What's New in Shock, February 2020?

The current issue of Shock contains three papers by 2019 New Investigator Awardees (1–3), three clinical studies (4–6), and eight basic studies (7–14). An increase in the lipolysis of white adipose tissue (WAT) promoted by extensive burn injury is a complication that enhances post-burn hypermetabolism, contributing to hyperlipidemia and hepatic steatosis. Furthermore, the systemic increase of free fatty acids (FFAs) due to burn-induced lipolysis and subsequent organ fatty infiltration may culminate in multiple organ dysfunction and, ultimately, death. Therefore, Barayan et al. (1) from Toronto University hypothesize that reducing WAT lipolysis to diminish the mobilization of FFAs may render an effective means to improve outcomes postburn. Using a murine model of thermal injury, they show that specific inhibition of hormone-sensitive lipase with Acipimox (a clinically used hypolipidemic niacin derivative) effectively suppresses burn-induced lipolysis in the inguinal WAT leading to lower levels of circulating FFAs. They further show that reduction of FFA mobilization by Acipimox significantly decreased liver weight and intracellular fat accumulation, suggesting that it may also improve organ function post-burn. The significance of the present study is that the authors show the pharmacological inhibition of lipolysis as a potentially powerful therapeutic strategy to counteract the detrimental metabolic effects induced by burn. Since Acipimox is a clinically used hypolipidemic agent, clinical study on the efficacy of lowering lipolysis on burn patients with Acipimox might be started soon. As the aged population is increasing very rapidly in many countries, the number of the aged trauma victims also is increasing. And the improvement of the outcome of the aged trauma patients is very important aspect in trauma care. On the other hand, the contribution of individual genetic determinants of aging to the adverse clinical outcomes and altered inflammation mediator networks characteristic of aged trauma patients is unknown. Therefore, Lamparello et al. (2) from University of Pittsburgh investigated whether aging-related nucleotide polymorphism would alter clinical outcomes and distinct inflammatory profiles in aged blunt trauma patients. And they found that an aging-related single nucleotide polymorphism (SNP), rs2075650, may influence clinical outcomes and inflammation networks in aged patients following blunt trauma, and that thus the SNP may serve as a predictive outcome biomarker in the setting of polytrauma. These findings are very much important to develop precision medicine in critical care medicine. Endothelial hyperpermeability (also sometimes termed endotheliopathy) draws much attention as important pathophysiological features in many kinds of critical illness such as hemorrhagic shock. And loss of cell-associated syndecan-1 (Sdc1), an important bridging protein, is a key component of endothelial hyperpermeability. Fresh frozen plasma (FFP) preserves Sdc1 and reduces permeability following hemorrhagic shock, although the key mediators remain unknown. Antithrombin III (ATIII) is a plasma protein with potent anti-inflammatory and endothelial protective activity. Therefore, Lopez et al. (3) from University of Texas hypothesized that the protective effects of FFP on endothelial Sdc1 and permeability are mediated, in part, through ATIII. And they measured ATIII and Sdc1 in severely injured patients for correlation analysis. Pearson correlation analysis showed a significant negative correlation between plasma levels of Sdc1 and ATIII in injured patients. Also, in vitro, FFP and ATIII prevented TN-induced hyperpermeability. ATIII-deficient FFP had no effect; however, ATIII restoration re-established its protective effects in a dose-dependent manner. And they conclude that ATIII plays a role in FFP-mediated protection of endothelial Sdc1 expression and barrier function, making it a potential therapeutic target to mitigate hemorrhagic shock-induced endothelial dysfunction. Since there is no effective therapeutic approach to endothelial hyperpermeability in the clinical settings, the results of the present study would be of great importance. The usefulness of blood lactate level as a prognostic biomarker on critically ill patients is now widely accepted and some papers also report its usefulness on traumatized and critically ill emergency patients even in prehospital settings. Martín-Rodríguez et al. (4) from Universidad de Valladolid, Spain reported the prognostic value of prehospital lactate levels to predict early mortality in acute cardiovascular disease. Since hand-held lactate analyzer is commercially available, the blood lactate level now can be checked even in the ambulance car in some countries including Japan and the measurement is reportedly very effective to give appropriate critical care when an emergency patient arrives at emergency department of a hospital as suggested by the authors. Choice of vasopressors in critically ill patients with circulatory failure has been discussed extensively and recent guidelines recommend norepinephrine for septic patients. van Loon et al. (5) from University of Twente in the Netherlands compared the effect of 5-h infusion of either 0.05 mg/kg/min of norepinephrine, 0.5 mg/kg/min of phenylephrine, and 0.04 IU/min vasopressin on macrocirculation monitored with arterial catheter-derived parameters with additional blood pressure waveform contour analysis (PCA) and sublingual microcirculation monitored with microcirculatory density and flow assessed using a handheld video microscope on healthy male volunteers with intravenous administration of 2 ng/kg lipopolysaccharide (LPS). And they find the LPS-induced decrease in blood pressure and systemic vascular resistance (SVR) was refractory to low-dose norepinephrine and phenylephrine, and to a lesser extent, to vasopressin. Only