bims-heshmo 2021-09-26 papers

bims-heshmo

Biomed News

on Trauma hemorrhagic shock — molecular basis

Issue of 2021–09–26
nine papers selected by
Andreia Luís, Ludwig Boltzmann Institute

Evaluating the Cost-effectiveness of Prehospital Plasma Transfusion in Unstable Trauma Patients: A Secondary Analysis of the PAMPer Trial.
Sulforaphane-Dependent Up-Regulation of NRF2 Activity Alleviates Both Systemic Inflammatory Response and Lung Injury After Hemorrhagic Shock/Resuscitation In Mice.
Treprostinil alleviates hepatic mitochondrial injury during rat renal ischemia-reperfusion injury.
A Functional Variant of CXCL16 Is Associated With Predisposition to Sepsis and MODS in Trauma Patients: Genetic Association Studies.
Rimonabant ameliorates hepatic ischemia/reperfusion injury in rats: Involvement of autophagy via modulating ERK- and PI3K/AKT-mTOR pathways.
Properdin Deficiency Impairs Phagocytosis and Enhances Injury at Kidney Repair Phase Post Ischemia-Reperfusion.
Chaperone-Mediated Autophagy of eNOS in Myocardial Ischemia-Reperfusion Injury.
LncRNA TUG1 attenuates ischaemia-reperfusion-induced apoptosis of renal tubular epithelial cells by sponging miR-144-3p via targeting Nrf2.
Phosphodiesterase 4 mediates interleukin-8-induced heterologous desensitization of the β2 -adrenergic receptor.

JAMA Surg. 2021 Sep 22.

Evaluating the Cost-effectiveness of Prehospital Plasma Transfusion in Unstable Trauma Patients: A Secondary Analysis of the PAMPer Trial.

Katherine A Hrebinko, Jason L Sperry, Francis X Guyette, Joshua B Brown, Brian J Daley, Richard S Miller, Brian G Harbrecht, Jeffrey A Claridge, Herb A Phelan, Matthew D Neal, Brian S Zuckerbraun, Mark H Yazer, Kristina J Nicholson.

Importance: Prehospital plasma transfusion is lifesaving for trauma patients in hemorrhagic shock but is not commonly used owing to cost and feasibility concerns.
Objective: To evaluate the cost-effectiveness of prehospital thawed plasma transfusion in trauma patients with hemorrhagic shock during air medical transport.
Design, Setting, and Participants: A decision tree and Markov model were created to compare standard care and prehospital thawed plasma transfusion using published and unpublished patient-level data from the Prehospital Plasma in Air Medical Transport in Trauma Patients at Risk for Hemorrhagic Shock (PAMPer) trial conducted from May 2014 to October 2017, health care and trauma-specific databases, and the published literature. Prehospital transfusion, short-term inpatient care, and lifetime health care costs and quality of life outcomes were included. One-way, 2-way, and Monte Carlo probabilistic sensitivity analyses were performed across clinically plausible ranges. Data were analyzed in December 2019.
Main Outcomes and Measures: Relative costs and health-related quality of life were evaluated by an incremental cost-effectiveness ratio at a standard willingness-to-pay threshold of $100 000 per quality-adjusted life-year (QALY).
Results: The trial included 501 patients in the modified intention-to-treat cohort. Median (interquartile range) age for patients in the thawed plasma and standard care cohorts were 44 (31-59) and 46 (28-60) years, respectively. Overall, 364 patients (72.7%) were male. Thawed plasma transfusion was cost-effective with an incremental cost-effectiveness ratio of $50 467.44 per QALY compared with standard care. The preference for thawed plasma was robust across all 1- and 2-way sensitivity analyses. When considering only patients injured by a blunt mechanism, the incremental cost-effectiveness ratio decreased to $37 735.19 per QALY. Thawed plasma was preferred in 8140 of 10 000 iterations (81.4%) on probabilistic sensitivity analysis. A detailed analysis of incremental costs between strategies revealed most were attributable to the in-hospital and postdischarge lifetime care of critically ill patients surviving severe trauma.
Conclusions and Relevance: In this study, prehospital thawed plasma transfusion during air medical transport for trauma patients in hemorrhagic shock was lifesaving and cost-effective compared with standard care and should become commonplace.

DOI: https://doi.org/10.1001/jamasurg.2021.4529
Shock. 2021 Sep 23.

Sulforaphane-Dependent Up-Regulation of NRF2 Activity Alleviates Both Systemic Inflammatory Response and Lung Injury After Hemorrhagic Shock/Resuscitation In Mice.

