bims-heshmo 2021-09-12 papers

bims-heshmo

Biomed News

on Trauma hemorrhagic shock — molecular basis

Issue of 2021–09–12
ten papers selected by
Andreia Luís, Ludwig Boltzmann Institute

Plasma and rhADAMTS13 reduce trauma-induced organ failure by restoring the ADAMTS13-VWF axis.
Biological Connection of Psychological Stress and Polytrauma under Intensive Care: The Role of Oxytocin and Hydrogen Sulfide.
Remote ischemic post‑conditioning alleviates ischemia/reperfusion‑induced intestinal injury via the ERK signaling pathway‑mediated RAGE/HMGB axis.
LncRNA-6395 promotes myocardial ischemia-reperfusion injury in mice through increasing p53 pathway.
Aesculin suppresses the NLRP3 inflammasome-mediated pyroptosis via the Akt/GSK3β/NF-κB pathway to mitigate myocardial ischemia/reperfusion injury.
Thrombin aggravates hypoxia/reoxygenation injury of astrocytes by activating the autophagy pathway mediated by SPRED2.
Protective effect of parecoxib sodium against ischemia reperfusion‑induced intestinal injury.
Extracellular vesicles in acute respiratory distress syndrome: Recent developments from bench to bedside.
Extracellular Vesicles and Thrombosis: Update on the Clinical and Experimental Evidence.
Platelet extracellular vesicles enhance the proangiogenic potential of adipose-derived stem cells in vivo and in vitro.

Blood Adv. 2021 Sep 14. 5(17): 3478-3491

Plasma and rhADAMTS13 reduce trauma-induced organ failure by restoring the ADAMTS13-VWF axis.

BloodNet

Trauma-induced organ failure is characterized by endothelial dysfunction. The aim of this study was to investigate the role of von Willebrand factor (VWF) and its cleaving enzyme, ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13) in the occurrence of endothelial permeability and organ failure in trauma. In an observational study in a level-1 trauma center, 169 adult trauma patients with clinical signs of shock and/or severe injuries were included. Trauma was associated with low ADAMTS13 and high VWF antigen levels, thus generating an imbalance of ADAMTS13 to VWF. Patients who developed organ failure (23%) had greater ADAMTS13-to-VWF imbalances, persistently lower platelet counts, and elevated levels of high-molecular-weight VWF multimers compared with those without organ failure, suggesting microthrombi formation. To investigate the effect of replenishing low ADAMTS13 levels on endothelial permeability and organ failure using either recombinant human ADAMTS13 (rhADAMTS13) or plasma transfusion, a rat model of trauma-induced shock and transfusion was used. Rats in traumatic hemorrhagic shock were randomized to receive crystalloids, crystalloids supplemented with rhADAMTS13, or plasma transfusion. A 70-kDa fluorescein isothiocyanate-labeled dextran was injected to determine endothelial leakage. Additionally, organs were histologically assessed. Both plasma transfusion and rhADAMTS13 were associated with a reduction in pulmonary endothelial permeability and organ injury when compared with resuscitation with crystalloids, but only rhADAMTS13 resulted in significant improvement of a trauma-induced decline in ADAMTS13 levels. We conclude that rhADAMTS13 and plasma transfusion can reduce organ failure following trauma. These findings implicate the ADAMTS13-VWF axis in the pathogenesis of organ failure.

DOI: https://doi.org/10.1182/bloodadvances.2021004404
Int J Mol Sci. 2021 Aug 25. pii: 9192. [Epub ahead of print]22(17):

Biological Connection of Psychological Stress and Polytrauma under Intensive Care: The Role of Oxytocin and Hydrogen Sulfide.

Tamara Merz, Oscar McCook, Nicole Denoix, Peter Radermacher, Christiane Waller, Thomas Kapapa.

