bims-heshmo 2021-09-05 papers

bims-heshmo

Biomed News

on Trauma hemorrhagic shock — molecular basis

Issue of 2021‒09‒05
ten papers selected by
Andreia Luís
Ludwig Boltzmann Institute

Evaluation of the thiol disulfide homeostasis in patients with traumatic hemorrhagic shock.
Regulator of G-protein signaling 14 protects the liver from ischemia reperfusion injury by suppressing TAK1 activation.
The α2AR/Caveolin-1/p38MAPK/NF-κB axis explains dexmedetomidine protection against lung injury following intestinal ischaemia-reperfusion.
Naked mole-rat brain mitochondria tolerate in vitro ischemia.
HepaticIschemia/Reperfusion Injuryinvolves functional tryptase/PAR-2 signaling in liver sinusoidal endothelial cell population.
Cardioprotective effect of MLN4924 on ameliorating autophagic flux impairment in myocardial ischemia-reperfusion injury by Sirt1.
Changes of pituitary adenylate cyclase activating polypeptide (PACAP) level in polytrauma patents in the early post-traumatic period.
Protective Effect of Adipose-Derived Mesenchymal Stem Cell Secretome against Hepatocyte Apoptosis Induced by Liver Ischemia-Reperfusion with Partial Hepatectomy Injury.
Oct4-dependent FoxC1 activation improves the survival and neovascularization of mesenchymal stem cells under myocardial ischemia.
Coordinated regulation of endothelial calcium signaling and shear stress-induced nitric oxide production by PKCβ and PKCη.

Ulus Travma Acil Cerrahi Derg. 2021 Sep;27(5): 516-525

Evaluation of the thiol disulfide homeostasis in patients with traumatic hemorrhagic shock.

Pinar İskender Uysal, Havva Şahin Kavaklı, Salim Neşelioğlu.

BACKGROUND: Traumatic hemorrhagic shock is a condition associated with a high mortality rate in the absence of timely diagnose and intervention. The class and severity of hemorrhagic shock are the key factors that guide the decisions in the management of these patients. This study aims to provide guidance for the timely administration of an appropriate treatment to patients with traumatic hemorrhagic shock, and thus, decrease morbidity and mortality, by determining shock severity and class more clearly with the use of the thiol disulfide homeostasis balance, which is an objective criterion.METHODS: This controlled, prospective, and clinical study was conducted in the Emergency Medicine Clinic at the University of Health Sciences, Ankara Numune Training and Research Hospital between October 1, 2018 and April 30, 2019. Thiol disulfide homeostasis was assessed in blood collected from patients and healthy volunteers. A total of one hundred two patients were included; of whom 52 were female and male volunteer patients aged 18 or older who presented to the emergency department with traumatic hemorrhagic bleeding and fifty were control subjects.
RESULTS: Patient and control groups demonstrated significantly different native thiol, total thiol, disulfide, disulfide/native thiol, and disulfide/total thiol levels (P-values for native thiol, total thiol, disulfide, disulfide/native thiol, and disulfide/total thiol: 0.001>, 0.001>, 0.018, 0.002, and 0.002, respectively). According to pairwise comparisons; Class-3 hemorrhagic shock was associated with significantly lower native thiol and total thiol levels compared to Class-1 and Class-2 hemorrhagic shock (Comparison of Class-1 and Class-3 hemorrhagic shock: p-value for native thiol = 0.001, p-value for total thiol = 0.002) (Comparison of Class-2 and Class-3 hemorrhagic shock: p-value for native thiol = 0.009, p-value for total thiol = 0.006). Total thiol levels were found to be lower in patients who died compared to those who survived (p=0.040).
CONCLUSION: Thiol disulfide homeostasis data were found to be correlated with the shock class and mortality. The assessment of thiol disulfide homeostasis can serve as a guide in the determination of the severity and classification of the disease, evaluation of the prognosis, and management of the treatment in traumatic hemorrhagic shock patients.

DOI: https://doi.org/10.14744/tjtes.2020.49765
Hepatology. 2021 Aug 28.

Regulator of G-protein signaling 14 protects the liver from ischemia reperfusion injury by suppressing TAK1 activation.

