Shock Induction Research Articles

P4605Landiolol, a beta-blocker, optimizes cardiac energetics and peripheral microhemodynamics better than ivabradine while reducing heart rate at hemodynamic resuscitation of experimental septic shock

Abstract Background Septic shock is associated with sympathetic over-activation characterized by tachycardia, which is associated with poor survival. Though several kinds of drugs are available to reduce heart rate (HR), it is not clear which drug should be used to reduce HR effectively in initial hemodynamic resuscitation in septic shock. Purpose The aim of this study was to experimentally investigate comparative effects of landiolol (a β-blocker) and ivabradine (an If-channel inhibitor) on initial hemodynamic resuscitation in a canine model of endotoxin shock. Methods We used 19 anesthetized dogs. Seven dogs were allocated to control (CT) group, six dogs to landiolol (BB) group, and six dogs to ivabradine (IVA) group. In all the groups, endotoxin shock was induced by intravenous infusion of Escherichia coli lipopolysaccharide (4 mg/kg) over 1 h. After induction of endotoxin shock, we started hemodynamic resuscitation to restore mean arterial pressure (AP) and cardiac output (CO) by infusing noradrenaline (NA) and Ringer acetate solution (RiA). Dose of NA and RiA were automatically titrated with use of a computer-controlled drug infusion system that we developed previously. Hemodynamic resuscitation was continued for 4 h. During resuscitation, the BB group was given landiolol infusion at a low-dose range (1–10 μg/kg/min, manually titrated), while the IVA group was given ivabradine at 0.25 mg/kg bolus-injected every 2 h. Results The drug infusion system automatically restored AP to 70 mmHg and CO to greater than 90% of baseline level in all the groups. The restored AP and CO were not significantly different among the three groups (Figure A, B). There were no significant differences in the computer-controlled infusion rate of NA and cumulated volume of RiA infused among the three groups (Figure C). During the first 2 h of resuscitation, HR was significantly reduced in the BB and IVA groups in comparison to the CT group (Figure D). However, only in the BB group, cardiac oxygen consumption was significantly lower than that in the CT group (Figure E). Blood lactate level decreased significantly after hemodynamic resuscitation only within the BB group (Figure F). Figure 1 Conclusions In the initial hemodynamic resuscitation of septic shock, both low-dose landiolol infusion and ivabradine injection may be used to reduce HR. However, to optimize cardiac energetics and peripheral microhemodynamics, low-dose landiolol infusion may be preferable to ivabradine injection. Acknowledgement/Funding This work was supported by JSPS KAKENHI Grant Number 15K01307, 18K12126.

Abstract 4706: Temperature-dependent transcription artifacts and cell population biases in scRNAseq data are minimized by tissue dissociation at low temperatures

Abstract Single cell RNA sequencing (scRNAseq) is a powerful tool, particularly for studying complex biological systems, such as tumor heterogeneity and the tumor microenvironment, which may not be resolved by sequencing of bulk material. Nonetheless, it is not without limitations, which include the technical challenges of generating a high quality single cell suspension. Dissociation of tissue to single cell suspension requires mechanical and enzymatic disruption, and the effect of these methods on gene expression or cellular population bias has not been established. In this study, we examined the effects of enzymatic dissociation on cell population capture and transcriptional changes at single cell resolution in breast and ovarian cancer patient samples, patient-derived breast cancer xenografts and cultured cell lines. scRNAseq data showed that enzymatic dissociation of tissues at 37oC with collagenase resulted in significant induction of heat shock, stress and immediate response genes, which was conserved across all tissues. This gene expression induction was not observed when tissues were dissociated at 6oC with a protease derived from a Himalayan glacier soil bacterium. Moreover, dissociation of patient tumors at low temperature enhanced the abundance of rare cell populations, including B-cells, T-Cells and cytotoxic T-cells, which were significantly depleted following dissociation at 37oC. These biases resulting from standard sample preparation methods could significantly affect biological interpretation of scRNAseq data, and can be minimized by dissociation of tissues at low temperature. Note: This abstract was not presented at the meeting. Citation Format: Ciara H. O'Flanagan, Kieran R. Campbell, Farhia Kabeer, Allen Zhang, Jamie Lim, Sohrab P. Shah, Samuel Aparicio. Temperature-dependent transcription artifacts and cell population biases in scRNAseq data are minimized by tissue dissociation at low temperatures [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4706.

