SHOCK, Vol. 40, No. 5, pp. 349Y351, 2013

Commentary WHAT’S NEW IN SHOCK? NOVEMBER 2013 Ashley Guillory, PhD, and Celeste C. Finnerty, PhD University of Texas Medical Branch, Galveston, Texas

The November issue of Shock offers a diverse complement of clinical and basic science reports as well as two review articles. The issue begins with a thorough review article by Kusadasi and Groeneveld (1) on the usage of mesenchymal stromal cells (MSCs) for the treatment of sepsis. This review provides the history of MSC research including their discovery, methods for obtaining MSCs, and the characteristics that make MSCs an attractive therapeutic agent. More importantly, the authors intensively discuss the potential mechanisms of action for MSC therapies in sepsis. Critical review of the results from both preclinical and clinical studies demonstrates the beneficial effects of MSC therapy in sepsis and other diseases. The safety of MSC therapy is discussed based on the paucity of adverse events reported in the literature as well as possible (theoretical) risks that may be associated with MSC therapy based on in vitro and in vivo basic science research. Finally, the authors conclude that not only is MSC therapy in general safe for humans, but also there is a high probability that MSC therapy will prove to be a novel mode of treatment for sepsis particularly if given in the early onset of the condition. The second review article from Samraj et al. (2) is an extensive review of biomarkers in sepsis care. This article is an excellent resource for anyone interested in biomarkers of sepsis and/or inflammation. The National Institutes of Health definition of biomarkers, their classifications and characteristics, and the rationale for the use of biomarkers in sepsis are explained in depth. Biomarkers are classified by their clinical application (diagnostic, prognostic, monitoring, surrogate, or stratification) and are discussed according to the associated biological function being evaluated: acute inflammatory response, infection, and impaired metabolism, and Bbiomarker[ is valid under some, but not all, circumstances. The authors discuss both currently used sepsis biomarkers as well as biomarkers that are currently being developed along with the preclinical data supporting their usage. The review is not limited to the discussion of the benefits of using biomarkers but also includes the limitations of biomarker usage such as the lack of specificity of interleukin 6 (IL-6) elevation. Combining biomarkers is suggested to overcome the limitations of specificity and sensitivity present in the current biomarkers when used alone, and there are several studies showing significant improvement in the diagnosis of sepsis when using a score derived from three biomarkers. The article concludes with a brief discussion of using genomics, proteomics, and metabolomics to identify novel biomarkers such as IL-27, which is the topic of Wong and colleagues’ (3) clinical report. Traumatic brain injury is well known to cause secondary injuries as a result of brain edema and increased intracranial

pressure along with other pathophysiological mechanisms. Although the initial injury cannot be reversed, there are therapies that can reduce the onset and severity of secondary injuries. These secondary injuries are mediated through a variety of neurochemical and immunological cascades, but Junger et al. (4) focused their investigation on blocking polymorphonuclear neutrophil activation by resuscitating traumatic brain injury patients with hypertonic saline before hospitalization. The authors determined that hypertonic saline administration partially restored normal PMN activity as well as apoptosis. However, these changes did not translate into improved clinical outcomes; mortality and the Extended Glasgow Outcome Scale score were similar in all groups. The authors suggest that combining hypertonic saline resuscitation with hyperosmotic fluid therapy subsequently during hospitalization may improve clinical outcomes. The effect of hypertonic saline with dextran on PMN activation was also investigated; however, the addition of dextran appeared to be more harmful than helpful. Development of acute respiratory distress syndrome (ARDS) following sepsis increases morbidity and mortality. Mikkelsen et al. (5) conducted a single-center retrospective study of septic patients in the emergency department to investigate the epidemiology of ARDS. Risk factors for ARDS development were also examined. The authors report that the incidence of ARDS in the emergency department was fairly low and that the majority of the ARDS cases were found in the intensive care unit. It was also noted that ARDS developed quickly and was associated with increased fatality rates. In addition, serum lactate levels, microbiologically proven infection, and lung injury prediction score were associated with increased risk of ARDS development, while being diabetic was protective. The authors suggest that at the time of admission, serum lactate levels and a validated lung injury prediction score can be used to stratify patients according to their risk of developing ARDS. Continuing along the theme of biomarkers for sepsis, the utility of IL-27, a novel sepsis biomarker that was identified using genome-wide expression analysis, is explored. Wong et al. (3) had previously verified the use of IL-27 as a biomarker in critically ill children, but this report focuses on the possibility of IL-27 as a sepsis biomarker in critically ill adults. Interleukin 27’s biomarker capability was compared with that of procalcitonin (PCT), a biomarker that is currently being used. Surprisingly, the performance of IL-27 in differentiating adults with and without sepsis as well as differentiating between the sources of infection was inferior to that of PCT. This contrasts what the authors previously found in critically ill children, where they reported that IL-27 consistently outperformed PCT. However, in patients with sepsis secondary to infection from 349

