WHAT'S NEW IN SHOCK, OCTOBER 2010?

This edition of Shock yet again presents a plethora of articles that provide unique information allowing better understanding the mechanisms and processes occurring during sepsis, ischemia/reperfusion, trauma, and shock. The first article by Kasten et al. (1) extensively reviewed the literature to elucidate the role of T cells as early mediators in the response to sepsis. In this review, one becomes aware of significant lymphocyte apoptosis that occurs within the first 24 h of septic insult. They postulate two mechanisms by which T-cell apoptosis reduction improves survival and bacterial clearance. The first is via reduction in production of IL-10 and transforming growth factor β secondary to decreased T-cell phagocytosis by macrophages, and second is via generation of interferon γ and IL-17 by T cells, which can enhance the innate immune function to blunt bacterial infection. However, they highlight that many of these cytokines have divergent effects that depend on the severity of sepsis and that the role of T-cell response in sepsis is yet to be fully elucidated. Novel treatment and therapeutic strategies to improve outcomes from sepsis depend on better understanding of the protective versus pathological T-cell response. In the article by Bingold et al. (2), the possible role of IL-22 in sepsis is investigated. Previously, animal studies had suggested a crucial role for IL-22 in sepsis. In this single-center study, the level of IL-22 was measured in healthy volunteers, patients undergoing abdominal surgery without sepsis, and those with positive diagnosis of abdominal sepsis. The authors found a significant increase in serum levels of IL-22 that they postulate can contribute to host defense and stabilization of mucosal barrier function in sepsis. The mechanisms are not entirely clear, but this represents an important novel aspect that may explain increased gut permeability subsequently leading to bacteremia. This study provides a novel platform that other investigators may now use to determine whether in other diseases IL-22 may play a central role. Decembrino et al. (3) determined the safety and efficacy of protein C (PC) concentrate administration in neonates with sepsis-induced coagulopathy. The authors included 18 neonates between 1 and 28 days who had severe sepsis or septic shock with coagulopathy and acquired PC deficiency and received PC concentrate. They found that in neonates that normalization of PC levels is safe, as the authors could not find any adverse effects, and speculate that normalization of PC levels is effective in modulating the inflammatory response and in controlling coagulopathy. This study is a wonderful preliminary study, adding to the growing evidence that PC plays a central role in sepsis-induced organ damage and needs further investigation. We completely agree with the authors who state clearly that a prospective randomized trial is necessary to fully evaluate the efficacy of normalizing PC levels. Cuschieri et al. (4) looked at the relationship between IL-6 levels after injury to the development of organ failure. Previous studies had suggested that IL-6 might serve as a biomarker for excessive inflammation. They evaluated patients within a multicenter developmental cohort with hemorrhagic shock. The IL-6 levels were measured within 12 h of injury, and the clinical and outcome data were prospectively obtained. An optimal IL-6 level was defined by developing a receiver operating characteristic curve and was evaluated within a single-center validation cohort. They determined an IL-6 level of 350 pg/mL to have the highest sensitivity and specificity. They subsequently determined that levels greater than 350 pg/mL were associated with increased multiorgan dysfunction syndrome scores, multiorgan dysfunction syndrome development, ventilator days, intensive care unit (ICU) length of stay, and hospital length of stay. However, elevation of IL-6 was not associated with increased mortality, but seems to correlate well with poor prognosis. They conclude that IL-6 level measurement may be a useful biomarker and help identify patients at higher risk for adverse outcomes. Having identified this crucial cutoff value, this opens multiple novel aspects: can IL-6 values be altered with perturbations to change patient outcomes? Will this cutoff hold true in a prospective setup? Is IL-6 a modulator or a response element? All these questions are of importance, and thus, this excellent study adds many fascinating aspects and questions. Lin et al. (5) examined the predictive value of outcome scoring systems in acute respiratory distress syndrome (ARDS) patients in the ICU. They