Cytochrome P450s Cyp4p1 and Cyp4p2 associated with the DDT tolerance in the Drosophila melanogaster strain 91-R

Cytochrome P450s are part of a super-gene family that has undergone gene duplication, divergence, over-expression and, in some cases, loss of function. One such case is the 91-R and 91-C strains of common origin, in Drosophila melanogaster, whereby 91-R (DDT resistant strain) overexpresses Cyp4p1 and Cyp4p2 and both genes are lost in 91-C (DDT susceptible strain). In this study, we used a comparative approach to demonstrate that transcription of Cyp4p1 and Cyp4p2 were constitutively up-regulated in the Drosophila melanogaster strain 91-R as compared to another DDT susceptible strain Canton-S which does not have a loss of function of these genes. Furthermore, significantly increased expression of Cyp4p1 and Cyp4p2 was induced in 91-R in response to sublethal DDT exposure, however, such induction did not occur in the DDT treated Canton-S. Additionally, fixed nucleotide variation within putative transcription factor binding sites of Cyp4p1 and Cyp4p2 promoters were observed between 91-R and Canton-S, however, their impact on transcription remains to be determined. Two GAL4/UAS transgenic strains with integrated heat shock-inducible Cyp4p1- or Cyp4p2-RNAi constructs within wild-type genetic backgrounds were developed. Following heat shock induction of Cyp4p1 and Cyp4p2 knockdown, these transgenic lines showed increased DDT mortality as compared to their corresponding non-heat shock controls. These results provide a functional link of Cyp4p1 and Cyp4p2 in conferring tolerance to DDT exposure.

Crystal Structure of the YcjX Stress Protein Reveals a Ras-Like GTP-Binding Protein

Stress proteins promote cell survival by monitoring protein homeostasis in cells and organelles. YcjX is a conserved protein of unknown function, which is highly upregulated in response to acute and chronic stress. Notably, heat shock induction of ycjX exceeded even levels observed for major stress-induced chaperones, including GroEL, ClpB, and HtpG, which use ATP as energy source. YcjX features a Walker-type nucleotide-binding domain indicating that YcjX might function as a molecular chaperone. Here, we present the first crystal structure of YcjX from Shewanella oneidensis solved at 1.9-Å resolution by SAD phasing. We show that YcjX is a GTP-binding protein that shares at its core the canonical alpha-beta domain of p21ras (Ras). However, unlike Ras, YcjX features several unique insertions, including an entirely α-helical domain not previously observed in Ras-like GTPases. We note that this helical domain is reminiscent of a similar domain in the Gα subunit of heterotrimeric G proteins, supporting a potential role for YcjX as a signal transducer of stress responses. To elucidate the mechanism of GTP hydrolysis, we determined crystal structures of YcjX bound to GDP and GDPCP, respectively, which crystallized in three different nucleotide switch conformations. Supported by targeted mutagenesis experiments, we show that YcjX utilizes a non-canonical switch 2′ motif not previously observed in Ras-like GTPases. Together, our structures provide atomic snapshots of YcjX in different functional states, illustrating the structural determinants for stress signaling.

Cerebral effects of resuscitation with either epinephrine or vasopressin in an animal model of hemorrhagic shock.