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SHOCK VOL. 40, NO. 5

nonlung sources, an additive effect was found when IL-27 was combined with PCT, resulting in an increase in diagnostic accuracy. Although this initial evaluation suggests that the use of IL-27 as a diagnostic biomarker for sepsis may be limited, further studies are needed to build on the results presented here. Kimmoun et al. (6) investigated the clinical features at admission of patients with Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). Fifty-one hospitals were surveyed for participation in this study, resulting in the identification of 21 patients with DRESS. Patients were included if they had a probable or definite DRESS score as assessed by the RegiSCAR scoring system. Mortality, echocardiographic ejection fraction, mechanical ventilation, hepatic and renal failure, and lactic acidosis were among the outcomes determined. This study determined that the mortality rate of DRESS patients in the intensive care unit was much higher than that previously reported (47% vs. 10%). However, this conclusion was accompanied by the caveat that a large number of shock patients may be the driving force behind the elevated mortality rate. The final clinical report revisits the field of ARDS by evaluating the safety and use of intrapleural steroid instillation in patients with ARDS and multiorgan dysfunction syndrome (MODS) (7). Acute respiratory distress syndrome with MODS has a high mortality rate, and the current therapeutic interventions have failed to improve survival, which is probably due to the variety of etiologies involved in the development and progression of ARDS. Huang et al. (7) concluded that intrapleural steroid instillation treatment was a greatly improved treatment for MODS with ARDS as evidenced by improved survival rates and clinical parameters. The basic science section of this month’s issue is launched by an article from Liu et al. (8) concerning the use of arginine vasopressin (AVP) and norepinephrine (NE) in a rat model of uncontrolled hemorrhagic shock. Uncontrolled hemorrhagic shock occurs as a result of severe trauma or war wounds. The most effective treatments are hemorrhage control and extensive fluid infusion; however, fluid infusion soon after trauma occurs is often impossible because of the limits of medical care at the scene of the incident. The authors proposed the use of AVP and NE combined as an early-stage treatment to stabilize the patient for a longer period until more definitive treatment can be administered. This hypothesis was tested through transection of the splenic parenchyma and one of the branches of the splenic artery and vein to induce uncontrolled hemorrhagic shock in rats. Hemodynamic parameters, blood loss, and survival time were observed. Hemodynamic parameters were significantly increased in the AVP- and NE-treated rats. In addition, subsequent treatments following hemorrhagic control were enhanced by early administration of AVP and NE. Thus, AVP and NE combined treatment may be a viable novel option for early treatment of hemorrhagic shock both in civilian and military settings. In a departure from sepsis, ARDS, and trauma, the next article addresses cytochrome c oxidase (CytOx) and ischemic preconditioning (9). Vogt et al. (9) investigated the effect of short periods of ischemia also known as ischemic preconditioning on mitochondrial CytOx activity in isolated Langendorff perfused rat hearts. The outcomes measured included hemodynamics,


respiration, and phosphorylation of the CytOx subunits. Ischemic preconditioning accompanied by high coronary blood flow during reperfusion resulted in an ATP-dependent inhibition of CytOx. However, the CytOx phosphorylation pattern remained unchanged, indicating that other factors such as the amount of phosphorylation may dictate kinetic properties instead. Toll-like receptors (TLRs) and their role in the innate immune response is a hot topic in many areas of disease research. Bergt et al. (10) investigated the effect of deficiency of TLR2, a TLR found in the adrenal gland of mice, in a mouse sepsis model. Wild-type and TLR2 knockout mice were subjected to cecal ligation and puncture and corticosterone production measurement following hydrocortisone treatment and lipoteichoic acid exposure. Interleukin 6 and IL-1" plasma levels and blood counts were also determined following the operation. Toll-like receptor 2 knockout mice had increased survival compared with wild-type mice following cecal ligation and puncture. Interestingly, the increase in survival was accompanied by higher IL-6 levels. Hydrocortisone therapy, however, reversed the positive effect of TLR2 deficiency resulting in decreased survival and decreased IL-1" plasma levels. Another interesting finding of this study was that TLR2 deficiency resulted in a normal adrenal stress response in response to polymicrobial sepsis or surgical stress. According to the authors, the clinical correlation of their results suggests that hydrocortisone treatment has significant adverse effects in patients with TLR2 polymorphisms that disrupt the function of the receptor. The premise of the article by Chen et al. (11) is that alterations in expression of key proteins of the renin-angiotensin system are a major contributor in the etiology of acute lung injury. Thus, at various time points, determination of pathological changes, lung edema and permeability, angiotensinconverting enzyme (ACE) mRNA and protein expression, and angiotensin (Ang II and Ang-[1Y7]) levels was performed in mice subjected to hind-limb ischemia and reperfusion. Additional experiments were performed with ACE2 overexpression and knockout. There was an imbalance of both ACE/ACE2 and Ang II/Ang-(1Y7) expression. Furthermore, this imbalance was associated with enhanced lung injury. Angiotensinconverting enzyme 2 overexpression partially rescued the imbalance of ACE/ACE2 and Ang II/Ang-(1Y7) expression, whereas ACE2 knockout increased the imbalance and resulted in more severe lung injury. Thus, the authors concluded that changes in the renin-angiotensin system promote the occurrence of acute lung injury following trauma. This issue of Shock is concluded by Rump and colleagues’ (12) report on the effect of "2-adrenergic receptorYdependent signaling and lipopolysaccharide (LPS) on aquaporin expression in vivo and in vitro using a mice and a human monocytic cell line (THP-1). Aquaporins are membrane transport proteins, and aquaporins 1 and 5 function to maintain the fluid balance in the airways. The authors had hypothesized that "2-adrenergic receptorYdependent signaling would block the effect of LPS treatment, a common method used to induce sepsis in animal models. Both LPS and cyclic AMP, the downstream effector of "2-adrenergic receptor signaling, increased aquaporin 1 expression but not aquaporin 5 expression in THP-1. In the in vivo setting, LPS decreased aquaporin 1 mRNA, whereas terbutaline,