retrospectively assessed data of critically ill patients with ARDS in two medical ICUs. They identified that Acute Physiology and Chronic Health Evaluation IV (APACHE IV), a-a O2 gradient, age, sepsis, and maximum rifle score on days 1 and 3 were independent predictors of hospital mortality. They also determined that the survival rates at 6 months after discharge were significantly different between APACHE IV mortality rate 35% or less and APACHE IV mortality rate 35% or greater. They also concluded that APACHE IV and RIFLEmax scores are predictors of mortality in ARDS patients. Similar to the study mentioned above, these fascinating data now need to be tested in a more prospective setup to determine whether they will hold true. In the article by Venet et al. (6), the alterations in leukocyte count were assessed in correlation with the diagnosis of septic shock. The decrease in circulation lymphocyte count has been well described in septic shock. To further elucidate the alterations in lymphocyte count, they looked at 21 septic shock patients within 2 h of institution of vasopressors. Flow cytometry phenotyping of leukocyte subpopulations was performed from the diagnosis of shock, every 6 h for the next 48 h. They determined that the numbers of every lymphocyte subpopulation (T, B, natural killer cells) were reduced. They also demonstrated that there was severe decrease in gene expression of transcription factors for TH1, TH2, CD4+CD25+, and TH17 lymphocytes. These alterations seem to be stable during the first 48 h despite resuscitation and antibiotic therapy, and no significant variation could be detected during that period in the lymphocyte subsets. So what is the meaning of these important data? Could this drop explain immunocompromise of these patients? How long does this decrease persist? Are there differences between vasopressors? Should we use vasopressors more carefully? All these questions have huge clinical relevance and need to be addressed. Decreased albumin concentration has been well described as an acute-phase response after injury. In their article, Martini et al. (7) examined the changes in albumin synthesis in severely burned patients using isotope infusion techniques. They examined five patients with burn total body surface area of 48% ± 4% and five healthy volunteers (matched to age and sex) as control. They infused an isotope on the day of study and drew blood samples hourly to determine albumin synthesis rates via mass spectroscopy. They were able to determine that despite decreased albumin concentration, albumin synthesis was enhanced in the severely burned patients. It is very interesting that liver shows an increased albumin synthesis, indicating that the liver is in a hypermetabolic state following the body's response to burn. If albumin synthesis is increased but albumin levels are known to be profoundly decreased for weeks after burn, the questions arises: Where does the albumin go? Initially after burn, it seems evident that albumin is lost due to the capillary leak. However, this leak is thought to be sealed 24 to 48 h after burn. Hence the question. We agree with the authors who stated that further investigations are required to determine the best treatment options in the injured patients with low albumin levels and mechanisms resulting in altered albumin levels. It is well known that diabetes is a leading comorbidity in sepsis. In the article by Osuchowski et al. (8), they set out to investigate the effect of untreated diabetes on survival and immunoinflammatory response in the acute phase of murine polymicrobial sepsis (using the Akita model). They examined the blood (for 5 days) and survival (for 28 days) of diabetic Akita and wild-type (WT) mice after cecal ligation and puncture (CLP). All Akita mice died by day 5 compared with 10 deaths of 28 in the WT mice. They also found that blood glucose declined after CLP (by 75% in Akita mice). They further examined the data after dividing the mice into Akita, WT-died, and WT-survived and observed that the hypoglycemia resolved in the WT-survived group, but intensified in the WT-died and Akita groups. They also observed that proinflammatory and anti-inflammatory cytokines dramatically increased in the WT-died group, in contrast to a lack of prelethal cytokine response in the Akita mice. This group also calculated a composite cytokine score on values obtained 24 h before death and determined that the score for the cytokines was lower in Akita mice compared with WT-died mice but identical to WT-survived scores. These data demonstrate that untreated diabetes severely exacerbates mortality in sepsis without the prelethal activation of