  This paper explored the potential mediating role of hydrogen sulfide (H2S) and the oxytocin (OT) systems in hemorrhagic shock (HS) and/or traumatic brain injury (TBI). Morbidity and mortality after trauma mainly depend on the presence of HS and/or TBI. Rapid "repayment of the O2 debt" and prevention of brain tissue hypoxia are cornerstones of the management of both HS and TBI. Restoring tissue perfusion, however, generates an ischemia/reperfusion (I/R) injury due to the formation of reactive oxygen (ROS) and nitrogen (RNS) species. Moreover, pre-existing-medical-conditions (PEMC's) can aggravate the occurrence and severity of complications after trauma. In addition to the "classic" chronic diseases (of cardiovascular or metabolic origin), there is growing awareness of psychological PEMC's, e.g., early life stress (ELS) increases the predisposition to develop post-traumatic-stress-disorder (PTSD) and trauma patients with TBI show a significantly higher incidence of PTSD than patients without TBI. In fact, ELS is known to contribute to the developmental origins of cardiovascular disease. The neurotransmitter H2S is not only essential for the neuroendocrine stress response, but is also a promising therapeutic target in the prevention of chronic diseases induced by ELS. The neuroendocrine hormone OT has fundamental importance for brain development and social behavior, and, thus, is implicated in resilience or vulnerability to traumatic events. OT and H2S have been shown to interact in physical and psychological trauma and could, thus, be therapeutic targets to mitigate the acute post-traumatic effects of chronic PEMC's. OT and H2S both share anti-inflammatory, anti-oxidant, and vasoactive properties; through the reperfusion injury salvage kinase (RISK) pathway, where their signaling mechanisms converge, they act via the regulation of nitric oxide (NO).

Keywords:  acute subdural hematoma; adverse childhood experiences; cystathionine-γ-lyase; early life stress; hemorrhagic shock; hydrogen sulfide; oxytocin; pig; posttraumatic stress disorder; traumatic brain injury

DOI:  https://doi.org/10.3390/ijms22179192
Mol Med Rep. 2021 Nov;pii: 773. [Epub ahead of print]24(5):

Remote ischemic post‑conditioning alleviates ischemia/reperfusion‑induced intestinal injury via the ERK signaling pathway‑mediated RAGE/HMGB axis.

Lei Mi, Nan Zhang, Jiyun Wan, Ming Cheng, Jianping Liao, Xiao Zheng.

  Intestinal ischemia reperfusion (I/R) injury is a tissue and organ injury that frequently occurs during surgery and significantly contributes to the pathological processes of severe infection, injury, shock, cardiopulmonary insufficiency and other diseases. However, the mechanism of intestinal I/R injury remains to be elucidated. A mouse model of intestinal I/R injury was successfully established and the model mice were treated with remote ischemic post‑conditioning (RIPOC) and/or an ERK inhibitor (CC‑90003), respectively. Histopathological changes of the intestinal mucosa were determined by hematoxylin and eosin staining. In addition, the levels of high‑mobility group box 1 (HMGB1) and receptor for advanced glycation end products (RAGE) expression were confirmed by reverse transcription‑quantitative polymerase chain reaction, western blotting and immunohistochemistry assays. The levels of antioxidants, oxidative stress markers (8‑OHdG) and interleukin 1 family members were evaluated by ELISA assays and the levels of NF‑κB pathway proteins were analyzed by western blotting. The data demonstrated that RIPOC could attenuate the histopathological features of intestinal mucosa in the intestinal I/R‑injury mouse models via the ERK pathway. It was also revealed that HMGB1 and RAGE expression in the mouse models could be markedly reduced by RIPOC (P<0.05) and that these reductions were associated with inhibition of the ERK pathway. Furthermore, it was demonstrated that RIPOC produced significant antioxidant and anti‑inflammatory effects following an intestinal I/R injury and that these effects were mediated via the ERK pathway (P<0.05). In addition, RIPOC was demonstrated to suppress the NF‑κB (p65)/NLR family pyrin domain containing 3 (NLRP3) inflammatory pathways in the intestinal I/R injury mouse models via the ERK pathway. The findings of the present study demonstrated that RIPOC helped to protect mice with an intestinal I/R injury by downregulating the ERK pathway.