Jia-Kai Zhang, Ming-Jie Ding, Hui Liu, Ji-Hua Shi, Zhi-Hui Wang, Pei-Hao Wen, Yi Zhang, Bing Yan, Dan-Feng Guo, Xiao-Dan Zhang, Ruo-Lin Tao, Zhi-Ping Yan, Yan Zhang, Zhen Liu, Wen-Zhi Guo, Shui-Jun Zhang.

  BACKGROUND & AIMS: Hepatic ischemia-reperfusion injury (IRI) is a common complication of hepatectomy and liver transplantation. However, the mechanisms underlying hepatic IRI have not been fully elucidated. The regulator of G-protein signaling 14 (RGS14) is a multifunctional scaffolding protein that integrates G-protein and mitogen-activated protein kinase (MAPK) signaling pathways. However, the role of RGS14 in hepatic IRI remains unclear.APPROACH & RESULTS: We found that RGS14 expression increased in mice subjected to hepatic IR surgery and during hypoxia reoxygenation in hepatocytes. We constructed global RGS14 knockout (RGS14-KO) and hepatocyte-specific RGS14 transgenic (RGS14-TG) mice to establish 70% hepatic IRI models. Histological H&E staining, levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), expression of inflammatory factors, and apoptosis were used to assess liver damage and function in these models. We found that RGS14 deficiency significantly aggravated IR-induced liver injury and activated hepatic inflammatory responses and apoptosis in vivo and in vitro. Conversely, RGS14 overexpression exerted the opposite effect of the RGS14-deficient models. Phosphorylation of transforming growth factor-β-activated kinase 1(TAK1) and its downstream effectors JNK and p38 increased in the liver tissues of RGS14-KO mice, but was repressed in those of RGS14-TG mice. Furthermore, inhibition of TAK1 phosphorylation rescued the effect of RGS14 deficiency on JNK and p38 activation, thus blocking the inflammatory responses and apoptosis.
CONCLUSIONS: RGS14 plays a protective role in hepatic IR by inhibiting the activation of the TAK1-JNK/p38 signaling pathway. This may be a potential therapeutic strategy for reducing incidences of hepatic IRI in the future.

Keywords:  Apoptosis; Hepatic injury; Inflammation; Liver ischemia reperfusion injury; RGS14

DOI:  https://doi.org/10.1002/hep.32133
J Cell Mol Med. 2021 Jun 10.

The α2AR/Caveolin-1/p38MAPK/NF-κB axis explains dexmedetomidine protection against lung injury following intestinal ischaemia-reperfusion.

Lin Xu, Taiyuan Li, Qiuhong Chen, Zhen Liu, Yuesheng Chen, Kai Hu, Xuekang Zhang.

  Intestinal ischaemia-reperfusion (I/R) injury can result in acute lung injury due to ischaemia and hypoxia. Dexmedetomidine (Dex), a highly selective alpha2-noradrenergic receptor (α2AR) agonist used in anaesthesia, is reported to regulate inflammation in organs. This study aimed to investigate the role and mechanism of Dex in lung injury caused by intestinal I/R. After establishing a rat model of intestinal I/R, we measured the wet-to-dry specific gravity of rat lungs upon treatments with Dex, SB239063 and the α2AR antagonist Atipamezole. Moreover, injury scoring and histopathological studies of lung tissues were performed, followed by ELISA detection on tumour necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6 expression. Correlation of Caveolin-1 (Cav-1) protein expression with p38, p-p38, p-p65 and p65 in rat lung tissues was analysed, and the degree of cell apoptosis in lung tissues after intestinal I/R injury was detected by TUNEL assay. The lung injury induced by intestinal I/R was a dynamic process. Moreover, Dex had protective effects against lung injury by mediating the expression of Cal-1 and α2A -AR. Specifically, Dex promoted Cav-1 expression via α2A -AR activation and mitigated intestinal I/R-induced lung injury, even in the presence of Atipamezole. The protective effect of Dex on intestinal I/R-induced lung injury was also closely related to α2A -AR/p38 mitogen-activated protein kinases/nuclear factor-kappaB (MAPK/NF-κB) pathway. Dex can alleviate pulmonary inflammation after in intestinal I/R by promoting Cav-1 to inhibit the activation of p38 and NF-κB. In conclusion, Dex can reduce pulmonary inflammatory response even after receiving threats from both intestinal I/R injury and Atipamezole.

