bims-heshmo 2021-10-31 papers

bims-heshmo

Biomed News

on Trauma hemorrhagic shock — molecular basis

Issue of 2021–10–31
eight papers selected by
Andreia Luís, Ludwig Boltzmann Institute

Utility of End Tidal Carbon Dioxide to predict hemorrhagic shock in multiple trauma patients.
Small Extracellular Vesicles Propagate the Inflammatory Response After Trauma.
Sepsis in Trauma: A Deadly Complication.
Cutaneous ischemia-reperfusion injury is exacerbated by IL-36 receptor antagonist deficiency.
Exosomal microRNA-98-5p from hypoxic bone marrow mesenchymal stem cells inhibits myocardial ischemia-reperfusion injury by reducing TLR4 and activating the PI3K/Akt signaling pathway.
MicroRNAs in shaping the resolution phase of inflammation.
Gene Co-Expression Analysis Identified Preserved and Survival-Related Modules in Severe Blunt Trauma, Burns, Sepsis, and Systemic Inflammatory Response Syndrome.
Glutathione S-Transferase and Clusterin, New Players in the Ischemic Preconditioning Renal Protection in a Murine Model of Ischemia and Reperfusion.

Turk J Med Sci. 2021 Oct 24.

Utility of End Tidal Carbon Dioxide to predict hemorrhagic shock in multiple trauma patients.

Gülşen Öztürk Örmeci, Özlem Yiğit, Oktay Eray.

   BACKGROUND/AIM: For identifying hemorrhagic shock in trauma patients, some objective data are needed. The use of base excess (BE) and lactate values have been originated. In this study, it was aimed to determine the usability of End Tidal Carbon Dioxide (ETCO2) in patients with multiple trauma for recognizing hemorrhagic shock.
MATERIALS AND METHODS: Patients who were admitted to the emergency department between June 2019 and February 2020 with high-energy multiple trauma were included in the study. ETCO? and BE values were measured. Correlation coefficients were calculated to determine correlations between ETCO2 and BE levels.
RESULTS: 122 patients were included in the study. 89 (73%) were men and 33 (27%) were women, and the mean age of the study population was 38.70±19.18. The mortality rate was 14.8% in the study population. The correlation between ETCO2 and BE values was significant (r: 0,27) and in the same range in the Bland-Altmann analysis. ETCO2 levels above 35 was specific for stage 1 hemorrhagic shock. ETCO2 levels below 30 were sensitive for stage 2 and 3 hemorrhagic shock and when the levels were measured below 22 it was found specific for stage 4 shock. The specificity increased to 99% at the levels below 18. The sensitivity for ETCO? values below 22 for predicting mortality was 33.33%, the specificity was 89.42%, the positive predictive value was 35.29% and the negative predictive value was 88.57%. The sensitivity for BE values below -10 for predicting mortality was 50%, the specificity was 93.27%, the positive predictive value was 56.25% and the negative predictive value was 91.51%.
CONCLUSION: ETCO2 measurement can be a useful parameter as a non-invasive and simple technique in predicting and classifying hemorrhagic shock, which is the leading cause of mortality in trauma patients. Mortality rates increased when ETCO2 was measured below 22 and these patients are more likely to be in the critical hemorrhagic shock state.

Keywords:  ETCO2; Trauma; base excess (BE); emergency department; hemorrhagic shock

DOI:  https://doi.org/10.3906/sag-2103-206
Adv Sci (Weinh). 2021 Oct 28. e2102381

Small Extracellular Vesicles Propagate the Inflammatory Response After Trauma.

Tanja Seibold, Jonathan Schönfelder, Florian Weeber, André Lechel, Milena Armacki, Mareike Waldenmaier, Christoph Wille, Annette Palmer, Rebecca Halbgebauer, Ebru Karasu, Markus Huber-Lang, Miriam Kalbitz, Peter Radermacher, Stephan Paschke, Thomas Seufferlein, Tim Eiseler.

