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Hirasawa, Hiroyuki

doi: 10.1097/SHK.0000000000000567

Department of Emergency and Critical Care Medicine, Chiba University Graduate School of Medicine, Eastern Chiba Medical Center, Japan


The current issue of Shock contains two review articles (1–2); three articles by the winner of 2015 New Investigator Award competition (3–5), two of them are basic research articles; and 10 basic studies articles (8–15). Therefore, 12 out of 13 original articles in this issue are basic study articles.

Chignalia et al. (1) provide a very important comprehensive review on the importance of glycocalyx in the pathophysiology of critical condition putting the emphasis on the importance in the pathophysiology of lung injury following trauma. Recently, glycocalyx increases its significance as a target of research because it is now evident that glycocalyx layer in the endothelium plays a very important role on inflammation and immunological response and that the disruption of glycocalyx is a very important aspect of endothelial hyperpermeability along with the disruption of tight junction of endothelial cells. Furthermore, this review article refers to the importance of the disruption of lung epithelial glycocalyx in the pathophysiology of lung injury following trauma. The authors also pointed out the importance of shredded constituents of glycocalyx in the blood stream as a biomarker of injury severity. They further mentioned the possibility of the development of novel, glycocalyx-targeted polymers for both protection of glycocalyx from proteolytic degradation and restoration of the glycocalyx following shedding. Thus, this excellent article of glycocalyx on endothelium and epithelium would stimulate new area of shock-related research.

The next review article in this issue is entitled “Obesity and Critical Illness: Insights From Animal Model” by Mittwede et al. (2). This is a timely topic because recently it is the matter of debate whether obesity has adverse effect on the outcome of septic patients or not. Even though the title indicates that the authors will specifically discuss on the animal model to investigate the influence of obesity on critical illness, they first discussed the animal models of hemorrhage, blunt trauma, traumatic brain injury, and sepsis in general. Then the authors reviewed the difficulties in the development of animal model to investigate the influence of obesity to critical illness. On the contrary, because the personalized medicine is badly needed even in critical care paying the attention to patients’ comorbid conditions including obesity, and because there is no effective specific care for the critically ill obese patients, the establishment of adequate model should be achieved as soon as possible as the authors suggested.

As mentioned above, there are three articles by the New Investigator Award competition winners. First one is by Hansen et al. (3) who investigated the efficacy of SRT1720, which is one of sirtuin-activating compounds, on organ injury induced by ischemia-reperfusion in mice. They hypothesized that because the maintenance of mitochondrial biogenesis is essential for cell survival and is regulated in part by sirtuin, the activation of sirtuin by ST1720 would reduce local and remote organ injury after intestinal ischemia/reperfusion injury. And they showed the protective effect of ST1720 on intestinal ischemia/reperfusion-induced organ injury. Because there is no particular therapeutic approach to the ischemia-reperfusion injury, this approach may open a unique approach to this critical condition. The second article by the winner is by Reeves et al. (4). They investigated whether administration of oxandrolone, a nonaromatizable testosterone analog, to children with severe burn injury for 2 years would yield greater effects on long-term bone mineral content (BMC) and bone mineral density compared with shorter period administration. Patients were followed prospectively from the time of administration until 5 years postburn in a single-center, intent-to-treat setting. This long-term administration of oxandrolone significantly increased whole-body BMC, lumbar spine BMC. Furthermore, they found that these effects were significantly pronounced for a longer time in patients who were in growth spurt years (7–18 yr). No adverse side effects were attributed to the long-term administration of oxandrolone. Long-term outcomes following critical illness is recently discussed extensively, and malnutrition including osteoporosis is recognized as one of adverse outcomes among survivors from critical illness such as severe burn. This clinical study indicates that long-term administration of oxandrolone is one of promising approaches to these problems. Because this study includes only 35 patients who received long-term oxandrolone administration and were conducted in a single center, multicenter randomized trial is needed before the wide application of this long-term administration of oxandrolone to severe burn patients to prevent osteoporosis. The third article by the winner is by Xu et al. (5). Using humanized transgenic mice, expressing either surfactant protein B (SP-B) T or C allele without mouse SP-B gene, they showed that infected mice by Staphylococcus aureus with SP-B C allele had increased mortality, lung injury, apoptosis, and NF-κB expression compared with infected SP-B T mice. More interestingly, they also showed that curcumins, the extract from a plant having several pharmacological properties including anti-inflammatory and antioxidant effects, attenuates lung injury and reduces mortality on those infected mice. This is a unique study showing both the relevance of genomics on the susceptibility to infection and the efficacy of plant extract to the critical condition induced by S. aureus infection.