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SHOCK NOVEMBER 2013 a "2-adrenergic receptor agonist, doubled aquaporin 1 mRNA expression. In addition, there was a time-dependent biphasic expression of aquaporin following costimulation of THP-1 with cyclic AMP and LPS. It is clear that aquaporin 1 and 5 expression is regulated through distinctly different pathways. Finally, in contrast to the authors’ hypothesis, "2-adrenergic receptor signaling did not mitigate the effects of LPS in vitro or in vivo as evidenced by a decrease in aquaporin 1 mRNA expression and increased lung wet weight. REFERENCES 1. Kusadasi N, Groeneveld ABJ: A perspective on mesenchymal stromal cell (MSC) transplantation in the treatment of sepsis. Shock 40:352Y357, 2013. 2. Samraj RS, Zingarelli B, Wong HR: Role of biomarkers in sepsis care. Shock 40:358Y365, 2013. 3. Wong HR, Lindsell CJ, Lahni P, Hart KW, Gibot S: Interleukin-27 as a sepsis diagnostic biomarker in critically ill adults. Shock 40:382Y386, 2013. 4. Junger WG, Rhind SG, Rizoli SB, Cuschieri J, Baker AJ, Shek PN, Hoyt DB, Bulger EM: Pre-hospital hypertonic saline resuscitation attenuates the activation and promotes apoptosis of neutrophils in patients with severe traumatic brain injury. Shock 40:366Y374, 2013. 5. Mikkelsen ME, Shah CV, Meyer NJ, Gaieski DF, Lyon S, Miltiades AN, Goyal M, Fuchs BD, Bellamy SL, Christie JD: The epidemiology of acute respiratory










distress syndrome in patients presenting to the emergency department with severe sepsis. Shock 40:375Y381, 2013. Kimmoun A, Dubois E, Perez P, Barbaud A, Levy B: Shock state: an unrecognized and underestimated presentation of drug reaction with eosinophilia and systemic symptoms. Shock 40:387Y391, 2013. Huang P-M, Lin T-H, Tsai P-R, Ko W-J: Intrapleural steroid instillation for multiple organ failure with acute respiratory distress syndrome. Shock 40: 392Y397, 2013. Liu L, Tian K, Xue M, Zhu Y, Lan D, Peng X, Wu Y, Li T: Small doses of arginine vasopressin in combination with norepinephrine Bbuy[ time for definitive treatment for uncontrolled hemorrhagic shock in rats. Shock 40: 398Y406, 2013. Vogt S, Ramzan R, Weber P, Troitzsch D, Rhiel A, Sattler A, Irqsusi M, Ruppert V, Moosdorf R: Ischemic preconditioning results in an ATP-dependent inhibition of cytochrome c oxidase. Shock 40:407Y413, 2013. Bergt S, Wagner N-M, Heidrich M, Butschkau A, Noldge-Schomburg GEF, Vollmar B, Roesner JP: Hydrocortisone reduces the beneficial effects of TLR2 deficiency on survival in a mouse model of polymicrobial sepsis. Shock 40:414Y419, 2013. Chen L-N, Yang X-H, Nissen DH, Chen Y-Y, Wang L-J, Wang J-H, Gao J-L, Zhang L-Y: Dysregulated renin-angiotensin system contributes to acute lung injury caused by hind-limb ischemia-reperfusion in mice. Shock 40:420Y429, 2013. Rump K, Brendt P, Frey UH, Schafter S, Siffert W, Peters J, Adamzik M: Aquaporin 1 and 5 expression evoked by the "-2 adrenoreceptor agonist terbutaline and LPS in mice and in the human monocytic cell line THP-1 is differentially regulated. Shock 40:430Y436, 2013.

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What's new in Shock? November 2013.

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