  Trauma is the leading cause of death in individuals under 44 years of age. Thorax trauma (TxT) is strongly associated with trauma-related death, an unbalanced innate immune response, sepsis, acute respiratory distress syndrome, and multiple organ dysfunction. It is shown that different in vivo traumata, such as TxT or an in vitro polytrauma cytokine cocktail trigger secretion of small extracellular nanovesicles (sEVs) from endothelial cells with pro-inflammatory cargo. These sEVs transfer transcripts for ICAM-1, VCAM-1, E-selectin, and cytokines to systemically activate the endothelium, facilitate neutrophil-endothelium interactions, and destabilize barrier integrity. Inhibition of sEV-release after TxT in mice ameliorates local as well as systemic inflammation, neutrophil infiltration, and distant organ damage in kidneys (acute kidney injury, AKI). Vice versa, injection of TxT-plasma-sEVs into healthy animals is sufficient to trigger pulmonary and systemic inflammation as well as AKI. Accordingly, increased sEV concentrations and transfer of similar cargos are observed in polytrauma patients, suggesting a fundamental pathophysiological mechanism.

Keywords:  endothelium; inflammation; neutrophils; small extracellular vesicles; trauma

DOI:  https://doi.org/10.1002/advs.202102381
Arch Med Res. 2021 Oct 24. pii: S0188-4409(21)00206-X. [Epub ahead of print]

Sepsis in Trauma: A Deadly Complication.

Fernanda Mas-Celis, Jimena Olea-López, Javier Alberto Parroquin-Maldonado.

  Sepsis is a major cause of death following a traumatic injury. As a life-threatening medical emergency, it is defined as the body's extreme response to an infection. Without timely treatment, sepsis can rapidly lead to tissue damage, and organ failure The capacity to limit tissue damage through metabolic adaptation and repair processes is associated with an excessive immune response of the host. It is important to make an early prediction of sepsis, based on the quick Sepsis associated Organ Failure Assessment Score (qSOFA), so an accurate treatment can be initiated reducing the morbidity and mortality at the emergency and UCI services. Many factors increase the rate of complications and the development of sepsis in a trauma patient, representing a challenge to orthopedic surgeons. Several early biomarkers that help to identify and predict the inflammatory and immune responses of the host going through polytrauma and sepsis have been studied; procalcitonin (PCT), C-reactive protein (CRP), glycosylated hemoglobin (HbA1c), the Neutrophil/lymphocyte ratio (NLR), Interleukin-17 (IL-17), Caspase-1, Vanin-1, High-density lipoproteins (HDL), and the Thrombin-activable fibrinolysis inhibitor (TAFI). Once sepsis is diagnosed, treatment must be immediately initiated with an appropriate empiric antimicrobial, an all-purpose supporting treatment, and metabolic control, followed by the specific antibiotic therapy based on blood culture. Since the participation of sepsis in polytrauma has been recognized as a key event in the outcome of patients at the ICU, the ability of the specialist to early recognize a septic process has become a key feature to reduce mortality and improve clinical prognosis.

Keywords:  Early prediction; Orthopedics; Polytrauma; Sepsis; Trauma surgery

DOI:  https://doi.org/10.1016/j.arcmed.2021.10.007
J Eur Acad Dermatol Venereol. 2021 Oct 26.

Cutaneous ischemia-reperfusion injury is exacerbated by IL-36 receptor antagonist deficiency.

Yoshihito Tanaka, Yohei Iwata, Kenta Saito, Hidehiko Fukushima, Soichiro Watanabe, Yurie Hasegawa, Masashi Akiyama, Kazumitsu Sugiura.