The use of epinephrine (EN) or vasopressin (VP) in hemorrhagic shock is well established. Due to its specific neurovascular effects, VP might be superior in concern to brain tissue integrity. The aim of this study was to evaluate cerebral effects of either EN or VP resuscitation after hemorrhagic shock. After shock induction fourteen pigs were randomly assigned to two treatment groups. After 60min of shock, resuscitation with either EN or VP was performed. Hemodynamics, arterial blood gases as well as cerebral perfusion pressure (CPP) and brain tissue oxygenation (PtiO2) were recorded. Interstitial lactate, pyruvate, glycerol and glutamate were assessed by cerebral and subcutaneous microdialysis. Treatment-related effects were compared using one-way ANOVA with post hoc Bonferroni adjustment (p < 0.05) for repeated measures. Induction of hemorrhagic shock led to a significant (p < 0.05) decrease of mean arterial pressure (MAP), cardiac output (CO) and CPP. Administration of both VP and EN sufficiently restored MAP and CPP and maintained physiological PtiO2 levels. Brain tissue metabolism was not altered significantly during shock and subsequent treatment with VP or EN. Concerning the excess of glycerol and glutamate, we found a significant EN-related release in the subcutaneous tissue, while brain tissue values remained stable during EN treatment. VP treatment resulted in a non-significant increase of cerebral glycerol and glutamate. Both vasopressors were effective in restoring hemodynamics and CPP and in maintaining brain oxygenation. With regards to the cerebral metabolism, we cannot support beneficial effects of VP in this model of hemorrhagic shock.

Standardized Hemorrhagic Shock Induction Guided by Cerebral Oximetry and Extended Hemodynamic Monitoring in Pigs.

Hemorrhagic shock ranks among the main reasons for severe injury-related death. The loss of circulatory volume and oxygen carriers can lead to an insufficient oxygen supply and irreversible organ failure. The brain exerts only limited compensation capacities and is particularly at high risk of severe hypoxic damage.This article demonstrates the reproducible induction of life-threatening hemorrhagic shock in a porcine model by means of calculated blood withdrawal. We titrate shock induction guided by near-infrared spectroscopyand extended hemodynamic monitoring to display systemic circulatory failure, as well as cerebral microcirculatory oxygen depletion. In comparison to similar models that primarily focus on predefined removal volumes for shock induction, this approach highlights a titration by means of the resulting failure of macro- and microcirculation.

Standardized Hemorrhagic Shock Induction Guided by Cerebral Oximetry and Extended Hemodynamic Monitoring in Pigs

Standardized Hemorrhagic Shock Induction Guided by Cerebral Oximetry and Extended Hemodynamic Monitoring in Pigs

Geriatric Polytrauma—Cardiovascular and Immunologic Response in a Murine Two-Hit Model of Trauma

BackgroundThe aims of the present study were to establish a clinically relevant two-hit model with trauma/hemorrhage followed by sepsis in older mice and investigate age-dependent cardiovascular and immunologic specificities under these conditions. Materials and methodsIn aged mice (12, 18, and 24 mo old), a femur fracture followed by hemorrhage was induced. After resuscitation, animals were monitored for 72 h before sepsis was induced. Vital signs were monitored during shock. Systemic interleukin (IL)-6 levels were measured daily. Expression of sarcoplasmic or endoplasmic reticulum calcium ATPase (SERCA) and IL-6 receptor were analyzed in heart, lung, and liver tissues. ResultsAfter induction of shock, mean arterial pressure decreased significantly in all groups (12 mo, P < 0.001; 18 mo, P < 0.001; 24 mo, P = 0.013). Compared with younger animals, 24-mo old mice were not able to adequately compensate for hypovolemia by an increase of heart rate (P = 0.711). Expression of SERCA2 (P = 0.002) and IL-6 receptor on myocytes (P = 0.037), lung (P = 0.005), and liver (P = 0.009) tissues were also lowest in this group. Systemic IL-6 values showed the most distinct posttraumatic response in 24-mo-old mice (P = 0.016). Survival rate decreased significantly with increased age (P = 0.005). ConclusionsThe increased mortality rate in older animals was associated with a limited compensatory physiological response and a more distinct immunologic reaction after trauma and sepsis. A decreased SERCA2 expression and missing feedback loops due to a reduced density of organ bound immune receptors might represent possible explanations for the observed age-dependent differences.

Evaluation of ventilator on lung profile of piglets (Sus scrofa) in hypovolemic shock treated with hypervolemic crystalloid resuscitation.