Post et al. (6) conducted the experimental study on the efficacy of fenoldopam, a DA1- and DA5-rceptor agonist, on the renal circulation, metabolism, and function using sheep sepsis model. Sepsis was induced by injecting autologous feces into the abdominal cavity. They found that fenoldpam did not improve renal blood flow, worsened microcirculatory alterations, and induced metabolic changes indicative of increased glycolysis, and that fenoldopam did not affect creatinine clearance or urine output. So, basically fenoldopam did not show any beneficial effect on the renal function in this model of sepsis. They suggest that different strategies will need to be developed to prevent and treat acute kidney injury in sepsis. Araújo et al. (7) investigated the role of nuclear transcription factor peroxisome proliferator-activated receptor γ (PPRA γ) in sepsis using mice model of cecal ligation and puncture and effect of PPRA γ agonist rosiglitazone. They noted increased bacterial killing in rosiglitazone-treated mice, correlated with increased generation of reactive oxygen species. They also noted rosiglitazone increased peritoneal neutrophil extracellular trap (NET)-mediated bacterial killing, which was reversed by PPRA γ antagonist treatment. They further observed that rosiglitazone enhanced the release of histones by polymorphonuclear leukocyte. And they concluded that rosiglitazone modulated the inflammatory response and increased bacterial clearance through PPRA γ activation and NET formation. However, it is also widely accepted that overwhelming NET formation is hazardous in the pathophysiology of sepsis causing endothelial damage and excessive histone release. Therefore, the authors may need to find out the optimal dosage and administration timing of rosiglitazone to show beneficial effect without adverse effect.

Karlsson et al. (8) investigated mitochondrial respiratory response in brain and liver of mouse model of sepsis-induced multiple organ failure. They thought that mitochondrial function played important role in the development of septic multiple organ failure and that derangement of mitochondrial function would be different among organs. They found diverse and tissue-specific mitochondrial respiratory response to sepsis. They also found that brain displayed an early impaired mitochondrial respiratory efficiency and that in the liver the primary change was a substantial activation of the maximal phosphorylating capacity. Those findings indicate that we may need organ-specific approach to prevent or treat organ failure following sepsis from the viewpoint of mitochondrial function. Opal et al. (9) finished an interesting study on the effect of one of SIRT1 activator compounds (STACs), SRT3025. They used two murine sepsis models: cecal ligation and puncture model to induce peritonitis and intratracheal installation of Streptococcus pneumoniae model to induce severe bacterial pneumonia. SRT3025 provided significant survival benefits over vehicle control in both the peritonitis and pneumonia models when administered with appropriate antimicrobial agents. SRT3025 treatment was also accompanied by striking changes in the transcription profiles in multiple inflammatory and metabolic pathways in liver, spleen, small bowel, and lung tissues. And very interestingly those organ-specific changes in the transcriptome analyses were similar following CLP or pneumococcal challenge despite different sets of pathogens at disparate sites of infection indicating that those changes were fundamental inflammatory response to infection in different organs. And they suggest that pharmacologic activation of SIRT1 modulates the innate host response and could present a novel treatment strategy for severe infection. As mentioned above, Hansen et al. (3) also showed the efficacy of STACs on sepsis in this issue. Therapeutic approach with STACs may be promising one which should be investigated rigorously.

