in regulating inflammation and tissue injury by spontaneous release of natural IgM and IL-10. We hypothesized that treatment with B-1a cells protects mice from intestinal I/R.
METHODS: Mesenteric ischemia was induced in mice by placing a vascular clip on the superior mesenteric artery for 60 minutes. At the time of reperfusion, B-1a cells or PBS control were instilled into the peritoneal cavity (PerC) of mice. PerC lavage, blood, intestine, and lungs were collected 4 h after reperfusion. Serum organ injury and inflammatory markers such as ALT, AST, LDH, lactate, IL-6, as well as lung and gut histology and myeloperoxidase (MPO) were assessed.
RESULTS: In intestinal I/R, B-1a cell frequency and number in the PerC were significantly decreased compared to sham-operated mice. There was an increase in the serum levels of ALT, AST, LDH, lactate, and IL-6 when comparing the vehicle group with the sham group. These increases were significantly reduced in the B-1a cell treated group. B-1a cell treatment significantly decreased the intestine and lung injury scores as well as MPO content, compared to vehicle treated mice. B-1a cell treatment resulted in a reduction of apoptotic cells in these tissues. Serum IgM levels were decreased in intestinal I/R, while treatment with B-1a cells significantly increased their levels towards normal levels.
CONCLUSIONS: B-1a cell treatment at the time of mesenteric reperfusion ameliorates end organ damage and reduces systemic inflammation through the improvement of serum IgM levels. Preserving B-1a cells pool could serve as a novel therapeutic avenue in intestinal I/R injury.

Keywords:  B-1a cells; Gut; Inflammation; Lung; Neutrophils; TLR4

DOI:  https://doi.org/10.1016/j.jss.2021.06.070
J Inflamm Res. 2021 ;14 3739-3753

Profiling the Expression of Circulating Acute-Phase Proteins, Cytokines, and Checkpoint Proteins in Patients with Severe Trauma: A Pilot Study.

Shao-Chun Wu, Cheng-Shyuan Rau, Pao-Jen Kuo, Fu-Yuan Shih, Hui-Ping Lin, Yi-Chan Wu, Ting-Min Hsieh, Hang-Tsung Liu, Ching-Hua Hsieh.

   Purpose: Severe trauma may lead to the systemic release of inflammatory mediators into the circulation with profound acute-phase responses; however, the understanding of the expression of these mediators remains limited. This study aimed to characterize the alterations in the expression of circulating acute-phase proteins, cytokines, and checkpoint proteins in patients with severe trauma injuries.
Patients and Methods: The study population included trauma patients in the intensive care unit (ICU) with an injury severity score equal to or greater than 16 and who had used a ventilator for 48 hours. A total of 12 female and 28 male patients were recruited for the study; six patients died and 34 survived. Blood samples collected at acute stages were compared with those drawn at the subacute stage, the time when the patients were discharged from the ICU, or before the discharge of the patients from the hospital.
Results: The study identified that the expression of acute-phase proteins, such as alpha-1-acid glycoprotein and C-reactive protein, and cytokines, including granulocyte colony-stimulating factor, interleukin-6, and interleukin-1 receptor antagonist, was elevated in the circulation after severe trauma. In contrast, the levels of acute-phase proteins, such as alpha-2-macroglobulin, serum amyloid P, and von Willebrand factor, and cytokines, including interleukin-4 and interferon gamma-induced protein 10, were reduced. However, there were no significant differences in the expression of checkpoint proteins in the circulation.
Conclusion: The dysregulated proteins identified in this study may serve as potential therapeutic targets or biomarkers for treating patients with severe trauma. However, the related biological functions of these dysregulated factors require further investigation to validate their functions.

Keywords:  biomarkers; circulation; critical illness; inflammatory reaction; severe trauma

DOI:  https://doi.org/10.2147/JIR.S324056
Inflammation. 2021 Aug 16.

The Influence of Macrophage-Activating Lipopeptide-2 in Regard to Liver-Specific Changes Within a Murine Two-Hit Model.

Weikang Wang, Ding Xu, Peng Luo, Yulong Shi, Thomas Tschernig, Johannes Greven, Frank Hildebrand, Klemens Horst.