cytokines. Another T-cell study is presented by Kasten et al. (9). The authors examined the impact of increasing antigen-dependent activation of CD4 T cells in a murine model of CLP using T-cell receptor transgenic II (OT-II) mice that are specific for chicken ovalbumin (OVA) in the context of major histocompatibility complex II. In a sophisticated study, the authors showed that increased antigen treatment resulted in increased numbers of activated splenic CD4 T cells. Vehicle-treated, septic OT-II mice had decreased survival, increased bacterial load, and increased levels of IL-6. Interestingly, this decrease in survival was abrogated when OT-II mice were injected with 1 μg OVA, which was correlated with normalized bacterial load and levels of IL-6. However, when OT-II mice were injected with 100 μg OVA, decreased survival was restored but, in contrast to vehicle-treated OT-II mice, had decreased bacterial load and enhanced IL-6 levels. Furthermore, neutrophil oxidative burst and phagocytosis were dependent on CD4 T-cell activation. Further, at very high levels of T-cell activation, intestinal permeability was significantly increased. The authors concluded that too little CD4 T-cell activation produces dysfunctional neutrophils leading to decreased bacteria clearance and survival, whereas too much CD4 T-cell activation produces a neutrophil phenotype that leads to efficient bacterial clearance but with increased tissue damage and mortality. This ying-yang phenomenon is present in various biological systems, but the authors conducted an elegant and sophisticated study to prove their hypothesis. Previous studies have implicated reactive oxygen species in the pathophysiology of reperfusion injury. In their article, Zifko et al. (10) determined the formation of RONS in rat organs and its pathophysiological relevance during restrictive reperfusion after hemorrhagic/traumatic shock. In comparison to sham-operated animals, the organ-specific distribution of RONS changed during restrictive reperfusion after hemorrhagic/traumatic shock. They were able to demonstrate that RONS formation increased in red blood cells and ileum, but decreased in the kidney and remained unchanged in other organs. They demonstrated that hypertonic saline followed by restrictive reperfusion resulted in increased oxidative burst capacity in circulating cells. Plasma RONS correlated with shock severity and organ dysfunction; however, RONS scavenging neither affected organ dysfunction, oxidative burst capacity, nor myeloperoxidase activity in the lung when compared with shock controls. From their data, the authors concluded that restrictive reperfusion increases RONS formation only in the intestine and red blood cells. In addition, RONS scavenging does not affect organ dysfunction at the end of restrictive reperfusion. Previously, Gao et al. (11) had provided evidence that proteosome is central to most genes induced in mouse macrophages in response to LPS stimulation. In their most recent study, they evaluated the role of macrophage proteosome in response to CpG DNA (unmethylated bacterial DNA). They applied microarray analysis to mRNA derived from murine macrophages stimulated by CpG DNA in the presence and absence of proteosome inhibitor (lactacystin). In this study, as in their previous studies, they were able to demonstrate that macrophage genes regulated by CpG DNA are also under the control of proteosomes. However, in contrast to LPS stimulation, these genes were induced at 18 h (CpG DNA stimulation) as compared with 4 h (LPS stimulation). Lactacystin treatment of macrophages blocked the CpG DNA-induced gene expression of TNF-α and other genes involved in the production of anti-inflammatory mediators. These experiments provide strong evidence that similar to LPS, macrophage proteosome is key regulator of CpG DNA-induced signaling pathway. In an interesting article by Hagiwara et al. (12), they examined the role of thrombomodulin (TM) in heat stroke (severe inflammatory response). Thrombomodulin is an important cofactor in the PC anticoagulant system, which inhibits inflammation. They tested their hypothesis that TM could prevent acute inflammation induced by heat stress in a rodent model. They measured the serum concentrations of IL-1β, IL-6, TNF-α, NO, and HMGB1 (high-mobility group box 1) protein at various time points after treatment. The levels of cytokines and HMGB1 protein decreased in the TM-treated animals over time. They also observed the inhibition of NO overproduction by recombinant TM during heat stress-induced inflammation. They concluded that because TM exhibited a strong anti-inflammatory effect in a rat model of acute inflammation induced by