Aim:This study was conducted to assess the effect of ventilators on the lung profile of piglets in the hypovolemic shock before and after the excessive resuscitation of the crystalloid fluid.Materials and Methods:Five male piglets were used in this study as the models of shock, and there are four phases of treatment: Stabilization, shock of bleeding, normovolemic resuscitation, and hypervolemic resuscitation. The application of mechanical ventilation to patients who suspected of having lung injury may worsen the patient’s conditions. The purpose of this study was to set the ventilator with the set of positive end-expiratory pressure (PEEP) of 5 cm H2O, thefraction of inspired oxygen (FiO2) of 0.5, and the inspiration: expiration (I: E) ratio of 1:2, which was applied from the stabilization phase. The shock induction was performed by removing the blood until the mean arterial pressure decreasing by 20% from the stabilization. The solution of NaCl 0.9% was used for the normovolemic and hypervolemic resuscitation. The parameter of observation consisted of extravascular lung water index (EVLWI) and pulmonary vascular permeability index (PVPI) on pulse contour cardiac output 2 and exhaled tidal volume (VTE), peak inspiratory pressure (PIP), and respiratory rate (RR) on ventilators.Results:EVLWI does not indicate pulmonary edema. A significant decrease in VTE without any significant alterations in EVLWI, PIP, and RR has indicated the shallow breathing in the shock condition. Therefore, the PVPI parameter cannot be used as a parameter for capillary permeability since its formulation does not reinforce the results of data in the shock condition. The set of the ventilator may prevent the increase of EVLWI, and the uses of ventilators do not worsen the patient’s conditions during the crystalloid resuscitation.Conclusion:The use of mechanical ventilator as the support does not worsen the hypovolemic condition and is safe to use as long as the lung profile is not indicated to have lung injury.

Transcriptional and post-transcriptional events trigger de novo infB expression in cold stressed Escherichia coli.

After a 37 to 10°C temperature downshift the level of translation initiation factor IF2, like that of IF1 and IF3, increases at least 3-fold with respect to the ribosomes. To clarify the mechanisms and conditions leading to cold-stress induction of infB expression, the consequences of this temperature shift on infB (IF2) transcription, infB mRNA stability and translation were analysed. The Escherichia coli gene encoding IF2 is part of the metY-nusA-infB operon that contains three known promoters (P-1, P0 and P2) in addition to two promoters P3 and P4 identified in this study, the latter committed to the synthesis of a monocistronic mRNA encoding exclusively IF2. The results obtained indicate that the increased level of IF2 following cold stress depends on three mechanisms: (i) activation of all the promoters of the operon, P-1 being the most cold-responsive, as a likely consequence of the reduction of the ppGpp level that follows cold stress; (ii) a large increase in infB mRNA half-life and (iii) the cold-shock induced translational bias that ensures efficient translation of infB mRNA by the translational apparatus of cold shocked cells. A comparison of the mechanisms responsible for the cold shock induction of the three initiation factors is also presented.

T cells feel the heat.

Having a fever helps T cells reach the site of infection, thanks to thermal sensing by heat shock proteins and induction of integrin-mediated T cell migration.

Immune parameters and outcomes during Ebola virus disease.

The West African Ebola virus epidemic from 2014-2016 highlighted the lack of knowledge about the pathogenicity of the virus and the factors responsible for outcome. A performant and rapid diagnosis is of crucial importance, as is overcoming the difficulty of providing high-quality patient management during such an extensive outbreak. Here, we propose to study the role of the immune mediators during Ebola virus disease and to define some molecules of importance in the outcome. Plasma from Guinean patients sampled during the outbreak were analyzed using RT-qPCR, magnetic bead assay, ELISA, and high-quality statistical analyses. We also performed a transcriptomic analysis in leukocytes samples. Therefore, we deeply characterized the immune responses involved in Ebola virus disease. We evaluated the immune patterns depending on the outcome of the disease. Survivors presented an efficient and well-balanced immune response, whereas fatalities were characterized by an intense inflammatory response, overexpression of multiple cytokines, and a "chemokine storm." The plasma concentration of most of the parameters tested increased until death. Statistical analyses also allowed us to define a panel of markers highly predictive of outcome. The immune response observed in fatalities was highly similar to that characterizing septic shock syndrome. Our results suggest that immune responses can play a major pathogenic role during severe Ebola virus infection and argue in favor of therapeutic approaches that act on both viral replication and the induction of shock syndrome. French Ministry of Foreign Affairs, the Agence Française de Développement, and the Institut Pasteur.