Weiqiang Liang, Johannes Greven, Athanassios Fragoulis, Klemens Horst, Felix Bläsius, Christoph Wruck, Thomas Pufe, Philipp Kobbe, Frank Hildebrand, Philipp Lichte.

ABSTRACT: Hemorrhagic shock/resuscitation (HS/R) is closely associated with overwhelming oxidative stress and systemic inflammation. As an effective activator of the nuclear factor-erythroid factor 2 related factor 2 (Nrf2) pathway, sulforaphane (SFN) exerts antioxidant and anti-inflammatory effects. We explored SFN's effects on alveolar macrophages (AMs), systemic inflammation, and pulmonary damage in an isolated murine HS/R model. Male C57/BL6 wild type and transgenic antioxidant response element (ARE)-luciferase (luc) mice (both n = 6 per group) were exposed to either pressure-controlled HS/R (mean arterial pressure 35-45 mmHg for 90 mins) or sham procedure (surgery without HS/R) or were sacrificed without intervention (control group). Fluid resuscitation was performed via the reinfusion of withdrawn blood and 0.9% saline. Sulforaphane or 0.9% saline (vehicle) was administrated intraperitoneally. Mice were sacrificed 6 h, 24 h, or 72 h after resuscitation. Bioluminescence imaging of ARE-luc mice was conducted to measure pulmonary Nrf2 activity. Plasma was collected to determine systemic cytokine levels. Alveolar macrophages were isolated before measuring cytokines in the supernatant and performing immunofluorescence staining, as well as Western blot for intracellular Nrf2. Histological damage was assessed via the acute lung injury score and wet/dry ratio.Hemorrhagic shock/resuscitation was associated with pulmonary Nrf2 activation. Sulforaphane enhanced pulmonary Nrf2 activity and the Nrf2-activation of AM, while it decreased lung damage. Sulforaphane exerted down-regulatory effects on AM-generated and systemic pro-inflammatory mediators, while it did not have such effects on interleukin-10 (IL-10).In conclusion, SFN beneficially enhances pulmonary Nrf2 activity and promotes Nrf2 accumulation in AMs' nuclei. This may exert not only local protective effects but also systemic effects via the down-regulation of pro-inflammatory cytokines. The administration of Nrf2 activator post-HS/R may represent an innovative treatment strategy.

DOI: https://doi.org/10.1097/SHK.0000000000001859
Biomed Pharmacother. 2021 Sep 21. pii: S0753-3322(21)00956-2. [Epub ahead of print]143 112172

Treprostinil alleviates hepatic mitochondrial injury during rat renal ischemia-reperfusion injury.

Joyce Hou, Evelyn Tolbert, Mark Birkenbach, Nisanne S Ghonem.

   BACKGROUND: Renal ischemia-reperfusion injury (IRI) causes acute kidney injury as well as liver injury. Renal IRI depletes hepatic antioxidants, promotes hepatic inflammation and dysfunction through Tlr9 upregulation. There is no treatment available for liver injury during renal IRI. This study examines the hepatoprotective role of treprostinil, a prostacyclin analog, during renal IRI.
METHODS: Male Sprague-Dawley rats were divided into four groups: control, sham, IRI-placebo, or IRI-treprostinil and subjected to bilateral ischemia (45 min) followed by reperfusion (1-72 h). Placebo or treprostinil (100 ng/kg/min) was administered subcutaneously via an osmotic minipump.
RESULTS: Treprostinil significantly reduced peak serum creatinine, BUN, ALT and AST levels vs. IRI-placebo. Treprostinil also restored hepatic levels of superoxide dismutase, glutathione, catalase, and Gclc expression to baseline, while reducing lipid peroxidation vs. IRI-placebo. Additionally, treprostinil significantly reduced elevated hepatic Tlr9, Il-1β, Ccl2, Vcam1, and Serpine1 mRNA expression. Renal IRI increased hepatic apoptosis which was inhibited by treprostinil through reduced cytochrome c and cleaved caspase-3 protein expression. Treprostinil enhanced hepatic ATP concentrations and mitochondrial DNA copy number and improved mitochondrial dynamics by restoring Pgc-1α expression and significantly upregulating Mfn1, Mfn2, and Sirt3 levels, while reducing Drp-1 protein vs. IRI-placebo. Non-targeted semi-quantitative proteomics showed improved oxidative stress indices and ATP subunits in the IRI-treprostinil group.
CONCLUSIONS: Treprostinil improved hepatic function and antioxidant levels, while suppressing the inflammatory response and alleviating Tlr9-mediated apoptotic injury during renal IRI. Our study provides evidence of treprostinil's hepatoprotective effect, which supports the therapeutic potential of treprostinil in reducing hepatic injury during renal IRI.