heat stress, TM may have a beneficial therapeutic effect in patients with heat stroke and possible role in the reducing the severity or even prevention of acute heat stroke. The role of IL-17 in antifungal host defense is controversial. In the article by van de Veerdonk et al. (13), they set out to assess the differential role of IL-17 pathway in two models of fungal sepsis: intravenous infection with live Candida albicans, in which the fungal growth is the main cause of mortality; and zymosan-induced multiorgan failure, in which the inflammatory pathology drives the mortality. In their study, the IL-17-deficient mice had higher mortality rates and higher fungal loads in their kidneys in the model of disseminated Candida infection. Also, these mice were unprotected against the multiorgan failure induced by zymosan. They concluded that host defense against systemic Candida infection depends on the IL-17 pathway; however, IL-17 does not seem to be involved in enhancing the inflammatory potential of neutrophils in the multiorgan failure model induced by zymosan. Also, these data can provide crucial information in developing novel treatment strategies in Candida infection. In literature, there have been reports that volatile anesthetics can have beneficial anti-inflammatory properties in sepsis. Therefore, Soehnlein et al. (14) set out to investigate the effect of isoflurane anesthesia on cardiovascular and respiratory function, PMN activation, and lung damage in endotoxemic sheep. They induced endotoxemia in both conscious and anesthetized sheep with the continuous infusion of LPS. They assessed the activation leukocytes by surface expression of CD11b and plasma myeloperoxidase concentration. They also measured lung damage by electron microscopy, bronchoalveolar lavage cell count, and analysis of lung vascular permeability. LPS infusion induced a hyperdynamic sepsis. In this study, they demonstrated that in the conscious group, the heart rate and cardiac output increased in compensation for decrease in total peripheral resistance; in contrast, the anesthetized sheep failed to show this compensation. These anesthetized sheep also had aggravated lung edema, tissue damage, enhanced neutrophil activation, and lung tissue accumulation. From their data, they concluded that isoflurane anesthesia with mechanical ventilation resulted in a blunted cardiovascular compensation in sepsis and enhanced leukocyte activation and may contribute to lung edema and tissue damage. All scientists conducting mouse studies have trouble with serial blood drawing examinations. That is why the study by Weixelbaumer et al. (15) is very important. The authors studied the influence of daily sampling in acutely septic mice upon survival and selected hematologic and organ function parameters, as well as complete blood cell count using resuspended blood cells. Daily sampling did not affect CLP-induced mortality, but daily decreased the red blood cell count and hemoglobin concentration. The authors found an excellent correlation between regular and resuspended complete blood cell count for all cell types except lymphocytes. The authors suggest that this method provides a feasible and safe translation of clinically relevant daily immunomonitoring in the mouse sepsis model. The last article by van Malenstein et al. (16) examines the sepsis-induced molecular changes in the porcine liver. Many investigators believe that the liver plays a central role for sepsis and sepsis survival. There are, however, investigators who argue that the liver is insignificant and plays no or only a minor role. This study adds to the evidence that the liver is crucial for postsepsis survival and outcome. The authors present a detailed molecular biological analysis of the events in the liver during sepsis, induced by peritoneal sepsis. Before and 21 h after induction of sepsis, liver samples were taken for microarray analysis. Pathway analysis revealed the following pathways involved in postsepsis changes: apoptosis, inflammation, and oxidant/redox balance. Further analysis identified three key regulator genes (IL8, CCL2, and CXCL2) among the first genes to be upregulated specifically in the sepsis group and that can directly or indirectly control the bulk of the sepsis response. These results indicate that inflammation in the liver triggers a vast response. A possible hypothesis is that that this response then induces metabolic and morphological changes that ultimately can lead to morbidity and mortality. In summary, the reader will enjoy the wide variety of excellent articles that will stimulate new experiments and new ideas.

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