Keywords:  Caveolin-1; NF-κB; dexmedetomidine; intestinal ischaemia-reperfusion; lung injury; p38MAPK; α2A-AR

DOI:  https://doi.org/10.1111/jcmm.16614
J Physiol. 2021 Sep 01.

Naked mole-rat brain mitochondria tolerate in vitro ischemia.

Hang Cheng, Matthew E Pamenter.

  KEY POINTS: Ischemia is highly deleterious to mammalian brain and this damage is largely mediated by mitochondrial dysfunction. Naked mole-rats are among the most hypoxia-tolerant mammals and their brain tolerates ischemia ex vivo, but the impact of ischemia on mitochondrial function is unknown. Naked mole-rat but not mouse brain mitochondria retain respiratory capacity and membrane integrity following ischemia or ischemia/reperfusion. Differences in free radical management and respiratory pathway control between species may mediate this tolerance. These results help us understand how natural models of hypoxia-tolerance also tolerate ischemia in brain.ABSTRACT: Naked mole-rats (NMRs; Heterocephalus glaber) are among the most hypoxia-tolerant mammals. There is evidence that NMR brain tolerates in vitro hypoxia and NMR brain mitochondria exhibit functional plasticity following in vivo hypoxia; however, if and how these organelles tolerate ischemia and how ischemic stress impacts mitochondrial energetics and redox regulation is entirely unknown. We hypothesized that mitochondria fundamentally contribute to in vitro ischemia resistance in NMR brain. To test this, we treated NMR and CD-1 mouse cortical brain sheets with an in vitro ischemic mimic and evaluated mitochondrial respiration capacity and redox regulation following 15- or 30-mins ischemia or ischemia/reperfusion (I/R). We found that, relative to mice, NMR brain largely retains mitochondrial function and redox balance post-ischemia and I/R. Specifically: i) ischemia reduced complex I and II -linked respiration ∼50-70% in mice, versus ∼20-40% in NMR brain, ii) NMR but not mouse brain maintained relatively steady respiration control ratios and robust mitochondrial membrane integrity, iii) electron leakage post-ischemia was lesser in NMR than mouse brain and NMR brain retained higher coupling efficiency, and iv) free radical generation during and following ischemia and I/R was lower from NMR brains than mice. Taken together, our results indicate that NMR brain mitochondria are more tolerant of ischemia and I/R than mice and retain respiratory capacity while avoiding redox derangements. Overall, these findings support the hypothesis that hypoxia-tolerant NMR brain is also ischemia-tolerant and suggest that NMRs may be a natural model of ischemia-tolerance in which to investigate evolutionarily derived solutions to ischemic pathology. This article is protected by copyright. All rights reserved.

Keywords:  electron transport system; free radicals; glutamate dehydrogenase; membrane integrity; mitochondrial permeability transition pore; mitochondrial respiration

DOI:  https://doi.org/10.1113/JP281942
Int Immunopharmacol. 2021 Aug 25. pii: S1567-5769(21)00688-3. [Epub ahead of print]100 108052

HepaticIschemia/Reperfusion Injuryinvolves functional tryptase/PAR-2 signaling in liver sinusoidal endothelial cell population.

Jian Song, Zhigang He, Muqing Yang, Tianyu Yu, Xiaodong Wang, Bin Liu, Jiyu Li.