  Trauma hemorrhage (TH) and subsequent sepsis are well known to frequently result in severe organ damage. Although macrophage-activating lipopeptide-2 (MALP-2) has been described to exert beneficial effects on organ damage, and further clinical course after both isolated trauma and sepsis, little is known about the impact of MALP-2 in a clinically realistic two-hit scenario of TH and subsequent sepsis. As the liver represents a key organ for the posttraumatic immune response and development of complications, the effects of MALP-2 on the posttraumatic hepatic immunologic response and tissue damage were investigated in a murine "two-hit" model. In C57BL/6 mice, blood pressure-controlled (35 ± 5 mm Hg) TH was induced. Cecal ligation and puncture (CLP) was performed 48 h after TH. Mice were divided into two control groups (control 1, TH and laparotomy without CLP; control 2, TH and CLP) and three experimental groups (TH + CLP) treated with MALP-2 at different timepoints (ETH, end of TH; ECLP, end of CLP; 6CLP, 6 h after CLP). The observation time lasted for 168 h after induction of TH. Kupffer cells (KC) were isolated and cultured, and MPO activity was analyzed. Cell culture supernatants were taken for cytokine analysis (TNF-α, IL-6, MCP-1, GM-CSF, IL-10). Histological analysis was performed using the Hepatic Injury Severity Scoring (HISS). Statistical evaluation was carried out using SPSS (version 24.0.0; IBM, Armonk, NY, USA). MPO activity of control 1 group was lowest compared with all the other groups (p < 0.01). MPO activity of control 2 group was significantly higher than that in all experimental groups (ETH (p < 0.01), ECLP (p < 0.01), and 6CLP (p = 0.03)). Within the experimental groups, MPO activity was significantly reduced in the ETH (p = 0.04) and the ECLP (p < 0.01) groups compared with the 6CLP group. Moreover, ETH was also associated with the most pronounced reduction of cytokine expression by KC (p < 0.05). HISS revealed the largest damage in the group control 2. TH and subsequent sepsis lead to a distinct immunologic reaction in the liver with an increase of cytokine expression of KC and pronounced infiltration of granulocytes with associated severe tissue damage. MALP application decreases the hepatic immune response and liver damage, with the most pronounced effects if applied at the end of TH.

Keywords:  MALP-2; cytokine; hepatic inflammation; sepsis; traumatic hemorrhage

DOI:  https://doi.org/10.1007/s10753-021-01534-8
J Thromb Haemost. 2021 Feb;19(2): 582-587

In vitro flow-based assay: From simple toward more sophisticated models for mimicking hemostasis and thrombosis.

Subcommittee on Biorheology

  In vitro flow-based assays are widely used to investigate the role of platelets and coagulation in hemostasis and thrombosis. Their main advantage over other assays relies on the fact that they integrate blood flow that regulates many aspects of platelet function, including adhesion, activation, and aggregation. Blood flow is also central in the regulation of coagulation through its ability to modulate the local concentrations of coagulation factors within and around thrombi. The most broadly used assay to study thrombus formation consists in perfusing whole blood over immobilized fibrillar collagen through a single channel, which helps to reproduce thrombus formation as it occurs in vivo after vascular injury, with platelets adhering, becoming activated, and forming a mural thrombus. This process can also be studied under conditions of thrombin generation, notably by recalcifying blood collected in sodium citrate. In this manuscript, we briefly discuss the advantages and limits of this broadly used "in vitro thrombus formation model." The main emphasis is on the description of the most recent developments regarding design of new flow models and new techniques, and how these may advance the landscape of in vitro studies into the formation of physiological or pathophysiological thrombi. Challenges linked to mimicking the formation of a hemostatic plug in a healthy vessel or a thrombus in diseased arteries and the complexity of reproducing the various aspects of venous thrombosis are discussed. Future directions are proposed to improve the physiological or pathophysiological relevance of current flow-based assays.

Keywords:  blood platelets; coagulation; hemostasis; rheology; thrombosis

DOI:  https://doi.org/10.1111/jth.15143
Oxid Med Cell Longev. 2021 ;2021 2514947

miRNA-27a Transcription Activated by c-Fos Regulates Myocardial Ischemia-Reperfusion Injury by Targeting ATAD3a.

Yandong Bao, Ying Qiao, Hang Yu, Zeying Zhang, Huimin Yang, Xin Xin, Yuqiong Chen, Yuxuan Guo, Nan Wu, Dalin Jia.

