The 2019 June issue of SHOCK presents its readers with 15 clinical and basic science studies covering the areas of sepsis and septic shock, cardiac arrest and resuscitation, hemorrhagic shock, ischemia and reperfusion, and other disease conditions. These articles significantly advance our knowledge in these fields for more accurate prognostication, better treatment, and improved understanding of the mechanisms underlying injury, damage, and mortality in these conditions.
The short-term changes in the number of circulating immune cells in individuals experimentally subjected to endotoxin injection are well known, but the long-term effects have not been adequately studied. To fill this knowledge gap, Rodriguez-Rosales et al. (1) challenged healthy subjects with endotoxin and then quantified several circulating immune cells at up to 20 days post endotoxin administration, and then compared the changes with those observed in patients during the first 9 days after the onset of septic shock. At 20 days post endotoxemia, the investigators observed an increase in the number of circulating HLA-DRint monocytes which differed from septic shock patients. They also detected elevated numbers of effector CD8+ cells and an increased percentage of activated CD8+ cells, and these phenomena were also present in sepsis patients. They concluded that experimental endotoxemia recapitulates the behavior of CD8+ T cells, making this model of sepsis relevant for the development of new therapies targeting this population of immune cells.
Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) has been used to resuscitate patients with acute myocardial infarction (AMI) complicated by cardiac arrest (CA). In order to determine predictors of successful weaning from VA-ECMO, Sugiura et al. (2) reviewed the clinical data of 55 patients with AMI complicated by CA and treated with VA-ECMO and percutaneous coronary intervention (PCI). The authors identified post-PCI thrombolysis in myocardial infarction (TIMI) flow grade, mean arterial pressure (MAP) at 4 h after ECMO initiation, and serum lactate at 24 h as independent predictors of successful weaning. Left ventricular ejection fraction at 24 and 48 h was significantly greater in the successful weaning group. Therefore, post-PCI TIMI flow grade, MAP at 4 h, and serum lactate at 24 h can be used to predict which patients may require adjunctive use of other circulatory mechanical devices in order to wean from ECMO.
Cerebral and cardiac dysfunction are a significant cause of morbidity and mortality in postcardiac arrest syndrome (PCAS) patients. In order to optimize life support for these patients, Sumi et al. (3) examined whether plasma ATP and adenylate levels could predict clinical outcome in 15 PCAS patients of which 8 died within 4 days after resuscitation and 2 lapsed into vegetative states. The concentrations of ATP in arterial blood samples immediately after return of spontaneous circulation (ROSC) were higher than healthy controls and correlated with lactate levels, Acute Physiology and Chronic Health Evaluation II scores, and the time it took to ROSC (time-to-ROSC). Plasma adenylate levels in patients who died after resuscitation were significantly higher than those in survivors. The authors suggested that circulating adenylate levels may help predict outcome in PCAS patients.
Multiple organ dysfunction syndrome (MODS) is frequent and often lethal. To evaluate the ability of tissue oxygen saturation (StO2) to predict patient responses in the early phase of MODS, Haertel et al. (4) determined the StO2 thenar region using a bedside near-infrared spectroscopy (NIRS) device. Survivors had significantly better occlusion slope (OS) and recovery slope (RS) values compared with non-survivors. As such, impaired OS and RS values in patients in the early phase of MODS are predictive of increased 28-day mortality.
Recombinant human thrombomodulin (rh-TM) has been reported to improve the survival of septic patients with disseminated intravascular coagulation (DIC). To determine whether administration of rh-TM and/or antithrombin (AT) III reduces the in-hospital mortality of septic DIC patients, Tanaka et al. (5) analyzed 3,193 patients from the Japanese Nationwide Registry database on sepsis. The in-hospital mortality of DIC patients treated with rh-TM and/or AT III was similar to that of DIC patients with no anticoagulation therapy. However, the in-hospital mortality of DIC patients treated with rh-TM and/or AT III was lower than that of patients treated with other anticoagulants. These data indicate that septic DIC should be treated preferentially with rh-TM and/or AT III.