  Mast cells (MCs) are tissue-resident effector cells that could be the earliest responder to release a unique, stimulus-specific set of mediators in hepatic ischemia-reperfusion (IR) injury However, how MCs function in the hepatic IR has remained a formidable challenge due to the substantial redundancy and functional diverse of these mediators. Tryptase is the main protease for degranulation of MCs and its receptor-protease-activated receptor 2 (PAR-2) is widely expressed in endothelial cells. It is unclear whether and how tryptase/PAR-2 axis participates in hepatic IR. We employed an experimental warm 70% liver IR model in mice and found that tryptase was accumulated in the circulation during hepatic IR and positively correlated with liver injury. Tryptase inhibition by protamine can significantly down-regulate the expression of adhesion molecules and reduce neutrophil infiltration within the liver. The level of inflammatory factors and chemokines were also consistent with the pathological change of the liver. In addition, the treatment with exogeneous tryptase in MC-deficient mice can induce the damage observed in wild type mice in the context of liver IR. In vitro, neutrophil infiltration and inflammatory factor secretion were regulated by Tryptase/PAR-2, involving the adhesion molecule expression to regulate neutrophil adhesion dependent on NF-κB pathway. Conclusion: tryptase/PAR-2 participates in liver injury through the activation of LSECs in the early phase of liver IR.

Keywords:  Hepatic ischemia–reperfusion; Liver sinusoidal endothelial cells; Mast cells; Receptor-protease-activated receptor 2; Tryptase

DOI:  https://doi.org/10.1016/j.intimp.2021.108052
Redox Biol. 2021 Aug 24. pii: S2213-2317(21)00273-1. [Epub ahead of print]46 102114

Cardioprotective effect of MLN4924 on ameliorating autophagic flux impairment in myocardial ischemia-reperfusion injury by Sirt1.

Ji Zhang, Jing Cui, Fei Zhao, Longhua Yang, Xueli Xu, Yangyang Shi, Bo Wei.

  Neddylation is essential for cardiomyocyte survival in the presence of oxidative stress, and it participates in autophagy regulation. However, whether MLN4924-an inhibitor of neddylation-exerts cardioprotective effects against myocardial ischemia/reperfusion (MI/R) remains unknown. In the present study, MLN4924 exerted strong cardioprotective effects, demonstrated by significantly elevated cell viability, a decreased LDH leakage rate, and improved cell morphology following H2O2-induced injury in vitro. MLN4924 also markedly decreased the serum myocardial zymogram level, ameliorated cardiac histopathological alterations, and alleviated left ventricular contractile dysfunction, thus limiting the cardiac infarct size in vivo compared with those in MI/R mice. Amazingly, such action of MLN4924 was abrogated by a combined treatment with the autophagic flux inhibitor, chloroquine. The mRFP-GFP-LC3 assay illustrated that MLN4924 restored the defective autophagic flux via enhancing the autolysosome formation. Notably, the expression levels of Rab7 and Atg5 were markedly up-regulated in MLN4924 treated cells and mice subjected to H2O2 or MI/R, respectively, while knockdown of Sirt1 in cells and heart tissue largely blocked such effect and induced autophagosome accumulation by inhibiting its fusion with lysosomes. Transmission electron microscopic analysis, histopathological assay and TUNEL detection of the heart tissues showed that the absence of Sirt1 blocked the cardioprotective effect of MLN4924 by further exacerbating the impaired autophagic flux during MI/R injury in vivo. Taken together, MLN4924 exhibited the strong cardioprotective action via restoring the impaired autophagic flux in H2O2-induced injury in vitro and in MI/R mice. Our work implicated that Sirt1 played a critical role in autophagosome clearance, likely through up-regulating Rab7 in MI/R.

Keywords:  Autophagic flux; MLN4924; Myocardial ischemia/reperfusion; Sirt1

DOI:  https://doi.org/10.1016/j.redox.2021.102114
Peptides. 2021 Aug 31. pii: S0196-9781(21)00153-4. [Epub ahead of print] 170645

Changes of pituitary adenylate cyclase activating polypeptide (PACAP) level in polytrauma patents in the early post-traumatic period.

Andrea Tamás, Dénes Tóth, Dániel Pham, Csaba Loibl, Szilárd Rendeki, Csaba Csontos, Martin Rozanovic, Lajos Bogár, Beáta Polgár, József Németh, Attila Gyenesei, Róbert Herczeg, Zalán Szántó, Dora Reglodi.