Keywords:  antioxidants; extracellular signal‑regulated kinase; inflammation; ischemia‑reperfusion

DOI:  https://doi.org/10.3892/mmr.2021.12413
Acta Pharmacol Sin. 2021 Sep 07.

LncRNA-6395 promotes myocardial ischemia-reperfusion injury in mice through increasing p53 pathway.

Lin-Feng Zhan, Qi Zhang, Lu Zhao, Xue Dong, Xin-Yu Pei, Li-Li Peng, Xiao-Wen Zhang, Bo Meng, Wen-di Shang, Zhen-Wei Pan, Chao-Qian Xu, Yan-Jie Lu, Ming-Yu Zhang.

  Myocardial ischemia-reperfusion (I/R) injury is a pathological process characterized by cardiomyocyte apoptosis, which leads to cardiac dysfunction. Increasing evidence shows that abnormal expression of long noncoding RNAs (lncRNAs) plays a crucial role in cardiovascular diseases. In this study we investigated the role of lncRNAs in myocardial I/R injury. Myocardial I/R injury was induced in mice by ligating left anterior descending coronary artery for 45 min followed by reperfusion for 24 h. We showed that lncRNA KnowTID_00006395, termed lncRNA-6395 was significantly upregulated in the infarct area of mouse hearts following I/R injury as well as in H2O2-treated neonatal mouse ventricular cardiomyocytes (NMVCs). Overexpression of lncRNA-6395 led to cell apoptosis and the expression change of apoptosis-related proteins in NMVCs, whereas knockdown of lncRNA-6395 attenuated H2O2-induced cell apoptosis. LncRNA-6395 knockout mice (lncRNA-6395+/-) displayed improved cardiac function, decreased plasma LDH activity and infarct size following I/R injury. We demonstrated that lncRNA-6395 directly bound to p53, and increased the abundance of p53 protein through inhibiting ubiquitination-mediated p53 degradation and thereby facilitated p53 translocation to the nucleus. More importantly, overexpression of p53 canceled the inhibitory effects of lncRNA-6395 knockdown on cardiomyocyte apoptosis, whereas knockdown of p53 counteracted the apoptotic effects of lncRNA-6395 in cardiomyocytes. Taken together, lncRNA-6395 as an endogenous pro-apoptotic factor, regulates cardiomyocyte apoptosis and myocardial I/R injury by inhibiting degradation and promoting sub-cellular translocation of p53.

Keywords:  H2O2; apoptosis; lncRNA; myocardial I/R injury; neonatal mouse ventricular cardiomyocytes; p53; ubiquitination

DOI:  https://doi.org/10.1038/s41401-021-00767-5
Phytomedicine. 2021 Aug 23. pii: S0944-7113(21)00230-0. [Epub ahead of print]92 153687

Aesculin suppresses the NLRP3 inflammasome-mediated pyroptosis via the Akt/GSK3β/NF-κB pathway to mitigate myocardial ischemia/reperfusion injury.

Xiao-Na Xu, Yu Jiang, Liu-Yan Yan, Su-Yue Yin, Yue-Hua Wang, Shou-Bao Wang, Lian-Hua Fang, Guan-Hua Du.