Keywords:  Apoptosis; Inflammation; Liver injury; Oxidative stress; Prostacyclin

DOI:  https://doi.org/10.1016/j.biopha.2021.112172
Front Genet. 2021 ;12 720313

A Functional Variant of CXCL16 Is Associated With Predisposition to Sepsis and MODS in Trauma Patients: Genetic Association Studies.

Jianhui Sun, Huacai Zhang, Di Liu, Li Cui, Qiang Wang, Lebin Gan, Dalin Wen, Jun Wang, Juan Du, Hong Huang, Anqiang Zhang, Jin Deng, Jianxin Jiang, Ling Zeng.

   Purpose: CXC chemokines are mediators which mediate immune cells migration to sites of inflammation and injury. Chemokine C-X-C motif ligand 16 (CXCL16) plays an important role in the occurrence and development of sepsis through leukocyte chemotaxis, leukocyte adhesion and endotoxin clearance. In this study, we selected a set of tagging single nucleotide polymorphisms (tag SNPs) in the CXCL16 gene and investigated their clinical relevance to the development of sepsis and multiple organ dysfunction syndrome (MODS) in patients with major trauma in three independent Chinese Han populations.
Methods: A total of 1,620 major trauma patients were enrolled in this study. Among these patients, 920 came from Chongqing in western China, 350 came from Zhejiang Province in eastern China, and 350 came from Guizhou Province in southwestern China. The improved multiplex ligation detection reaction (iMLDR) method was employed in the genotyping and genetic association analyses to determine the associations between CXCL16 haplotypes and sepsis morbidity rate and higher MOD scores in three cohorts.
Results: Only CXCL16 T123V181 haplotype was associated with an increased risk for sepsis morbidity and higher MOD scores in the three cohorts (OR = 1.89, P = 0.001 for the Chongqing cohort; OR = 1.76, P = 0.004 for the Zhejiang cohort; OR = 1.55, P = 0.012 for the Guizhou cohort). The effect of T123V181 haplotype on the chemotaxis, migration and endotoxin clearance of immune cells were further observed. Protein modeling analysis showed that T123 and V181 might alter the structure of the CXCL16 active center. Thus it enhanced the chemotaxis and adhesion ability of immunocytes.
Conclusion: We demonstrate the mechanism of CXCL16 T123V181 haplotype which regulates the sepsis morbidity rate and thus provide a new biomarker for early diagnosis of sepsis and MODS.
Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT01713205 (https://www.clinicaltrials.gov/ct2/results?cond=&term=+NCT01713205&cntry=&state=&city=&dist=).

Keywords:  CXCL16; multiple organ dysfunction; sepsis; single nucleotide polymorphisms; trauma

DOI:  https://doi.org/10.3389/fgene.2021.720313
Int Immunopharmacol. 2021 Sep 15. pii: S1567-5769(21)00776-1. [Epub ahead of print]100 108140

Rimonabant ameliorates hepatic ischemia/reperfusion injury in rats: Involvement of autophagy via modulating ERK- and PI3K/AKT-mTOR pathways.

Samar Rezq, Reham Hassan, Mona F Mahmoud.

  Hepatic ischemia/reperfusion (HIR), which can result in severe liver injury and dysfunction, is usually associated with autophagy and endocannabinoid system derangements. Whether or not the modulation of the autophagic response following HIR injury is involved in the hepatoprotective effect of the cannabinoid receptor 1(CB1R) antagonist rimonabant remains elusive and is the aim of the current study. Rats pre-treated with rimonabant (3 mg/kg) or vehicle underwent 30 min hepatic ischemia followed by 6 hrs. reperfusion. Liver injury was evaluated by serum ALT, AST, bilirubin (total and direct levels) and histopathological examination. The inflammatory, profibrotic and oxidative responses were investigated by assessing hepatic tumor necrosis factor α (TNFα), nuclear factor kappa B (NF-κB), transforming growth factor (TGF-β), lipid peroxidation and reduced glutathione. The hepatic levels of CB1R and autophagic markers p62, Beclin-1, and LC3 as well as the autophagic signaling inhibitors ERK1/2, PI3K, Akt and mTOR were also determined. Rimonabant significantly attenuated HIR-induced increases in hepatic injury, inflammation, profibrotic responses and oxidative stress and improved the associated pathological features. Rimonabant modulated the expression of p62, Beclin-1, and LC3, down-regulated CB1R, and dcreased pERK1/2, PI3K, Akt, and mTOR activities. The current study suggests that rimonabant can protect the liver from IR injury at least in part by inducing autophagy, probably by modulating ERK- and/or PI3K/AKT-mTOR signaling.