  In polytrauma patients who survive the primary insult, the imbalance between the pro- and anti-inflammatory processes seems to be responsible for life-threatening complications such as sepsis or multiple organ dysfunction syndrome. Measurement of C-reactive protein (CRP) and procalcitonin (PCT) is a standard way for differentiating between infectious (bacterial) and non-infectious inflammation. Monitoring of immune cell functions, like leukocyte anti-sedimentation rate (LAR) can be also useful to diagnose infectious complications. Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide with well-known immunomodulatory and anti-inflammatory effects. The aim of our study was to determine the changes of PACAP38 levels in polytrauma patients in the early post-traumatic period in intensive care unit and analyse possible correlation of its level with conventional (CRP, PCT) and unconventional (LAR) laboratory parameters. Twenty polytrauma patients were enrolled. Blood samples were taken daily for five days. We observed significant correlation between PACAP38 and CRP levels on day 4 and 5 as well as between PACAP38 and LAR levels all of the days. This could be due to the anti-inflammatory and cytoprotective functions of PACAP38 as part of an endogenous response to the trauma induced systemic inflammatory response syndrome. These significant correlations could have clinical importance to monitor the dynamic balance of pro- and anti-inflammatory processes in case of polytraumatic patients.

Keywords:  Biomarker; C-reactive protein; Leukocyte anti-sedimentation rate; Pituitary adenylate cyclase activating polypeptide; Polytrauma; Procalcitonin

DOI:  https://doi.org/10.1016/j.peptides.2021.170645
Stem Cells Int. 2021 ;2021 9969372

Protective Effect of Adipose-Derived Mesenchymal Stem Cell Secretome against Hepatocyte Apoptosis Induced by Liver Ischemia-Reperfusion with Partial Hepatectomy Injury.

Zhihui Jiao, Yajun Ma, Yue Wang, Tao Liu, Qianzhen Zhang, Xiaoning Liu, Chenxi Piao, Boyang Liu, Hongbin Wang.

Ischemia-reperfusion injury (IRI) is an inevitable complication of liver surgery and liver transplantation. Hepatocyte apoptosis plays a significant role in the pathological process of hepatic IRI. Adipose-derived stem cells (ADSCs) are known to repair and regenerate damaged tissues by producing bioactive factors, including cytokines, exosomes, and extracellular matrix components, which collectively form the secretome of these cells. The aim of this study was to assess the protective effects of the ADSCs secretome after liver ischemia-reperfusion combined with partial hepatectomy in miniature pigs. We successfully established laparoscopic liver ischemia-reperfusion with partial hepatectomy in miniature pigs and injected saline, DMEM, ADSC-secretome, and ADSCs directly into the liver parenchyma immediately afterwards. Both ADSCs and the ADSC-secretome improved the IR-induced ultrastructural changes in hepatocytes and significantly decreased the proportion of TUNEL-positive apoptotic cells along with caspase activity. Consistent with this, P53, Bax, Fas, and Fasl mRNA and protein levels were markedly decreased, while Bcl-2 was significantly increased in the animals treated with ADSCs and ADSC-secretome. Our findings indicate that ADSCs exert therapeutic effects in a paracrine manner through their secretome, which can be a viable alternative to cell-based regenerative therapies.

DOI: https://doi.org/10.1155/2021/9969372
Stem Cell Res Ther. 2021 Aug 28. 12(1): 483

Oct4-dependent FoxC1 activation improves the survival and neovascularization of mesenchymal stem cells under myocardial ischemia.

Zhou Ji, Songsheng Chen, Jin Cui, Weiguang Huang, Rui Zhang, Jianrui Wei, Shaoheng Zhang.