vasopressin exerted effects on PCA parameters compared with placebo, by mitigating the LPS-induced decrease in diastolic blood pressure by stabilizing SVR and cardiac output. The endotoxemia-induced decreased indices of microvascular flow and density were not influenced by vasopressor therapy. Even though the results of the present study involving human volunteers with LPS intravenous injection are interesting, I regret the fact that those three vasopressors were intravenously administered 1 h before the administration of LPS in the present study, a kind of pretreatment, which does not mimic the clinical situation. Cardiogenic shock requiring mechanical circulatory support in patients who underwent heart valve surgery is a serious complication. Therefore, prediction of the occurrence of such complication using a biomarker would be of clinical relevance. Duchnowski et al. (6) from Warsaw Institute of Cardiology, Poland found that high-sensitivity Troponin T measured immediately after surgery remained an independent predictor of the primary end point and that the postoperative high-sensitivity Troponin T can be used to predict a postoperative cardiogenic shock requiring mechanical circulatory support. This is an important finding. However, this is a derivate study and a validation study may be investigated before long. Military prehospital care for hemorrhage is often characterized by use of tourniquets (TQ) and permissive hypotensive resuscitation (PHR) with crystalloids or colloids, but these treatments have not been previously combined in an animal model. Although albumin resuscitation solutions have been tested, the potential effects of nonesterified fatty acids (NEFAs) bound to albumin have not been evaluated in vivo, and few studies have investigated concentrated albumin solutions to reduce fluid requirements. Penn et al. (7) from TriService Research Laboratory, San Antonio, Texas created a militarily relevant rat model of trauma and hemorrhagic shock (T/HS) (27 mL/kg hemorrhage) with TQ and PHR and investigated the ability of resuscitation with concentrated (250 mg/mL) albumin, followed by Plasmalyte as needed to maintain PHR, to reduce fluid volumes (vs. Plasmalyte alone). Albumin was free of nonesterified fatty acids or saturated with oleic acid. Their findings suggest incorporating TQ and PHR in T/HS models may result in high mortality and fluid requirements and that oleic acid-saturated albumin, but not NEFA-free albumin or Plasmalyte alone, may provide a benefit to early survival and resuscitation volume. However they also suggest that a hemolytic mechanism may have later consequences, and that therefore caution is advised. Since this is an experimental study using a small animal (rats), further preclinical study using a larger animal may be necessary before this therapeutic approach will be applied in clinical settings. Hiengrach et al. (8) from Chulalongkorn University, Bangkok, Thailand investigated the influence of gut fungi in chronic colitis by repeated oral administration of Candida albicans in a 3% dextran sulfate solution (DSS) induced-colitis mouse model. And they conclude that Candida enhances DSS colitis severity through gut dysbiosis (gut bacterial selection), enhanced gut leakage-induced bacteremia, and induced systemic inflammatory responses. They also conclude that the impact of C albicans upon the gastrointestinal murine model might be important for future model development and the DSS model with Candida administration might be a useful additional model and that insight into the gut fungal burden and/or gut perm-selectivity may provide new biomarkers or novel treatment strategies for inflammatory bowel diseases. Recently, the importance of maintenance of normal microbiome in gut and the pathological importance of pathobiome (derangement of microbiome) is emphasized and the present study might add significant information when a researcher develops a new model of pathobiome animal. Zöllner et al. (9) in Imperial College Parturition Research Group, Chelsea and Westminster Hospital, London, UK, reported in their previous work that pregnancy exacerbates the hypotensive response to both infection and LPS. The high levels of progesterone (P4) associated with pregnancy have been suggested to be responsible for the pregnancy-induced changes in the cardiovascular response to infection. Therefore, they test the hypothesis that P4 supplementation exacerbates the hypotensive response of the maternal cardiovascular system to LPS. They used female CD1 mice being implanted radiotelemetry probes to measure hemodynamic function noninvasively. And mice were challenged by intraperitoneal injection of LPS (10 mg of serotype 0111:B4). The authors indicate that the present study demonstrates that P4 supplementation prevented LPS-induced hypotension in pregnant mice in association with reduced myocardial inflammatory cytokine gene expression and that these observations suggest that rather than being detrimental, P4 supplementation has a protective effect on the maternal cardiovascular response to sepsis. This is an interesting finding. However, I have a little bit concern on the model. Recently, many concerns are expressed on the sepsis model developed with intravenous or intraperitoneal LPS injection. Therefore, I wish the authors perform same kind of experimental study using other models of sepsis such as cecal ligation and puncture model or intraperitoneal injection of fecal slurry model. Hypoxia-inducible factor (HIF)-1α has increasingly recognized its importance as a transcription factor that is critical for tissue adaptation to hypoxia and inflammation. Li et al. (10) from Shanghai Jiao Tong University in China previously reported that normoxic activation of HIF-1α in cancer involves inhibition or mutation of the metabolic enzyme succinate dehydrogenase (SDH). And they also found that local inhibition of HIF-1α ameliorates acute