Keywords:  Autophagy; Cannabinoid receptor 1; Hepatic ischemia/reperfusion; Rimonabant

DOI:  https://doi.org/10.1016/j.intimp.2021.108140
Front Immunol. 2021 ;12 697760

Properdin Deficiency Impairs Phagocytosis and Enhances Injury at Kidney Repair Phase Post Ischemia-Reperfusion.

Yuanyuan Wu, Zinah D Zwaini, Nigel J Brunskill, Xinyue Zhang, Hui Wang, Ravinder Chana, Cordula M Stover, Bin Yang.

  Properdin, a positive regulator of complement alternative pathway, participates in renal ischemia-reperfusion (IR) injury and also acts as a pattern-recognition molecule affecting apoptotic T-cell clearance. However, the role of properdin in tubular epithelial cells (TECs) at the repair phase post IR injury is not well defined. This study revealed that properdin knockout (PKO) mice exhibited greater injury in renal function and histology than wild-type (WT) mice post 72-h IR, with more apoptotic cells and macrophages in tubular lumina, increased active caspase-3 and HMGB1, but better histological structure at 24 h. Raised erythropoietin receptor by IR was furthered by PKO and positively correlated with injury and repair markers. Properdin in WT kidneys was also upregulated by IR, while H2O2-increased properdin in TECs was reduced by its small-interfering RNA (siRNA), with raised HMGB1 and apoptosis. Moreover, the phagocytic ability of WT TECs, analyzed by pHrodo Escherichia coli bioparticles, was promoted by H2O2 but inhibited by PKO. These results were confirmed by counting phagocytosed H2O2-induced apoptotic TECs by in situ end labeling fragmented DNAs but not affected by additional serum with/without properdin. Taken together, PKO results in impaired phagocytosis at the repair phase post renal IR injury. Properdin locally produced by TECs plays crucial roles in optimizing damaged cells and regulating phagocytic ability of TECs to effectively clear apoptotic cells and reduce inflammation.

Keywords:  apoptosis; inflammation; ischemia–reperfusion injury; phagocytosis; properdin; repair

DOI:  https://doi.org/10.3389/fimmu.2021.697760
Circ Res. 2021 Sep 22.

Chaperone-Mediated Autophagy of eNOS in Myocardial Ischemia-Reperfusion Injury.

Jaganathan Subramani, Venkatesh Kundumani-Sridharan, Kumuda C Das.

Rationale: Nitric oxide (NO) produced by endothelial nitric oxide synthase (eNOS) protects against myocardial ischemia-reperfusion injury (I/R). However, reperfusion of myocardium results in superoxide (O2•-) generation, which promotes eNOS glutathionylation that produces O2•- instead of NO. It is unclear whether glutathionylated eNOS (SG-eNOS) continues to produce O2•- indefinitely or undergoes a time-dependent degradation. Objective: To determine whether SG-eNOS continues to produce O2•- in I/R for a prolonged period causing accentuated I/R injury or it undergoes a time-dependent degradation. Methods and Results: Since SG-eNOS produces significant O2•- instead of NO, we sought to determine the time-course of SG-eNOS levels in the HCAEC in hypoxia/reoxygenation (H/R) by western analysis and immunoprecipitation. SG-eNOS was degraded by chaperone-mediated autophagy (CMA), as inhibitors of CMA rescued eNOS expression. We further confirmed CMA by high resolution confocal and electron microscopy. We showed that SG-eNOS is targeted by HSC70 chaperone via its interaction with glutathionylated-cysteine 691 and 910. Glutathionylation of cysteine 691 residue in H/R exposes 735QRYRL739 motif for interaction with HSC70, and consequent transportation to LAMP2A vesicle, where it is degraded by lysosomal proteases. Mutagenesis of these residues in eNOS inhibited its CMA. Using contrast echocardiography and electron paramagnetic resonance spectrometry (EPR), we found that Trx-Tg mice show improved myocardial perfusion and decreased myocardial apoptosis in I/R due to deglutathionylation of SG-eNOS and restoration of NO generation. Further, WT mice treated with recombinant human Trx (rhTrx) were protected against eNOS CMA, and restored NO production with improved myocardial perfusion and decreased I/R injury. Conclusions: SG-eNOS undergoes degradation via CMA, following prolonged retention in the cytosol. CMA of SG-eNOS terminates O2•- generation preventing further tissue damage but causes irreversible loss of eNOS and NO availability. Prompt deglutathionylation of SG-eNOS prevents CMA, promotes NO production, and improved myocardial perfusion, resulting in amelioration of reperfusion injury.