   BACKGROUND: Aesculin (AES), an effective component of Cortex fraxini, is a hydroxycoumarin glucoside that has diverse biological properties. The nucleotide-binding domain leucine-rich repeat-containing receptor, pyrin domain-containing 3 (NLRP3) inflammasome has been heavily interwoven with the development of myocardial ischemia/reperfusion injury (MIRI). Nevertheless, it remains unclear whether AES makes a difference to the changes of the NLRP3 inflammasome in MIRI.
PURPOSE: We used rats that were subjected to MIRI and neonatal rat cardiomyocytes (NRCMs) that underwent oxygen-glucose deprivation/restoration (OGD/R) process to investigate what impacts AES exerts on MIRI and the NLRP3 inflammasome activation.
METHODS: The establishment of MIRI model in rats was conducted using the left anterior descending coronary artery ligation for 0.5 h ischemia and then untying the knot for 4 h of reperfusion. After reperfusion, AES were administered intraperitoneally using 10 and 30 mg/kg doses. We evaluated the development of reperfusion ventricular arrhythmias, hemodynamic changes, infarct size, and the biomarkers in myocardial injury. The inflammatory mediators and pyroptosis were also assessed. AES at the concentrations of 1, 3, and 10 μM were imposed on the NRCMs immediately before the restoration process. We also determined the cell viability and cell death in the NRCMs exposed to OGD/R insult. Furthermore, we also analyzed the levels of proteins that affect the NLRP3 inflammasome activation, pyroptosis, and the AKT serine/threonine kinase (Akt)/glycogen synthase kinase 3 beta (GSK3β)/nuclear factor-kappa B (NF-κB) signaling pathway via western blotting.
RESULTS: We found that AES notably attenuated reperfusion arrhythmias and myocardia damage, improved the hemodynamic function, and ameliorated the inflammatory response and pyroptosis of cardiomyocytes in rats and NRCMs. Additionally, AES reduced the NLRP3 inflammasome activation in rats and NRCMs. AES also enhanced the phosphorylation of Akt and GSK3β, while suppressing the phosphorylation of NF-κB. Moreover, the allosteric Akt inhibitor, MK-2206, abolished the AES-mediated cardioprotection and the NLRP3 inflammasome suppression.
CONCLUSIONS: These findings indicate that AES effectively protected cardiomyocytes against MIRI by suppressing the NLRP3 inflammasome-mediated pyroptosis, which may relate to the upregulated Akt activation and disruption of the GSK3β/NF-κB pathway.

Keywords:  Aesculin (AES); Akt/GSK3β/NF-κB pathway; Myocardial ischemia/reperfusion injury (MIRI); NLRP3 inflammasome; Pyroptosis

DOI:  https://doi.org/10.1016/j.phymed.2021.153687
Exp Ther Med. 2021 Oct;22(4): 1107

Thrombin aggravates hypoxia/reoxygenation injury of astrocytes by activating the autophagy pathway mediated by SPRED2.

Xiaoning Wang, Weiwei Lu, Bing Liu, Yunhe Xu.

  Autophagy plays an important role in ischemia/reperfusion brain injury, however, the signaling pathways involved in cell autophagy are not fully understood. The present study aimed to investigate the roles and molecular mechanisms of thrombin and Sprouty-related EVH1 domain-2 (SPRED2) on autophagy in hypoxia/reoxygenation (H/R) induced astrocytes. Reverse transcription-quantitative PCR and western blot analyses were performed to detect the expression levels of thrombin and SPRED2. Western blot analysis was also performed to detect the protein expression levels of Beclin 1, microtubule-associated protein light chain 3 (LC3)-II and LC3-I. The MTT assay was performed to assess cell viability, while ELISA was performed to determine the supernatant levels of interleukin (IL)-1β, IL-6 and tumor necrosis factor-α. The results demonstrated that the effects of H/R induction on inflammatory factor secretion, oxidative stress, autophagy and cell viability in astrocytes were aggravated by thrombin, the effects of which were reversed following SPRED2 knockdown. Taken together, the results of the present study suggest that thrombin aggravates H/R injury in astrocytes by activating the SPRED2-mediated autophagy.

Keywords:  Sprouty-related EVH1 domain-2; autophagy; hypoxia/reoxygenation; inflammatory factor; oxidative stress; thrombin

DOI:  https://doi.org/10.3892/etm.2021.10541
Mol Med Rep. 2021 Nov;pii: 776. [Epub ahead of print]24(5):

Protective effect of parecoxib sodium against ischemia reperfusion‑induced intestinal injury.

Mei Li, Zhi Zheng.