   BACKGROUND: Loss-of-function homozygous or compound heterozygous mutations in IL36RN, which encodes interleukin-36 receptor antagonist (IL-36Ra), has been implicated in the pathogenesis of skin disorders. However, the pathogenic role of IL-36Ra in cutaneous ischemia-reperfusion (I/R) injury remains unclear.
OBJECTIVES: We investigated the role of IL36Ra in cutaneous I/R injury.
METHODS: We examined I/R injury in Il36rn-/- mice. The area of wounds, numbers of infiltrated cells, apoptotic cells, and neutrophil extracellular trap (NET) formation were assessed. The expression levels of various genes were analysed using real-time RT-PCR. The expression of high mobility group box 1 (HMGB1), an endogenous toll-like receptor (TLR) 4 ligand, was confirmed using immunohistology, and serum HMGB1 levels were measured by ELISA. Cytokine production by stimulated cultured J774A.1 and HaCaT cells was examined.
RESULTS: IL-36Ra deficiency resulted in significantly delayed wound healing and increased neutrophil and macrophage infiltration into the wound tissues. Il36rn-/- mice had increased mRNA expression levels of CXCL1, CXCL2, CCL4, TNF-α, TGF-β, IL-1β, IL-6, and IL-36γ relative to wild-type mice. Apoptosis was identified in keratinocytes by TUNEL assay. HMGB1 expression in the I/R site was decreased in both keratinocytes and adnexal cells, while serum HMGB1 levels were significantly elevated after reperfusion. The mRNA levels of various cytokines, including IL-1β, were elevated in J774A.1 cells through TLR4 signalling by HMGB1 stimulation. In addition, HaCaT cells stimulated with IL-1β showed significantly increased CXCL1, TNF-α, IL-6, IL-36β, and IL-36γ mRNA expression. Furthermore, NET formation was increased by IL-36Ra deficiency. Finally, either the blockade of TLR4 signalling by TAK-242 or inhibition of NET formation by Cl-amidine normalised exacerbated I/R injury in Il36rn-/- mice.
CONCLUSIONS: This study indicated that IL-36Ra deficiency exacerbates cutaneous I/R injury due to excessive inflammatory cell recruitment, NET formation, and excessive cytokine and chemokine production via the TLR4 pathway by HMGB1 released from epidermal apoptotic cells.

Keywords:  Cl-amidine; IL-36 receptor antagonist (IL36Ra) deficiency; TAK-242; cutaneous ischemia-reperfusion injury (I/R injury); high mobility group box 1 (HMGB1); neutrophil extracellular traps (NETs)

DOI:  https://doi.org/10.1111/jdv.17767
Int Immunopharmacol. 2021 Oct 26. pii: S1567-5769(21)00228-9. [Epub ahead of print]101(Pt B): 107592

Exosomal microRNA-98-5p from hypoxic bone marrow mesenchymal stem cells inhibits myocardial ischemia-reperfusion injury by reducing TLR4 and activating the PI3K/Akt signaling pathway.

Leiying Zhang, Qingxia Wei, Xiaomin Liu, Ting Zhang, Shuying Wang, Lingling Zhou, Liyang Zou, Fengyan Fan, Hongxu Chi, Jiayi Sun, Deqing Wang.

   OBJECTIVE: MicroRNAs (miRNAs) are essential biomarkers during development of human diseases. We aimed to explore the role of hypoxia-induced bone marrow mesenchymal stem cells (BMSCs)-derived exosomal miR-98-5p in myocardial ischemia-reperfusion injury (MI/RI).
METHODS: BMSCs were isolated, cultured, stimulated by hypoxia and transfected with adenovirus expressing miR-98-5p. The exosomes were extracted from BMSCs and named as BMSC-exos. The rat MI/RI models were established by ligation of left anterior descending artery and were respectively injected. Then, hemodynamic indices, myocardial enzymes, oxidative stress factors, inflammatory factors, macrophage infiltration and infarct size in these rats were determined. Expression of miR-98-5p, toll-like receptor 4 (TLR4) and the phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) signaling pathway-related proteins was assessed. The target relation between miR-98-5p and TLR4 was confirmed by bioinformatic method and dual luciferase report gene assay.
RESULTS: MiR-98-5p was downregulated, TLR4 was upregulated and the PI3K/Akt signaling pathway was inactivated in MI/RI rat myocardial tissues. Exosomal miR-98-5p from hypoxic BMSCs promoted cardiac function and suppressed myocardial enzyme levels, oxidative stress, inflammation response, macrophage infiltration and infarct size in I/R myocardial tissues. Moreover, TRL4 was targeted by miR-98-5p and miR-98-5p activated PI3K/Akt signaling pathway.
CONCLUSION: Hypoxia-induced BMSC-exos elevated miR-98-5p to protect against MI/RI. This study may be helpful for treatment of MI/RI.