MicroRNA-27a (miR-27a) has been implicated in myocardial ischemia-reperfusion injury (MIRI), but the underlying mechanism is not well understood. This study is aimed at determining the role of miR-27a in MIRI and at investigating upstream molecules that regulate miR-27a expression and its downstream target genes. miR-27a expression was significantly upregulated in myocardia exposed to ischemia/reperfusion (I/R) and cardiomyocytes exposed to hypoxia/reoxygenation (H/R). c-Fos could regulate miR-27a expression by binding to its promoter region. Moreover, overexpression of miR-27a led to a decrease in cell viability, an increase in LDH and CK-MB secretion, and an increase in apoptosis rates. In contrast, suppression of miR-27a expression resulted in the opposite effects. ATPase family AAA-domain-containing protein 3A (ATAD3a) was identified as a target of miR-27a. miR-27a regulated the translocation of apoptosis-inducing factor (AIF) from the mitochondria to the nucleus and H/R-induced apoptosis via the regulation of ATAD3a. It was found that inhibiting miR-27a in vivo by injecting a miR-27a sponge could ameliorate MIRI in an isolated rat heart model. In conclusion, our study demonstrated that c-Fos functions as an upstream regulator of miR-27a and that miR-27a regulates the translocation of AIF from the mitochondria to the nucleus by targeting ATAD3a, thereby contributing to MIRI. These findings provide new insight into the role of the c-Fos/miR-27a/ATAD3a axis in MIRI.

DOI: https://doi.org/10.1155/2021/2514947
Cell Rep. 2021 Aug 17. pii: S2211-1247(21)00981-5. [Epub ahead of print]36(7): 109547

Hypoxic preconditioning protects against ischemic kidney injury through the IDO1/kynurenine pathway.

Rafael Torosyan, Shengping Huang, Prashant V Bommi, Ratnakar Tiwari, Si Young An, Michael Schonfeld, Ganeshkumar Rajendran, Matthew A Kavanaugh, Benjamin Gibbs, Agnieszka D Truax, Samuel Bohney, M Wade Calcutt, Evan W Kerr, Roberta Leonardi, Peng Gao, Navdeep S Chandel, Pinelopi P Kapitsinou.

  Prolonged cellular hypoxia leads to energetic failure and death. However, sublethal hypoxia can trigger an adaptive response called hypoxic preconditioning. While prolyl-hydroxylase (PHD) enzymes and hypoxia-inducible factors (HIFs) have been identified as key elements of oxygen-sensing machinery, the mechanisms by which hypoxic preconditioning protects against insults remain unclear. Here, we perform serum metabolomic profiling to assess alterations induced by two potent cytoprotective approaches, hypoxic preconditioning and pharmacologic PHD inhibition. We discover that both approaches increase serum kynurenine levels and enhance kynurenine biotransformation, leading to preservation of NAD+ in the post-ischemic kidney. Furthermore, we show that indoleamine 2,3-dioxygenase 1 (Ido1) deficiency abolishes the systemic increase of kynurenine and the subsequent renoprotection generated by hypoxic preconditioning and PHD inhibition. Importantly, exogenous administration of kynurenine restores the hypoxic preconditioning in the context of Ido1 deficiency. Collectively, our findings demonstrate a critical role of the IDO1-kynurenine axis in mediating hypoxic preconditioning.

Keywords:  IDO1; NAD(+); PHDs; hypoxia; ischemia-reperfusion; kidney; kynurenic acid; kynurenine; preconditioning

DOI:  https://doi.org/10.1016/j.celrep.2021.109547
Cell Signal. 2021 Aug 12. pii: S0898-6568(21)00207-2. [Epub ahead of print] 110118

UBE2D3 contributes to myocardial ischemia-reperfusion injury by regulating autophagy in dependence of p62/SQSTM1.

Xun Wang, Ping Yang, Yongliang Jiang, Yazhou Xu, Nan Wang, Peng Rao, Lin Yang, Lin Sun, Di Lu.

  The impairment of autophagic flux has been widely recognized in myocardial ischemia-reperfusion (I/R) injury, but its underlying mechanism contributing to impaired autophagic flux is poorly understood. As celluar major degradation systems, autophagy and ubiquitin proteasome(UPS) participate in the multitudinous progression of disease by interactive relationship. Especially UBE2D3, the ubiquitin-binding enzyme E2 family, is closely related to the regulation impairment of autophagic flux under I/R in our study. Therefore, this study aims to further explore the regulatory mechanism of UBE2D3 in I/R induced autophagy. We determined interference with UBE2D3 alleviated injury of myocardial cells both in vivo and in vitro. Conversely, when inhibiting proteasome function by injecting MG-132, myocardial infarct size of rats became increasingly enhanced, along with the high expression levels of LDH and CK-MB in serum, compared with myocardial I/R injury without treatment of MG-132. This had been caused by UBE2D3 promoting p62/SQSTM1(p62) ubiquitination(Ub), which lead to worsen the impairment of autophagic flux induced by myocardial I/R injury. In addition, UBE2D3 could also participate in the regulation of autophagy by negatively regulating mTOR. But more surprisingly, this mechanism was independent of the known mTOR-beclin1 pathway. These results suggested that in myocardial I/R injury, UBE2D3 promoted p62 ubiquitination to aggravate the impairment of autophagic flux. Moreover, mTOR was also involved in its regulation of autophagic flux in a way escaped from beclin1.