DOI: https://doi.org/10.1161/CIRCRESAHA.120.317921
J Cell Mol Med. 2021 Sep 21.

LncRNA TUG1 attenuates ischaemia-reperfusion-induced apoptosis of renal tubular epithelial cells by sponging miR-144-3p via targeting Nrf2.

Sheng Zhao, Wu Chen, Wei Li, Weimin Yu, Siqi Li, Ting Rao, Yuan Ruan, Xiangjun Zhou, Cong Liu, Yucheng Qi, Fan Cheng.

  Renal ischaemia/reperfusion (I/R) injury may induce kidney damage and dysfunction, in which oxidative stress and apoptosis play important roles. Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) are reported to be closely related to renal I/R, but the specific molecular mechanism is still unclear. The purpose of this research was to explore the regulatory effect of lncRNA TUG1 on oxidative stress and apoptosis in renal I/R injury. This research revealed that in renal I/R injury and hypoxia/reperfusion (H/R) injury in vitro, the expression level of lncRNA TUG1 was upregulated, and oxidative stress levels and apoptosis levels were negatively correlated with the expression level of lncRNA TUG1. Using bioinformatics databases such as TargetScan and microRNA.org, microRNA-144-3p (miR-144-3p) was predicted to be involved in the association between lncRNA TUG1 and Nrf2. This study confirmed that the level of miR-144-3p was significantly reduced following renal I/R injury and H/R injury in vitro, and miR-144-3p was determined to target Nrf2 and inhibit its expression. In addition, lncRNA TUG1 can reduce the inhibitory effect of miR-144-3p on Nrf2 by sponging miR-144-3p. In summary, our research shows that lncRNA TUG1 regulates oxidative stress and apoptosis during renal I/R injury through the miR-144-3p/Nrf2 axis, which may be a new treatment target for renal I/R injury.

Keywords:  LncRNA TUG1; Nrf2; apoptosis; miR-144-3p; renal ischaemia/reperfusion injury

DOI:  https://doi.org/10.1111/jcmm.16924
FASEB J. 2021 Oct;35(10): e21946

Phosphodiesterase 4 mediates interleukin-8-induced heterologous desensitization of the β2 -adrenergic receptor.

Thomas C Rich, Silas J Leavesley, Angela P Brandon, Cilina A Evans, S Vamsee Raju, Brant M Wagener.

  Acute respiratory distress syndrome (ARDS) is a life-threatening illness characterized by decreased alveolar-capillary barrier function, pulmonary edema consisting of proteinaceous fluid, and inhibition of net alveolar fluid transport responsible for resolution of pulmonary edema. There is currently no pharmacotherapy that has proven useful to prevent or treat ARDS, and two trials using beta-agonist therapy to treat ARDS demonstrated no effect. Prior studies indicated that IL-8-induced heterologous desensitization of the beta2-adrenergic receptor (β2 -AR) led to decreased beta-agonist-induced mobilization of cyclic adenosine monophosphate (cAMP). Interestingly, phosphodiesterase (PDE) 4 inhibitors have been used in human airway diseases characterized by low intracellular cAMP levels and increases in specific cAMP hydrolyzing activity. Therefore, we hypothesized that PDE4 would mediate IL-8-induced heterologous internalization of the β2 -AR and that PDE4 inhibition would restore beta-agonist-induced functions. We determined that CINC-1 (a functional IL-8 analog in rats) induces internalization of β2 -AR from the cell surface, and arrestin-2, PDE4, and β2 -AR form a complex during this process. Furthermore, we determined that cAMP associated with the plasma membrane was adversely affected by β2 -AR heterologous desensitization. Additionally, we determined that rolipram, a PDE4 inhibitor, reversed CINC-1-induced derangements of cAMP and also caused β2 -AR to successfully recycle back to the cell surface. Finally, we demonstrated that rolipram could reverse CINC-1-mediated inhibition of beta-agonist-induced alveolar fluid clearance in a murine model of trauma-shock. These results indicate that PDE4 plays a role in CINC-1-induced heterologous internalization of the β2 -AR; PDE4 inhibition reverses these effects and may be a useful adjunct in particular ARDS patients.

Keywords:  FRET; acute lung injury; internalization; recycling; trauma

DOI:  https://doi.org/10.1096/fj.202002712RR