  BACKGROUND: The administration of mesenchymal stem cells (MSCs) remains the most promising approach for cardiac repair after myocardial infarct (MI). However, their poor survival and potential in the ischemic environment limit their therapeutic efficacy for heart repair after MI. The purpose of this study was to investigate the influence of FoxC1-induced vascular niche on the activation of octamer-binding protein 4 (Oct4) and the fate of MSCs under hypoxic/ischemic conditions.METHODS: Vascular microenvironment/niche was induced by efficient delivery of FoxC1 transfection into hypoxic endothelial cells (ECs) or infarcted hearts. MSCs were cultured or injected into this niche by utilizing an in vitro coculture model and a rat MI model. Survival and neovascularization of MSCs regulated by Oct4 were explored using gene transfer and functional studies.
RESULTS: Here, using gene expression heatmap, we demonstrated that cardiac ECs rapidly upregulated FoxC1 after acute ischemic cardiac injury, contributing to an intrinsic angiogenesis. In vitro, FoxC1 accelerated tube-like structure formation and increased survival of ECs, resulting in inducing a vascular microenvironment. Overexpression of FoxC1 in ECs promoted survival and neovascularization of MSCs under hypoxic coculture. Overexpression of Oct4, a FoxC1 target gene, in MSCs enhanced their mesenchymal-to-endothelial transition (MEndoT) while knockdown of Oct4 by siRNA altering vascularization. In a rat MI model, overexpression of FoxC1 in ischemic hearts increased post-infarct vascular density and improved cardiac function. The transplantation of adOct4-pretreated MSCs into these ischemic niches augments MEndoT, enhanced vascularity, and further improved cardiac function. Consistently, these cardioprotective effects of FoxC1 was abrogated when Oct4 was depleted in the MSCs and was mimicked by overexpression of Oct4.
CONCLUSIONS: Together, these studies demonstrate that the FoxC1/Oct4 axis is an essential aspect for survival and neovascularization of MSCs in the ischemic conditions and represents a potential therapeutic target for enhancing cardiac repair.

Keywords:  Angiogenesis; FoxC1; Hypoxic; Mesenchymal stem cells; Niche; Oct4

DOI:  https://doi.org/10.1186/s13287-021-02553-w
Cell Signal. 2021 Aug 30. pii: S0898-6568(21)00214-X. [Epub ahead of print] 110125

Coordinated regulation of endothelial calcium signaling and shear stress-induced nitric oxide production by PKCβ and PKCη.

Tenderano T Muzorewa, Donald G Buerk, Dov Jaron, Kenneth A Barbee.

  BACKGROUND: Protein Kinase C (PKC) is a promiscuous serine/threonine kinase regulating vasodilatory responses in vascular endothelial cells. Calcium-dependent PKCbeta (PKCβ) and calcium-independent PKCeta (PKCη) have both been implicated in the regulation and dysfunction of endothelial responses to shear stress and agonists.OBJECTIVE: We hypothesized that PKCβ and PKCη differentially modulate shear stress-induced nitric oxide (NO) production by regulating the transduced calcium signals and the resultant eNOS activation. As such, this study sought to characterise the contribution of PKCη and PKCβ in regulating calcium signaling and endothelial nitric oxide synthase (eNOS) activation after exposure of endothelial cells to ATP or shear stress.
METHODS: Bovine aortic endothelial cells were stimulated in vitro under pharmacological inhibition of PKCβ with LY333531 or PKCη targeting with a pseudosubstrate inhibitor. The participation of PKC isozymes in calcium flux, eNOS phosphorylation and NO production was assessed following stimulation with ATP or shear stress.
RESULTS: PKCη proved to be a robust regulator of agonist- and shear stress-induced eNOS activation, modulating calcium fluxes and tuning eNOS activity by multi-site phosphorylation. PKCβ showed modest influence in this pathway, promoting eNOS activation basally and in response to shear stress. Both PKC isozymes contributed to the constitutive and induced phosphorylation of eNOS. The observed PKC signaling architecture is intricate, recruiting Src to mediate a portion of PKCη's control on calcium entry and eNOS phosphorylation. Elucidation of the importance of PKCη in this pathway was tempered by evidence of a single stimulus producing concurrent phosphorylation at ser1179 and thr497 which are antagonistic to eNOS activity.
CONCLUSIONS: We have, for the first time, shown in a single species in vitro that shear stress- and ATP-stimulated NO production are differentially regulated by classical and novel PKCs. This study furthers our understanding of the PKC isozyme interplay that optimizes NO production. These considerations will inform the ongoing design of drugs for the treatment of PKC-sensitive cardiovascular pathologies.

Keywords:  Calcium; Nitric oxide; PKC; Phosphorylation; Shear stress; eNOS

DOI:  https://doi.org/10.1016/j.cellsig.2021.110125