Keywords:  Bone marrow mesenchymal stem cell; Exosome; MicroRNA-98-5p; Myocardial ischemia–reperfusion injury; Phosphatidylinositol-3-kinase/protein kinase B signaling pathway; Toll-like receptor 4

DOI:  https://doi.org/10.1016/j.intimp.2021.107592
Semin Cell Dev Biol. 2021 Apr 29. pii: S1084-9521(21)00066-5. [Epub ahead of print]

MicroRNAs in shaping the resolution phase of inflammation.

Raza Ali Naqvi, Meenal Gupta, Anne George, Afsar R Naqvi.

  Inflammation is a host defense mechanism orchestrated through imperative factors - acute inflammatory responses mediated by cellular and molecular events leading to activation of defensive immune subsets - to marginalize detrimental injury, pathogenic agents and infected cells. These potent inflammatory events, if uncontrolled, may cause tissue damage by perturbing homeostasis towards immune dysregulation. A parallel host mechanism operates to contain inflammatory pathways and facilitate tissue regeneration. Thus, resolution of inflammation is an effective moratorium on the pro-inflammatory pathway to avoid the tissue damage inside the host and leads to reestablishment of tissue homeostasis. Dysregulation of the resolution pathway can have a detrimental impact on tissue functionality and contribute to the diseased state. Multiple reports have suggested peculiar dynamics of miRNA expression during various pro- and anti-inflammatory events. The roles of miRNAs in the regulation of immune responses are well-established. However, understanding of miRNA regulation of the resolution phase of events in infection or wound healing models, which is sometimes misconstrued as anti-inflammatory signaling, remains limited. Due to the deterministic role of miRNAs in pro-inflammatory and anti-inflammatory pathways, in this review we have provided a broad perspective on the putative role of miRNAs in the resolution of inflammation and explored their imminent role in therapeutics.

Keywords:  Inflammation; MicroRNA; Pathogenesis; Post-transcriptional regulation; Resolution; Wound healing

DOI:  https://doi.org/10.1016/j.semcdb.2021.03.019
Int J Gen Med. 2021 ;14 7065-7076

Gene Co-Expression Analysis Identified Preserved and Survival-Related Modules in Severe Blunt Trauma, Burns, Sepsis, and Systemic Inflammatory Response Syndrome.

Jingrui Huo, Lei Wang, Yi Tian, Wenjie Sun, Guoan Zhang, Yan Zhang, Ying Liu, Jingjing Zhang, Xiaohui Yang, Yingfu Liu.

   Background: Severe trauma and burns accompanied by sepsis are associated with high morbidity and mortality. Little is known about the transcriptional similarity between trauma, burns, sepsis, and systemic inflammatory response syndrome (SIRS). Uncovering key genes and molecular networks is critical to understanding the biology of disease. Conventional analysis of gene changes (fold change) analysis is difficult for time-serial data such as post-injury blood transcriptome.
Methods: Weighted gene co-expression network analysis (WGCNA) was applied to the trauma dataset to identify modules and hub genes. Module stability was tested by half sampling. Module preservations of burns, sepsis, and SIRS were calculated using trauma as reference. Module functional enrichment was analyzed in gProfiler server. Candidate drugs were screened using Connectivity Map based on hub genes. The modules were visualized in Cytoscape.
Results: Seventeen modules were identified. The modules were robust to the exclusion of half the sample. They were involved in lymphocyte and platelet activation, erythrocyte differentiation, cell cycle, translation, and interferon signaling. In addition, highly connected hub genes were identified in each module, such as GUCY1B1, BCL11B, HMMR, and CEACAM6. High BCL11B (M13) or low CEACAM6 (M27) expression indicates better survival prognosis in sepsis patients regardless of endotype class and age. Network preservation in burns, sepsis, and SIRS showed a general similarity between trauma and burns. M4, M5, M13, M16, M20, and M27 were significantly associated with injury time in trauma and burns. High M13 (T cell activation), low M15 (cell cycle), and low M27 (neutrophil activation) indicate better survival of sepsis patients, regardless of endotype class and age. Moreover, the modules can efficiently separate patients with different diseases. Some modules and hub genes have good prognostic performance in sepsis. Based on the hub genes of each module, six candidate drugs were screened.
Conclusion: This study first compared the gene co-expression modules in trauma, burns, sepsis, and SIRS. The identified modules are useful for disease prognosis and drug discovery. BCL11B and CEACAM6 may be promising biomarkers for sepsis risk assessment.