Cortés et al. (10) published a unique study on the effect of ischemic preconditioning using a unique sheep model of sepsis. The sepsis is induced by injecting autologous feces into the abdominal cavity, and remote ischemic preconditioning was performed by inflating the balloon of a catheter in the aortic bifurcation for 2-min periods, followed by a 4-min deflation period. The procedure was performed 4 times before sepsis induction and 4-hourly afterward. Microcirculatory variables were better preserved in the conditioned than in the control group. And they noticed oliguria, hypotension, and death occurred later in the conditioned than in the control group. They conclude that in their sepsis model, remote ischemic pre- and postconditioning decreases organ dysfunction, preserves microcirculation and prolongs survival. As mentioned, this is a unique study on the effect of preconditioning on sepsis. However, preconditioning for septic patients cannot happen in clinical settings, and the way of ischemic preconditioning in the present study is not practically applicable. Yin et al. (11) investigated the association between changes in sublingual microcirculation and bulbar conjunctival microcirculation in a rat model of cardiac arrest. Because the number of patients who successfully resuscitated after cardiac arrest is increasing, there is increasing interest in the pathophysiology of postcardiac arrest syndrome. The authors measured sublingual and bulbar conjunctival microcirculatory blood flow using a sidestream dark-field imaging device, and both perfused vessels density (PVD) and microcirculatory flow index (MFI) were recorded. The postresuscitation PVD and MFI significantly decreased in both sublingual and bulbar conjunctival sites, and the values in sublingual and bulbar conjunctival sites were closely correlated. The changes were correlated with the severity of postresuscitation myocardial dysfunction. The authors indicated that sublingual site could be substituted by bulbar conjunctival at least in the rat model of cardiac arrest. The results of the present study suggest that measurement of conjunctival microcirculation may provide an accessible and convenient option as sublingual site for monitoring microcirculation in humans.

Wang et al. (12) investigated the impact of systemic hypertension and left ventricular hypertrophy (LVH) on outcome of cardiopulmonary resuscitation and therapeutic hypothermia in a cardiac arrest model of rat. They found that systemic hypertension and LVH did not affect return of spontaneous circulation, but that survival was dismal due to elevated severity of cardiac and cerebral injury in hypertensive animals regardless of short-duration hypothermia. This is an important piece of work because systemic hypertension and LVH are major risk factors of cardiac arrest, and we might need to personalize specific therapeutic approach for those patients. Jiang et al. (13) investigated the effect of intraperitoneal resuscitation with different concentration of sodium pyruvate on intestinal ischemia/reperfusion injury in hemorrhagic shock in rats. The rationale for intraperitoneal resuscitation is that during early intravenous resuscitation the splanchnic vasculature remains contracted, and as ischemia persists, reperfusion injury occurs and that intraperitoneal resuscitation can ameliorate visceral vasoconstriction following intravenous resuscitation, regulate microcirculation, protect endothelial cells, and reduce third spacing of fluid. They found that peritoneal resuscitation using sodium pyruvate solution combined with intravascular resuscitation provides protection against intestinal ischemia-reperfusion injury following hemorrhagic shock and resuscitation. They further found that under the same hypertonic condition, 1.1% sodium pyruvate solution showed significant advantage compared with 2.2% and 1.6% solution. They suggest that underlying mechanisms may include the maintenance of hemodynamic stability, regulation of homeostasis, inhibition of oxidative stress and inflammation, and protection of intestinal epithelial tight junction barrier function. Peritoneal resuscitation is clinically feasible. However, the efficacy should be confirmed in larger animal models before the clinical application of this new resuscitation to hemorrhagic shock.

Nullens et al. (14) investigated the effect of GTS-21, an alpha7 nicotinic acetylcholine receptor (alpha7nACR) agonist, on cecal ligation puncture-induced inflammatory, gastrointestinal motility, and colonic permeability changes in mice model because the inhibition of gastrointestinal motility together with mucosal barrier dysfunction will lead to increased bacterial translocation. In addition, it is reported that alpha7nACR have anti-inflammatory properties. The results of the study indicate that peripheral targeting of the vagal anti-inflammatory pathway proves beneficial in an animal mode in an animal model of polymicobial abdominal sepsis.

Lin et al. (15) investigated whether vistatin, pre-B cell-enhancing factor or nicotinamide phosphoribosyltransferase, would promote foam cell formation, a key event in the pathogenesis of atherosclerosis, in RAW 264.7 macrophage. And they noticed vistatin treatment increased oxidized low-density lipoproteins uptake and decreased cholesterol efflux and finally promoted foam cell formation. These results indicate some inhibitor of vistatin might have therapeutic potential to prevent atherosclerosis.