  Ischemia reperfusion (I/R)‑induced intestinal injury is a pathophysiological process leading to oxidative stress and inflammatory responses, and revealing its underlying mechanisms is essential for developing therapeutic strategies. Cyclooxygenase (COX) has been reported to be involved in I/R injury. Parecoxib sodium, a selective inhibitor for COX‑2, exerts protective effects, such as reducing I/R‑induced injuries in the heart, kidney and brain. However, the potential role of parecoxib sodium in protecting the small intestine against I/R‑induced injury has rarely been investigated. Therefore, the aim of the present study was to elucidate the effects and potential mechanisms of parecoxib sodium in I/R‑induced intestinal injury. In total, 60 Sprague‑Dawley rats were randomly divided into four groups: Control (sham operation) group, intestinal I/R group, 10 mg/kg parecoxib sodium‑pre‑treated I/R (I/R + Pare/10) group and the 20 mg/kg parecoxib sodium‑pre‑treated I/R (I/R + Pare/20) group. A regular I/R model was established to induce the intestinal injury in rats. Parecoxib sodium at 10 or 20 mg/kg was intraperitoneally administered into rats in both I/R + Pare groups once daily for 5 consecutive days prior to ischemia. Blood samples and small intestinal tissues were collected at 2 h after reperfusion. Changes in the levels of malondialdehyde, nitric oxide, interleukin (IL)‑1β, IL‑8, intercellular cell adhesion molecule‑1 and IL‑10, as well as the total antioxidant capacity were determined using ELISA, as were the activities of superoxidase dismutase and myeloperoxidase. Furthermore, the protein expression levels of total caspase‑3, cleaved caspase‑3, Bcl‑2 and Bax were examined via western blot analysis. In addition, the daily survival rate post‑reperfusion was examined for 7 days. It was revealed that parecoxib sodium increased the levels of antioxidants and suppressed the intestinal oxidative injury induced by I/R. Moreover, parecoxib sodium downregulated the expression levels of the proinflammatory factors, but upregulated the expression levels of anti‑inflammatory factors. The results also demonstrated that parecoxib sodium attenuated I/R‑induced apoptosis and increased the survival rate of rats. Thus, administration of parecoxib sodium prior to intestinal I/R attenuated intestinal injury and increased the rat survival rate by inhibiting I/R‑induced inflammation, oxidative stress and apoptosis.

Keywords:  inflammation; intestinal injury; ischemia reperfusion; parecoxib sodium

DOI:  https://doi.org/10.3892/mmr.2021.12416
Int Immunopharmacol. 2021 Sep 01. pii: S1567-5769(21)00754-2. [Epub ahead of print]100 108118

Extracellular vesicles in acute respiratory distress syndrome: Recent developments from bench to bedside.

Chao Quan, Mingrui Wang, Huan Chen, Huali Zhang.

  Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), characterized by a large number of inflammatory cell aggregation and alveolar cell damage in pathophysiology, have extremely high morbidity and mortality in critically ill patients. In recent years, more and more studies have found that there are abundant extracellular vesicles (EVs) in animal models and patients with ALI/ARDS, and they play a critical role in the pathogenesis of lung injury. Clarifying the mechanisms of EVs in lung injury is of great significance in the diagnosis and treatment of ALI/ARDS. In this review, we will summarize the recent findings on the roles of EVs derived from different cells in ALI/ARDS, along with the formation, function, and related effects of EVs, and explore their potential clinical application for the diagnosis and treatment of ALI/ARDS.

Keywords:  Exosomes; Microvesicles; acute lung injury (ALI); acute respiratory distress syndrome (ARDS); extracellular vesicles (EVs)

DOI:  https://doi.org/10.1016/j.intimp.2021.108118
Int J Mol Sci. 2021 Aug 27. pii: 9317. [Epub ahead of print]22(17):

Extracellular Vesicles and Thrombosis: Update on the Clinical and Experimental Evidence.

Konstantinos Zifkos, Christophe Dubois, Katrin Schäfer.