Keywords:  Autophagy; Myocardial ischemia-reperfusion injury; UBE2D3; Ubiquitylation; p62/SQSTM1

DOI:  https://doi.org/10.1016/j.cellsig.2021.110118
Inflamm Regen. 2021 Aug 18. 41(1): 26

Calcineurin-nuclear factor for activated T cells (NFAT) signaling in pathophysiology of wound healing.

Takahiro Manabe, Heamin Park, Takashi Minami.

  Wound healing occurred with serial coordinated processes via coagulation-fibrinolysis, inflammation following to immune-activation, angiogenesis, granulation, and the final re-epithelization. Since the dermis forms critical physical and biological barriers, the repair system should be rapidly and accurately functioned to keep homeostasis in our body. The wound healing is impaired or dysregulated via an inappropriate microenvironment, which is easy to lead to several diseases, including fibrosis in multiple organs and psoriasis. Such a disease led to the dysregulation of several types of cells: immune cells, fibroblasts, mural cells, and endothelial cells. Moreover, recent progress in medical studies uncovers the significant concept. The calcium signaling, typically the following calcineurin-NFAT signaling, essentially regulates not only immune cell activations, but also various healing steps via coagulation, inflammation, and angiogenesis. In this review, we summarize the role of the NFAT activation pathway in wound healing and discuss its overall impact on future therapeutic ways.

Keywords:  Angiogenesis; Coagulation; Inflammation; NFAT; Wound healing

DOI:  https://doi.org/10.1186/s41232-021-00176-5
Sci Rep. 2021 Aug 20. 11(1): 16999

Uridine treatment prevents myocardial injury in rat models of acute ischemia and ischemia/reperfusion by activating the mitochondrial ATP-dependent potassium channel.

Irina B Krylova, Elena N Selina, Valentina V Bulion, Olga M Rodionova, Natalia R Evdokimova, Natalia V Belosludtseva, Maria I Shigaeva, Galina D Mironova.

The effect of uridine on the myocardial ischemic and reperfusion injury was investigated. A possible mechanism of its cardioprotective action was established. Two rat models were used: (1) acute myocardial ischemia induced by occlusion of the left coronary artery for 60 min; and (2) myocardial ischemia/reperfusion with 30-min ischemia and 120-min reperfusion. In both models, treatment with uridine (30 mg/kg) prevented a decrease in cell energy supply and in the activity of the antioxidant system, as well as an increase in the level of lipid hydroperoxides and diene conjugates. This led to a reduction of the necrosis zone in the myocardium and disturbances in the heart rhythm. The blocker of the mitochondrial ATP-dependent potassium (mitoKATP) channel 5-hydroxydecanoate limited the positive effects of uridine. The data indicate that the cardioprotective action of uridine may be related to the activation of the mitoKATP channel. Intravenously injected uridine was more rapidly eliminated from the blood in hypoxia than in normoxia, and the level of the mitoKATP channel activator UDP in the myocardium after uridine administration increased. The results suggest that the use of uridine can be a potentially effective approach to the management of cardiovascular diseases.

DOI: https://doi.org/10.1038/s41598-021-96562-7
Sci Rep. 2021 Aug 18. 11(1): 16975

Cx43 mediates changes in myofibroblast contraction and collagen release in human amniotic membrane defects after trauma.

Eleni Costa, Babatunde O Okesola, Christopher Thrasivoulou, David L Becker, Jan A Deprest, Anna L David, Tina T Chowdhury.

The wound healing capacity of the fetal membranes after spontaneous or iatrogenic membrane rupture is unclear. We examined the healing mechanisms in amniotic membrane (AM) defects after trauma. Traumatised human AM defects were cultured for 4 days. Markers for nuclear (DAPI), cell type (vimentin, αSMA) and healing (Cx43, TGFβ1, collagen) were examined by immunofluorescence (IMF) confocal microscopy, Second Harmonic Generation (SHG) imaging and RT-qPCR. After trauma, AMCs and myofibroblasts migrated to the AM wound edge. Within four days, αSMA expressing myofibroblasts showed abundant Cx43 localized in the cytoplasmic processes. The highly contractile spindle-shaped myofibroblasts were present in the defect site and released collagen. In contrast, AMCs expressed vimentin and formed Cx43 plaques between cells found in the outer edges of the wound. Whilst AMCs were absent in the defect site, αSMA expressing myofibroblasts continued to elongate and polarize the collagen fibres. Both TGFβ1 and Cx43 gene expression were significantly increased after trauma. Cx43 has differential effects on AM cell populations that increase cellularity, contraction and potentially migration to the wound edge resulting in collagen polarisation in the AM defect site. Establishing how Cx43 regulates AM cell function could be an approach to repair defects in the membranes after trauma.