lung injury (ALI) induced by T/HS in rats. In the present study, they found pulmonary activation of HIF-1α and inhibition of SDH during THS-induced ALI in rats and transcriptional activation of HIF-1α during ALI induced by T/HS lymph via SDH pathway in vitro. Furthermore, they show that pharmacologic inhibition of HIF-1α attenuates lung inflammation and pulmonary edema during ALI by T/HS and that activation of HIF-1α is detrimental to ALI induced by T/HS. Thus, their data suggest that HIF-1α activation by T/HS is necessary for T/HS-induced lung injury and a critical role for SDH in the initiation of acute inflammatory response after ALI. However, since this is a preclinical study, we should be cautious to consider the clinical application of the result in the present study. Sun et al. (11) from Shaghai Jiao Tong University in China underwent the study aiming at investigating the changes of bile acids in the liver during hemorrhagic shock (HS) and their potential to attenuate liver injury via activation of SIRT1 (sirtuin 1)-FXR (famesoid X receptor) signaling. They used a Sprague–Dawley (SD) rat HS model, whereas HepG2 cells were hypoxically cultured to simulate HS in vitro. And they found that tauroursodeoxycholic acid (TUDCA) in the liver decreased significantly after HS and that SIRT1 and FXR expression was time-dependently downregulated by HS or hypoxia condition. They also observed that TUDCA upregulated SIRT1–FXR activity, which inhibited expression and acetylation of NF-κB and p53 and increased FoxM1 expression, leading to decreased inflammatory response and apoptosis and increased proliferative capacity in hepatocytes, and attenuation of liver injury. As mentioned above, the critical illness among the aged population is a very important aspect of modern critical care and it is pointed out that the aged people show poorer outcome compared with young population. And the immunosuppression among the aged population, which is sometimes referred to as immunosenescence, is thought to be the cause of the poor outcome in the aged septic population. T-cell exhaustion is reportedly the main cause of sepsis-induced immunosuppression. However, the trend, impact, and mechanism of T-cell exhaustion are still unclear. On the other hand, it has been reported that interleukin (IL)-15 improves survival rate of septic mice via its antiapoptotic effect on T cells. However, it is still unclear how IL-15 reverses prolonged T-cell exhaustion in aged septic mice. Therefore, Saito et al. (12) from Kobe University, Japan investigated the study to clarify the trend of sepsis-induced T-cell exhaustion and whether IL-15 prevents aging-induced persistent T-cell exhaustion in septic mice. They used a sepsis model with intraperitoneal injection of preserved cecal slurry and found that sepsis-induced T-cell exhaustion was more severe and prolonged in aged mice. They also found that IL-15 could improve sepsis-induced T exhaustion by increasing the frequency of naïve CD4+ and CD8+ T-cell distribution and downregulating the expression of PD-1 on T cell and Treg population, with increasing NK cells and macrophage and phagocytosis activity in aged septic mice. Taking those interesting results they suggest that IL-15 may potentially improve T-cell exhaustion over an extended period. Thus, this interesting experimental study shows the possibility of effective treatment with IL-15 for immunosuppression among the aged population to which there is no effective treatment at this moment. There are many experimental studies investigating the effect of pharmacological agents against sepsis. This study by Irahara et al. (13) from Nippon University, Japan is very unique in terms of the investigation of the efficacy of non-pharmacological electrical stimulation (ENMS) on energy substrate metabolism and survival in mice endotoxin model. They previously demonstrated that low-intensity exercise in the acute phase of endotoxic shock has therapeutic effects such as improving lipid metabolism and prolonging survival by stimulating peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α expression. However, in a clinical setting, it may be unsafe for patients in the acute phase of sepsis to exercise. NMES has effects similar to exercise and was shown to be beneficial as an early rehabilitation strategy for patients in the intensive care unit who have sepsis. In the present study, they show that ENMS is an effective early intervention even in hemodynamically unstable patients. Additionally, they showed that NMES exerts therapeutic effects under conditions that induce a mild switch in energy metabolism from glucose to lipid predominant metabolism through PGC-1α upregulation and suppression of inflammation. I hope that the authors proceed to the clinical study on ENMS in near future, since this approach seems to be safe even on critically ill patients. Barrier dysfunction not only in endothelium but also in gut mucosa recently draws much attention as important pathophysiological features of sepsis. Sepsis is associated with primary injury to the intestinal mucosa, which in turn induces bacterial translocation and hyperpermeability. Cholecystokinin (CCK) is a peptide synthesized by several cell types, whose immunomodulatory activity has been reported in experimental models of inflammation. Taking those previous findings into consideration, Saia et al. (14) from University of São Paulo, Brazil, hypothesized that the CCK treatment could modulate the inflammatory response and protect the integrity of the intestinal barrier in endotoxemic rats. In synergy with previous findings from their research group, they demonstrated that CCK preserves the integrity of the intestinal mucosa and that it might be a promising hormonal adjuvant therapy for the treatment of sepsis. The results of the present study may be advanced to clinical application soon.

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