Sphingosine-1-phosphate (S1P) and ceramide are major cell membrane sphingolipids, which contribute to signaling events that mediate response to stress such as sepsis. While ceramide promotes cell cycle arrest and apoptosis, S1P exerts a pro-survival and mitogenic activity. To investigate their predictive value in sepsis mortality, Wu et al. (6) determined the circulating levels of S1P and ceramide in 33 septic patients within the 24 h of being admitted to the intensive care unit (ICU). Compared with healthy and ICU controls, septic patients had significantly decreased plasma S1P and increased ceramide concentrations. Plasma S1P and ceramide predicted septic mortality, sequential (sepsis-related) organ failure assessment (SOFA) score, and the HLA-DR expression on circulating monocytes. The expression and activity of platelet sphingosine kinases 1/2 (SphK1/2) were also decreased, possibly explaining the decreased plasma S1P levels during sepsis.
Psychosocial stress in somatic and affective disorders is commonly associated with activation of the immune system and chronic low-grade inflammation. To determine the effects of psychosocial stress on hemorrhagic shock (HS) and resuscitation, Langgartner et al. (7) hemorrhaged and resuscitated male mice housed either singly or together with dominant males. Chronic subordinate colony mice had increased adrenal weight, indicating that the stress paradigm worked. However, prior psychosocial stress had no effect on survival, organ function, metabolism, oxidative/nitrosative stress, or inflammatory readouts after hemorrhage and resuscitation. The authors concluded that chronic psychosocial stress during adulthood is not sufficient to promote hemodynamic complications, organ dysfunction, or metabolic disturbances, and did not increase the risk of MOF after hemorrhage and resuscitation.
Sepsis patients with cancer have a markedly increased mortality than sepsis patients who were previously healthy. To evaluate the mechanisms by which cancer predisposes to sepsis mortality, Lyons et al. (8) first injected mice with a pancreatic cancer cell line and then induced sepsis by cecal ligation and puncture (CLP). Sepsis mortality was increased in mice with cancer. Cancer septic mice had increased CD4+ T cells and CD8+ T cells, associated with decreased CD4+ T cell apoptosis 24 h after CLP. Further, splenic CD8+ T cell activation was decreased in cancer septic mice. It was concluded that the host response to the combination of cancer and sepsis is dependent, at least in part, on both chronic comorbidity and acute illness.
Hemorrhagic shock causes shedding of the syndecan-1 ectodomain leading to loss of the endothelial glycocalyx. Early administration of fresh frozen plasma (FFP), however, protects the pulmonary endothelial barrier integrity due in part to restoration of endothelial syndecan-1. To investigate the role of fibrinogen, a major component of FFP, as an endothelial protector, Wu and Kozar (9) exposed pulmonary endothelial cells to FFP and measured changes in syndecan-1, fibrinogen, and barrier integrity. FFP promoted cell surface expression of syndecan-1 and increased barrier integrity. Furthermore, these changes were dependent on the presence of fibrinogen in the FFP, and syndecan-1 was shown to colocalize with fibrinogen. These data suggest that fibrinogen associates with cell surface syndecan-1 to enhance endothelial barrier integrity.
Total Salvianolic Acid Injection (TSI) is a preparation of active components of Salvia miltiorrhiza Bunge, which was approved by the Chinese State Food and Drug Administration in 2011 for the prevention and treatment of ischemic stroke. Sirtuin1 (Sirt1) and Sirtuin3 (Sirt3) are known to regulate mitochondrial function. To evaluate whether TSI protects against ischemia/reperfusion (I/R) injury through Sirt1 and/or Sirt3, Huang et al. (10) subjected rats to myocardial I/R with or without TSI treatment. TSI reduced infarct size, promoted myocardial blood flow, decreased cardiac apoptosis, protected the heart from oxidative insults, and attenuated the I/R-elicited downregulation of Sirt1, Sirt3, NDUFA10 and SDHA. TSI treatment's protective effects in H9c2 cells, however, were abrogated after transfection with either Sirt1 siRNA or Sirt3 siRNA. These results demonstrated that TSI attenuates myocardial I/R via inhibition of oxidative stress related to the activation of NDUFA10 and SDHA through the upregulation of Sirt1 and Sirt3.