Keywords:  Connectivity Map; SIRS; WGCNA; hub gene

DOI:  https://doi.org/10.2147/IJGM.S336785
Cell Physiol Biochem. 2021 Oct 27. 55(5): 635-650

Glutathione S-Transferase and Clusterin, New Players in the Ischemic Preconditioning Renal Protection in a Murine Model of Ischemia and Reperfusion.

Consuelo Pasten, Yeimi Herrera-Luna, Mauricio Lozano, Jocelyn Rocco, Cristobal Alvarado, Jéssica Liberona, Luis Michea, Carlos E Irarrázabal.

   BACKGROUND/AIMS: Renal ischemia and reperfusion injury (IRI) involves oxidative stress, disruption of microvasculature due to endothelial cell damage, loss of epithelial cell polarity secondary to cytoskeletal alterations, inflammation, and the subsequent transition into a mesenchymal phenotype. Ischemic preconditioning (IPC) has been proposed as a therapeutic strategy to avoid/ameliorate the IRI. Since previous results showed that IPC could have differential effects in kidney cortex vs. kidney medulla, in the present study we analyzed the effectiveness and molecular mechanisms implicated in IPC in both kidney regions.
METHODS: We evaluated 3 experimental groups of BALB/c male mice: control (sham surgery); renal ischemia (30 min) by bilateral occlusion of the renal pedicle and reperfusion (48 hours) (I/R); and renal IPC (two cycles of 5 min of ischemia and 5 min of reperfusion) applied just before I/R. Acute kidney injury was evaluated by glomerular filtration rate (GFR), Neutrophil Gelatinase-Associated Lipocalin (NGAL) blood level, and histologic analysis. Oxidative stress was studied measurement the Glutathione S-Transferase (GST) activity, GSH/GSSG ratio, and lipoperoxidation levels. Inflammatory mediators (IL-1β, IL-6, Foxp3, and IL-10) were quantified by qRT-PCR. The endothelial (PECAM-1), epithelial (AQP-1), mesenchymal (Vimentin, Fascin, and Hsp47), iNOS, clusterin, and Hsp27 expression were evaluated (qRT-PCR and/or Western blot).
RESULTS: The IPC protocol prevented the decrease of GFR, reduced the plasma NGAL, and ameliorated morphological damage in the kidney cortex after I/R. The IPC also prevented the downregulation of GST activity, lipoperoxidation and ameliorated the oxidized glutathione. In addition, IPC prevented the upregulation of vimentin, fascin, and Hsp47, which was associated with the prevention of the downregulation of AQP1 after I/R. The protective effect of IPC was associated with the upregulation of Hsp27, Foxp3, and IL-10 expression in the renal cortex. However, the upregulation of iNOS, IL-1β, IL-6, and clusterin by I/R were not modified by IPC.
CONCLUSION: IPC conferred better protection in the kidney cortex as compared to the kidney medulla. The protective effect of IPC was associated with amelioration of oxidative stress, tubular damage, and the induction of markers of Treg lymphocytes activity in the cortical region. Further studies are needed to evaluate if lower tubular cell stress/damage after I/R may explain the preferential induction of Treg response in the kidney cortex induced by IPC.

Keywords:  Glutathione S-transferase; Clusterin; Ischemia and reperfusion; Ischemic preconditioning

DOI:  https://doi.org/10.33594/000000442