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1. Chignalia AZ, Yetimakman F, Christiaans SC, Unal S, Bayrakci B, Wagener BM, Russell RT, Kerby JD, Pittet J-F, Dull RO. The glycocalyx and trauma: a review. Shock 2016; 45:338–348.
2. Mittwede PN, Clemmer JS, Bergin PF, Xiang L. Obesity and critical illness: insights from animal models. Shock 2016; 45:349–358.
3. Hansen LW, Khader A, Yang W-L, Prince JM, Nicastro JM, Coppa GF, Wang P. Sirtuin 1 activator SRT1720 protects against organ injury induced by intestinal ischemia-reperfusion. Shock 2016; 45:359–366.
4. Reeves PT, Herndon DN, Tanksley JD, Jennings K, Klein GL, Mlcak RP, Clayton RP, Crites NN, Hays JP, Andersen C, et al. Five-year outcomes after long-term oxandrolone administration in severely burned children: a randomized clinical trial. Shock 2016; 45:367–374.
5. Xu Y, Ge L, Abdel-Razek O, Jain S, Liu Z, Hong Y, Nieman G, Johnson F, Golub LM, Cooney RN, et al. Differential susceptibility of human SP-B genetic variants on lung injury caused by bacterial pneumonia and the effect of a chemically modified curcumin. Shock 2016; 45:375–384.
6. Post EH, Su F, Taccone FS, Hosokawa K, Herpain A, Creteur J, Vincent J-L, De Backer D. The effects of Fenoldopam on renal function and metabolism in an ovine model of septic shock. Shock 2016; 45:385–392.
7. Araújo CV, Campbell C, Gonçalves-de-Albuquerque CF, Molinaro R, Cody MJ, Yost CC, Bozza PT, Zimmerman GA, Weyrich AS, Castro-Faria-Neto HC, et al. A PPARγ agonist enhances bacterial clearance through neutrophil extracellular trap formation and improves survival in sepsis. Shock 2016; 45:393–403.
8. Karlsson M, Hara N, Morata S, Sjövall F, Kilbaugh T, Hansson MJ, Uchino H, Elmér E. Diverse and tissue-specific mitochondrial respiratory response in a mouse model of sepsis-induced multiple organ failure. Shock 2016; 45:404–410.
9. Opal SM, Ellis JL, Suri V, Freudenberg JM, Vlasuk GP, Li Y, Chahin AB, Palardy JE, Parejo N, Yamamoto M, et al. Pharmacological SIRT1 activation improves mortality and markedly alters transcriptional profiles that accompany experimental sepsis. Shock 2016; 45:411–418.
10. Cortés DO, Su F, Santacruz C, Hosokawa K, Donadello K, Creteur J, De Backer D, Vincent J-L. Ischemic conditioning protects the microcirculation, preserves organ function, and prolongs survival in sepsis. Shock 2016; 45:419–427.
11. Yin L, Yang Z, Yu H, Qian J, Zhao S, Wang J, Wu X, Cahoon J, Tang W. Changes in sublingual microcirculation is closely related with that of bulbar conjunctival microcirculation in a rat model of cardiac arrest. Shock 2016; 45:428–433.
12. Wang P, Zhang L, Gong Y, Zhang H, Wang X, Li Y. Impacts of systemic hypertension and left ventricular hypertrophy on outcome of cardiopulmonary resuscitation and therapeutic hypothermia in a cardiac arrest model of rat. Shock 2016; 45:434–440.
13. Jiang L-L, Zhang J-J, Zhang Z-Z, He X-H, Chen D-L, Wang Y-L. Effect of intraperitoneal resuscitation with different concentrations of sodium pyruvate on intestinal ischemia reperfusion injury in hemorrhagic shock rat. Shock 2016; 45:441–449.
14. Nullens S, Staessens M, Peleman C, Schrijvers DM, Malhotra-Kumar S, Francque S, Matteoli G, Boeckxstaens GE, De Man JG, De Winter BY. Effect of GTS-21, an alpha7 nicotinic acetylcholine receptor agonist, on CLP-induced inflammatory, gastrointestinal motility and colonic permeability changes in mice. Shock 2016; 45:450–459.
15. Lin Y-T, Jian D-Y, Kwok C-F, Ho L-T, Juan C-C. Visfatin promotes foam cell formation by dysregulating CD36, SRA, ABCA1 and ABCG1 expression in RAW264.7 macrophages. Shock 2016; 45:460–468.
© 2016 by the Shock Society