Tyrosine kinase receptor (Tie2) is an endothelial cell membrane receptor whose levels are reduced in animal models of critical illness. However, the functional consequences of Tie2 reduction on microvascular endothelial behavior are unknown. Therefore, Jongman et al. (11) generated heterozygous Tie2 knockout mice and investigated the effect of Tie2 partial deletion on the inflammatory status of endothelial cells after HS and resuscitation or a challenge with LPS. The authors did not find differences after HS and resuscitation, but discovered that LPS-induced expression of E-selectin, VCAM-1, and ICAM-1, and CD45 in organs were attenuated in the kidneys and liver of Tie2+/− mice, but not in the other organs studied. After LPS exposure, the reduced expression of E-selectin and VCAM-1 protein, and the reduced influx of CD45+ cells were visible in a microvascular bed-specific pattern in the kidneys and liver of Tie2+/− mice. As such, heterozygous deletion of Tie2 was associated with an organ-restricted, microvascular bed-specific attenuation of endothelial inflammatory response to LPS.
The role of long noncoding RNAs (lncRNAs) in the inflammatory response remains largely unexplored. Li et al. (12) addressed this issue by performing high-throughput sequencing to identify the profiles of mRNA and lncRNA transcriptomes in RAW264.7 cells after LPS stimulation. They found a total of 325 lncRNAs and 1,187 mRNAs to be significantly altered by ate least four-fold. Further validation with qRT-PCR demonstrated that Cd40 and Traf1 mRNAs were significantly upregulated, whereas Slc43a2 and Ccnd1 were downregulated in RAW264.7 cells treated with LPS. mRNAs and lncRNAs were mainly involved in the immune response, inflammation response, chemokine receptor binding, protein binding, and regulation of cytokine production. The coexpression network profile for mRNAs and lncRNAs from the immune category suggested that lncRNAs play an important role in the regulation of functional mRNA expression in LPS-induced inflammation.
Heat stroke refers to the presence of hyperthermia accompanied by central nervous system dysfunction. The hippocampus is a particularly vulnerable region in the early stage of heat stroke. Liu et al. (13) evaluated whether heat stroke affects rat spatial learning and memory, as well as hippocampal iron content, ferroportin 1 (Fpn1), and hepcidin. Heat stroke reduced learning ability and memory, and increased the hippocampal iron concentration. Expression of Fpn1 protein significantly decreased in the hippocampus, while expression of hepcidin increased. Interestingly, Fpn1 mRNA expression in the hippocampus increased. The authors concluded that heat stroke impairment of learning and memory may be related to local changes in iron metabolism and iron-regulatory proteins.
Bacterial pneumonia is a leading cause of death in the intensive care unit. NR4A1 is an early response gene that has been identified as a vital regulator of immune and inflammatory responses. To explore the role of NR4A1 in pneumonia, Cui et al. (14) studied the effects of Escherichia coli (E coli) on wild-type (WT) and NR4A1 knockout mice. NR4A1 was rapidly induced in alveolar macrophages after exposure to E coli. Alveolar macrophages from WT mice treated with an NR4A1 antagonist and from NR4A1 knockout mice showed an enhanced phagocytic function. Similarly, WT mice treated with an NR4A1 antagonist and NR4A1 knockout mice had improved survival after E coli pneumonia. The investigators concluded that NR4A1 impairs the phagocytic capacity of alveolar macrophages and disrupts the host defense against invading bacteria, worsening the outcome of E coli pneumonia in mice.
In the final article, Behaghel et al. (15) sought to investigate whether remote ischemic conditioning (rIC) can influence renal function recovery in a rat model of renal I/R injury. At 24 h, renal function was similar in rats subjected to renal I/R with and without rIC, but was significantly lower in rats treated with erythropoietin. Similarly, the 7-day survival was similar in rats subjected to renal I/R with and without rIC, but significantly improved in rats treated with erythropoietin. In conclusion, rIC affected neither acute renal dysfunction nor early mortality in a severe I/R renal injury rat model, contrary to EPO pretreatment.