DOI: https://doi.org/10.1038/s41598-021-94767-4
J Am Coll Emerg Physicians Open. 2021 Aug;2(4): e12533

The Doppler shock index measured by a wearable ultrasound patch accurately detects moderate-to-severe central hypovolemia during lower body negative pressure.

Jon-Émile S Kenny, Mai Elfarnawany, Zhen Yang, Matt Myers, Andrew M Eibl, Joseph K Eibl, Jenna L Taylor, Chul Ho Kim, Bruce D Johnson.

   Objective: Moderate-to-severe hemorrhage is a life-threatening condition, which is challenging to detect in a timely fashion using traditional vital signs because of the human body's robust physiologic compensatory mechanisms. Measuring and trending blood flow could improve diagnosis of clinically significant exsanguination. A lightweight, wireless, wearable Doppler ultrasound patch that captures and trends blood flow velocity could enhance hemorrhage detection.
Methods: In 11 healthy volunteers undergoing simulated hemorrhage and resuscitation during graded lower body negative pressure (LBNP) and release, we studied the relationship between stroke volume (SV) and common carotid artery velocity time integral (VTI) and corrected flow time (FTc). We assessed the diagnostic accuracy of 2 variations of a novel metric, the Doppler shock index (ie, the DSIVTI and DSIFTc), at capturing moderate-to-severe central hypovolemia defined as a 30% reduction in SV. The DSIVTI and DSIFTc are calculated as the heart rate divided by either the VTI or FTc, respectively.
Results: A total of 17,822 cardiac cycles were analyzed across 22 LBNP protocols. The average SV reduction to the lowest tolerated LBNP stage was 40%; there was no clinically significant fall in the mean arterial pressure. Correlations between changing SV and the common carotid artery VTI and FTc were strong (R 2 of 0.87, respectively) and concordant. The DSIVTI and DSIFTc accurately detected moderate-to-severe central hypovolemia with values for the area under the receiver operator curves of 0.96 and 0.97, respectively.
Conclusion: In a human model of hemorrhage and resuscitation, measures from a wearable Doppler ultrasound patch correlated strongly with SV and identified moderate-to-severe central hypovolemia with excellent diagnostic accuracy.

Keywords:  carotid Doppler; corrected flow time; hemodynamic monitoring; hemorrhage; velocity time integral

DOI:  https://doi.org/10.1002/emp2.12533
J Extracell Vesicles. 2021 Aug;10(10): e12133

Extracellular vesicles from in vivo liver tissue accelerate recovery of liver necrosis induced by carbon tetrachloride.

Jaemin Lee, Sae Rom Kim, Changjin Lee, Ye In Jun, Seoyoon Bae, Yae Jin Yoon, Oh Youn Kim, Yong Song Gho.

  Extracellular vesicles (EVs) are nano-sized vesicles composed of proteolipid bilayers carrying various molecular signatures of the cells. As mediators of intercellular communications, EVs have gained great attention as new therapeutic agents in the field of nanomedicine. Therefore, many studies have explored the roles of cell-derived EVs isolated from cultured hepatocytes or stem cells as inducer of liver proliferation and regeneration under various pathological circumstances. However, study investigating the role of EVs directly isolated from liver tissue has not been performed. Herein, to understand the pathophysiological role and to investigate the therapeutic potential of in vivo liver EVs, we isolated EVs from both normal and carbon tetrachloride (CCl4)-induced damaged in vivo liver tissues. The in vivo EVs purified from liver tissues display typical features of EVs including spherical morphology, nano-size, and enrichment of tetraspanins. Interestingly, administration of both normal and damaged liver EVs significantly accelerated the recovery of liver tissue from CCl4-induced hepatic necrosis. This restorative action was through the induction of hepatocyte growth factor at the site of the injury. These results suggest that not only normal liver EVs but also damaged liver EVs play important pathophysiological roles of maintaining homeostasis after tissue damage. Our study, therefore, provides new insight into potentially developing in vivo EV-based therapeutics for preventing and treating liver diseases.

Keywords:  extracellular vesicles; hepatocyte growth factor; isolation; liver failure; therapeutics; tissue engineering

DOI:  https://doi.org/10.1002/jev2.12133