  Extracellular vesicles (EVs) compose a heterogenous group of membrane-derived particles, including exosomes, microvesicles and apoptotic bodies, which are released into the extracellular environment in response to proinflammatory or proapoptotic stimuli. From earlier studies suggesting that EV shedding constitutes a cellular clearance mechanism, it has become evident that EV formation, secretion and uptake represent important mechanisms of intercellular communication and exchange of a wide variety of molecules, with relevance in both physiological and pathological situations. The putative role of EVs in hemostasis and thrombosis is supported by clinical and experimental studies unraveling how these cell-derived structures affect clot formation (and resolution). From those studies, it has become clear that the prothrombotic effects of EVs are not restricted to the exposure of tissue factor (TF) and phosphatidylserines (PS), but also involve multiplication of procoagulant surfaces, cross-linking of different cellular players at the site of injury and transfer of activation signals to other cell types. Here, we summarize the existing and novel clinical and experimental evidence on the role and function of EVs during arterial and venous thrombus formation and how they may be used as biomarkers as well as therapeutic vectors.

Keywords:  arterial; endothelial cells; extracellular vesicles; thrombosis; venous

DOI:  https://doi.org/10.3390/ijms22179317
Stem Cell Res Ther. 2021 Sep 09. 12(1): 497

Platelet extracellular vesicles enhance the proangiogenic potential of adipose-derived stem cells in vivo and in vitro.

Yanan Tang, Jiayan Li, Weiyi Wang, Bingyi Chen, Jinxing Chen, Zekun Shen, Jiaxuan Hou, Yifan Mei, Shuang Liu, Liwei Zhang, Zongjin Li, Shaoying Lu.

   BACKGROUND: Adipose-derived mesenchymal stem cells (ADSC)-based therapy is an outstanding treatment strategy for ischaemic disease. However, the therapeutic efficacy of this strategy is not ideal due to the poor paracrine function and low survival rate of ADSCs in target regions. Platelet extracellular vesicles (PEVs) are nanoparticles derived from activated platelets that can participate in communication between cells. Accumulating evidence indicates that PEVs can regulate the biological functions of several cell lines. In the present study, we aimed to investigate whether PEVs can modulate the proangiogenic potential of ADSCs in vitro and in vivo.
METHODS: PEVs were identified using scanning electron microscope (SEM), flow cytometry (FCM) and nanoparticle tracking analysis (NTA). The CCK8 assay was performed to detect proliferation of cells. Transwell and wound healing assays were performed to verify migration capacity of cells. AnnexinV-FITC/PI apoptosis kit and live/dead assay were performed to assess ADSCs apoptosis under Cocl2-induced hypoxia condition. The underlying mechanisms by which PEVs affected ADSCs were explored using real time-PCR(RT-PCR) and Western blot. In addition, matrigel plug assays were conducted and mouse hindlimb ischaemic models were established to investigate the proangiogenic potential of PEV-treated ADSCs in vivo.
RESULTS: We demonstrated that ADSC could internalize PEVs, which lead to a series of biological reactions. In vitro, dose-dependent effects of PEVs on ADSC proliferation, migration and antiapoptotic capacity were observed. Western blotting results suggested that multiple proteins such as ERK, AKT, FAK, Src and PLCγ1 kinase may contribute to these changes. Furthermore, PEVs induced upregulation of several growth factors expression in ADSCs and amplified the proliferation, migration and tube formation of HUVECs induced by ADSC conditioned medium (CM). In in vivo experiments, compared with control ADSCs, the injection of PEV-treated ADSCs resulted in more vascularization in matrigel plugs, attenuated tissue degeneration and increased blood flow and capillary density in ischaemic hindlimb tissues.
CONCLUSION: Our data demonstrated that PEVs could enhance the proangiogenic potential of ADSCs in mouse hindlimb ischaemia. The major mechanisms of this effect included the promotion of ADSC proliferation, migration, anti-apoptosis ability and paracrine secretion.

Keywords:  Adipose-derived stem cells; Angiogenesis; Ischaemic hindlimb; Platelet-derived extracellular vesicles

DOI:  https://doi.org/10.1186/s13287-021-02561-w