We thank the authors for their instigating contributions and welcome all to this issue of SHOCK!
1. Rodriguez-Rosales YA, Kox M, van Rijssen E, van Cranenbroek B, van Welie M, Pickkers P, Joosten I, Koenen HJPM. Long-term effects of experimental human endotoxemia on immune cell function: similarities and differences with sepsis. Shock
2. Sugiura A, Abe R, Nakayama T, Hattori N, Fujimoto Y, Himi T, Sano K, Oda S, Kobayashi Y. Predictors of successful weaning from veno-arterial extracorporeal membrane oxygenation after coronary revascularization for acute myocardial infarction complicated by cardiac arrest: a retrospective multicenter study. Shock
3. Sumi Y, Ledderose C, Li L, Inoue Y, Okamoto K, Kondo Y, Sueyoshi K, Junger WG, Tanaka H. Plasma adenylate levels are elevated in cardiopulmonary arrest patients and may predict mortality. Shock
4. Haertel F, Reisberg D, Peters M, Nuding S, Schroeder J, Werdan K, Ebelt H. Prognostic value of tissue oxygen saturation using a vascular occlusion test in patients in the early phase of multiorgan dysfunction syndrome. Shock
5. Tanaka K, Takeba J, Matsumoto H, Ohshita M, Annen S, Moriyama N, Nakabayashi Y, Aibiki M. Anticoagulation therapy using RH-thrombomodulin and/or antithrombin III agent is associated with reduction in in-hospital mortality in septic disseminated intravascular coagulation: a nationwide registry study. Shock
6. Wu X, Hou J, Li H, Xie G, Zhang X, Zheng J, Wang J, Gao F, Yao Y, Liu H, et al. Inverse correlation between plasma sphingosine-1-phosphate and ceramide concentrations in septic patients and their utility in predicting mortality. Shock
7. Langgartner D, Wachter U, Hartmann C, Gröger M, Vogt J, Merz T, McCook O, Fink M, Kress S, Georgieff M, et al. Effects of psychosocial stress on subsequent hemorrhagic shock and resuscitation in male mice. Shock
8. Lyons JD, Chen C-W, Liang Z, Zhang W, Chihade DB, Burd EM, Farris AB, Ford ML, Coopersmith CM. Murine pancreatic cancer alters T cell activation and apoptosis and worsens survival after cecal ligation and puncture. Shock
9. Wu F, Kozar RA. Fibrinogen protects against barrier dysfunction through maintaining cell surface syndecan-1 in vitro
10. Huang D-D, Wei X-H, Mu H-N, Pan C-S, Li Q, Hu B-H, Chang X, Yan L, Fan J-Y, Liu Y-Y, et al. Total salvianolic acid injection prevents ischemia/reperfusion-induced myocardial injury via antioxidant mechanism involving mitochondrial respiratory chain through the upregulation of Sirtuin1 and Sirtuin3. Shock
11. Jongman RM, Zwiers PJ, van de Sluis B, van der Laan M, Moser J, Zijlstra JG, Dekker D, Huijkman N, Moorlag HE, Popa ER, et al. Partial deletion of Tie2 affects microvascular endothelial responses to critical illness in a vascular bed and organ-specific way. Shock
12. Li L, Zhang Y, Luo H, Huang C, Li S, Liu A, Jiang Y. Systematic identification and analysis of expression profiles of mRNAs and IncRNAs in macrophage inflammatory response. Shock
13. Liu J, Wang M, Zhang Y, Zhang S, Zhang H, Wu S. Dysfunction of iron metabolism and iron-regulatory proteins in the rat hippocampus after heat stroke. Shock
14. Cui P, Wu S, Xu X, Ye H, Hou J, Liu X, Wang H, Fang X. Deficiency of the transcription factor NR4A1 enhances bacterial clearance and prevents lung injury during Escherichia coli
15. Behaghel V, Tamareille S, Rabant M, Mirebeau-Prunier D, Bière L, Macchi L, Prunier F. Remote ischemic conditioning in a model of severe renal ischemia–reperfusion injury. Shock