EFFECT OF COPAIBA OIL IN INTESTINAL MUCOSA OF RATS SUBMITTED TO HYPOVOLEMIC SHOCK.

ABSTRACT Background: Hypovolemic shock is a common disease in polytrauma patients and may develop ischemia in various organs, increasing morbidity and mortality. The bowel is usually most affected by this condition. Aim: To evaluate the effects of copaiba oil on the intestinal mucosa’s injury of rats submitted to hypovolemic shock. Method: Fifteen rats were divided into three groups: sham - simulated surgery; ischemia - animals submitted to hypovolemic shock; and copaiba - animals submitted to hypovolemic shock previously treated with copaiba oil. Mean blood pressure, arterial blood gas after shock induction, degree of intestinal lesion and villus length were evaluated. Results: The sham presented the lowest values of lactate and PaCO2 and the highest values of mean arterial pressure, pH and bicarbonate in relation to the other groups. The degree of mesenteric lesion was zero in the sham group; 3.00±1.00 in the ischemia group; and 3.00±0.71 in the copaiba group. The villus length was 173.60±8.42 in the sham, 142.77±8.33 in the ischemia and 143.01±9.57 in the copaiba group. There was a significant difference between the sham and the other groups (p<0.05); however, there not significant difference between groups Ischemia and copaiba. Conclusion: Administration of copaiba oil did not reduce the intestinal mucosa lesion of rats after hypovolemic shock.

Slow as Compared to Rapid Rewarming After Mild Hypothermia Improves Survival in Experimental Shock

BackgroundAccidental hypothermia following trauma is an independent risk factor for mortality. However, in most experimental studies, hypothermia clearly improves outcome. We hypothesized that slow rewarming is beneficial over rapid rewarming following mild hypothermia in a rodent model of hemorrhagic shock. Materials and methodsWe subjected 32 male Wistar rats to severe hemorrhagic shock (25–30 mmHg for 30 min). Rats were assigned to four experimental groups (normothermia, hypothermia, rapid rewarming [RW], and slow RW). During induction of severe shock, all but the normothermia group were cooled to 34°C. After 60 min of shock, rats were resuscitated with Ringer's solution. The two RW groups were rewarmed at differing rates (6°C/h versus 2°C/h). ResultsSlow RW animals exhibit a significantly prolonged survival compared with the rapid RW animals (P < 0.05). Nevertheless, hypothermic animals show a significant survival benefit as compared to all other experimental groups. Whereas seven animals of the hypothermia group survived to the end of the experiment, none of the other animals did (P < 0.001). No significant differences were found regarding acid base status, metabolism, parameters of organ injury, and coagulation. ConclusionsThe results indicate that even slow RW with 2°C/h may be still too fast in the setting of experimental hemorrhage. Too rapid rewarming may result in a loss of the protective effects of hypothermia. As rewarming is ultimately inevitable in patients with trauma, potential effects of rewarming on patient outcome should be further investigated in clinical studies.

Tranexamic acid decreases rodent hemorrhagic shock-induced inflammation with mixed end-organ effects.

Beyond its anti-fibrinolytic mechanism, tranexamic acid has been suggested to have anti-inflammatory properties which may contribute to the survival benefit it provides to trauma patients. The objective of this study was to assess possible immunomodulatory effects of tranexamic acid as well as potential amelioration of end-organ injury in a rodent hemorrhagic shock model. Controlled hemorrhagic shock was induced in adult Sprague Dawley rats to a mean arterial pressure of 30 mmHg. Groups of 10 rats were administered intravenous tranexamic acid (300mg/kg) or vehicle control (normal saline) intravenously 15 minutes after the induction of shock. After 60 minutes of hemorrhagic shock, resuscitation was started. Animals were euthanized at six, 24, or 72 hours from the start of shock. Serum laboratory values to include inflammatory biomarkers were measured, and end organ histology was evaluated. Tranexamic acid treatment was associated with a significant decrease in serum IL-1β at six and 24 hours and IL-10 at 24 hours from start of shock compared to vehicle control. Histologic analysis demonstrated mild decreases in both perivascular pulmonary edema and follicular mesenteric lymph node hyperplasia in the tranexamic acid treatment group but also increased myocardial lymphocytic infiltration with necrosis and degeneration. Tranexamic acid was also associated with a small but significant increase in peripheral neutrophil count as well as a significant decrease in neutrophil aggregation in pulmonary tissue at six hours post-injury. These data thus demonstrate a mixed effect of tranexamic acid. While there was an improvement in pulmonary edema and a suppressive effect on several key inflammatory mediators, there was also increased myocardial degeneration and necrosis, which is possibly related to the pro-thrombotic effect of tranexamic acid.

SiRNA interfering STAT3 enhances DDP sensitivity in cervical cancer cells.

Signal transducer and activator of transcription 3 (STAT3) is an important regulatory protein in the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, which regulates cell proliferation, apoptosis, and other biological processes. It is closely related to tumor occurrence, progress, and resistance. Cisplatin (DDP) resistant cervical cancer cell line was established by shock induction to investigate the role of STAT3 in cervical cancer cells drug resistance. The expression of STAT3 in different chemotherapy response cervical cancer tissues was compared. The cervical cancer was divided into two groups upon STAT3 median level. Cervical cancer cell inhibitory rate by DDP treatment was compared. Western blot was used to detect STAT3 and phosphorylated STAT3 (p-STAT3) expressions in CaSki and CaSki/DDP cells. Cell apoptosis rate was tested by flow cytometry. CaSki/DDP cells were divided into small interfere RNA-normal control (siRNA-NC) group and siRNA-STAT3 group. Cell proliferation was evaluated by EdU staining. The rate of STAT3 over-expression in cervical cancer patients with no significant chemotherapy response was markedly higher than that with a significant response. The inhibitory effect of DDP on tumor cells derived from patients with low STAT3 expression was significantly higher, while the apoptosis rate was apparently lower than that of CaSki/DDP cells from patients with high STAT3 expression. siRNA-STAT3 transfection significantly reduced the expressions of STAT3 and p-STAT3, decreased cell proliferation, and enhanced cell apoptosis in CaSki/DDP cells. STAT3 over-expression is associated with DDP resistance in cervical cancer. Decreasing STAT3 can significantly promote the apoptosis of cervical cancer CaSki cells and decrease the DDP resistance.

Interaction of Mannose-Binding Lectin With Lipopolysaccharide Outer Core Region and Its Biological Consequences.

Lipopolysaccharide (LPS, endotoxin), the main surface antigen and virulence factor of Gram-negative bacteria, is composed of lipid A, core oligosaccharide, and O-specific polysaccharide (O-PS) regions. Each LPS region is capable of complement activation. We have demonstrated that LPS of Hafnia alvei, an opportunistic human pathogen, reacts strongly with human and murine mannose-binding lectins (MBLs). Moreover, MBL–LPS interactions were detected for the majority of other Gram-negative species investigated. H. alvei was used as a model pathogen to investigate the biological consequences of these interactions. The core oligosaccharide region of H. alvei LPS was identified as the main target for human and murine MBL, especially l-glycero-d-manno-heptose (Hep) and N-acetyl-d-glucosamine (GlcNAc) residues within the outer core region. MBL-binding motifs of LPS are accessible to MBL on the surface of bacterial cells and LPS aggregates. Generally, the accessibility of outer core structures for interaction with MBL is highest during the lag phase of bacterial growth. The LPS core oligosaccharide–MBL interactions led to complement activation and also induced an anaphylactoid shock in mice. Unlike Klebsiella pneumoniae O3 LPS, robust lectin pathway activation of H. alvei LPS in vivo was mainly the result of outer core recognition by MBL; involvement of the O-PS is not necessary for anaphylactoid shock induction. Our results contribute to a better understanding of MBL–LPS interaction and may support development of therapeutic strategies against sepsis based on complement inhibition.

Hepatic topographical changes of endoplasmic reticulum stress and unfolded protein response signaling after hemorrhagic shock and reperfusion

BackgroundEndoplasmic reticulum (ER) stress plays a crucial role in cell death decisions in context of various diseases. Although it is known that ER stress occurs in livers subjected to hemorrhagic shock and reperfusion (HS/R), there is no understanding about the influence of the liver architecture on ER stress and the activation of the unfolded protein response (UPR). Materials and methodsMice were subjected to a pressure-controlled HS (30 ± 5 mmHg) for 90 min. Mice were sacrificed 2, 4, 6, 8, 10, 14, 18, and 24 h after shock induction. Plasma levels of inflammatory cytokines (IL-6, CXCL1, CXCL9, CXCL10, CCL2, CCL3) and transaminases were measured. Hematoxylin and eosin stains of paraffin-embedded liver tissue sections were evaluated for liver damage. Immunohistochemistry was used to analyze the hepatic topography of ER stress marker binding immunoglobulin protein and the activation of the three major pathways of the UPR. ResultsCompared with sham-operated mice, HS/R led to profound liver damage and an elevation of inflammatory cytokines. We found time-dependent topographical changes of ER stress in the livers. Furthermore, the three major pathways of the UPR represented by protein kinase RNA-like ER kinase, activating transcription factor 6, and inositol-requiring enzyme 1 were activated in differing ways dependent on the zonation within the liver acinus. ConclusionsThese findings show that the liver architecture must be taken into account when investigating the role of ER stress and the UPR in ischemia-reperfusion injury after HS/R.

A Study of Ginseng Effects on Spermatogenesis Multiplications (TDI, RI, SI) Proceeding Scrotal Heat Shock Induction in Rat

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Effects of resuscitation with human albumin 5%, hydroxyethyl starch 130/0.4 6%, or crystalloid on kidney damage in an ovine model of septic shock

BackgroundColloid solutions have been associated with kidney dysfunction in septic animals and humans. The present study investigated the influence of resuscitation with human albumin (HA) 5%, hydroxyethyl starch (HES) 130/0.4 6%, and balanced crystalloids on ultrastructural kidney damage, kidney function, and survival in a model of ovine septic shock. MethodsAfter induction of peritoneal septic shock, animals were randomised to one of the following groups: (1) HA 5%, (2) HES 130/0.4 6%, (3) balanced crystalloid, and (4) control (each n=10). Causal therapy included re-laparotomy, peritoneal lavage, and antimicrobial therapy. Sequential kidney biopsies were obtained for the assessment of the electron microscopic tubular injury (EMTI) score. ResultsSerum creatinine and urea were highest in the control group, and there were no differences between the intervention groups. Cumulative diuresis was significantly higher in the HA group [1.0 ml kg−1 h−1 (0.6; 1.2)] compared with control [0.7 ml kg−1 h−1 (0.6; 0.9), P<0.05]. Creatinine clearance was highest in the HA and crystalloid groups. Ultrastructural kidney damage was highest in the control group [EMTI score 7.8 (6.7; 9.0)] without differences between intervention groups. Survival was 100% in the colloid groups vs 90% (crystalloid) and 60% (control, all P<0.05). ConclusionIn an ovine model of septic shock, kidney function and cumulative diuresis were preserved in the 5% albumin and crystalloid resuscitation groups, whereas HES 130/0.4 6% resulted in diminished creatinine clearance. Differences in kidney function between resuscitation fluids could not be explained by differences in ultrastructural kidney damage. Clinical trial registration84-02.04.2011.A300.