What’S New in Shock, December 2014?

The important role of mesenteric lymph after trauma and hemorrhage is the theme of several articles in this month’s Shock. Authors from the University of Colorado investigated changes in mesenteric lymph using two different state-of-the-art techniques. Injured patients not dying from hemorrhage or traumatic brain injury still succumb to multiple organ failure. The lymphatic system is known to transport gut-derived proinflammatory mediators to the systemic circulation that contribute to its development. The specific mediators remain somewhat elusive but are derived from breakdown of the gut barrier after trauma and shock. Dzieciatkowska et al. (1) start off this month’s journal with a proteomic analysis of human plasma and lymph collected from critically ill or injured patients and from patients undergoing semielective spine surgery or organ donation compared with normal healthy control plasma and lymph. Proteomic analysis was performed using immune-affinity deletion and revealed several interesting findings. Foremost, the proteome of lymph was not the same as that of plasma, with a number of unique proteins found only in the lymph. This led the authors to conclude that the mesenteric lymph is not a mere plasma ultrafiltrate but rather a substance that contains unique proteins that, in postshock trauma patients, may lead to multiple organ failure. Continuing on the same theme of the mesenteric lymph, D’Alessandro et al. (2) used label-free mass spectrometry to assess dynamic changes in postshock mesenteric lymph in a rodent model of hemorrhagic shock. Through a series of elegant analysis of early changes in the soluble protein components of postshock lymph, a potentially important area of future investigations was uncovered relating to the impairment of serine proteases/antiproteases. The authors demonstrated an early decrease in serine proteases with a progressive increase in extracellular matrix proteins and matrix metalloproteinases, which they linked to neutrophil priming. Further investigation into inflammation after hemorrhagic shock was done using intravital microscopy in the rat mesenteric microcirculation to examine the effects of induced hypothermia. Therapeutic hypothermia has been studied in the laboratory and clinically for a variety of conditions. The association of hypothermia with the bloody vicious triad of hypothermia, acidosis, and coagulopathy of trauma and hemorrhagic shock has understandably led to some reservation using this technique to the bleeding patient. Using a pressure-controlled rodent model of hemorrhagic shock followed by induced hypothermia during resuscitation, Coyan et al. (3) demonstrated a significant attenuation of leukocyte adherence and mast cell degranulation in mesenteric venules compared with animals not undergoing cooling. As evidence accumulates on the pathologic role of a dysfunctional endothelium after hemorrhagic shock, this work suggests that maybe we should rethink the evils of hypothermia. Induced hypothermia may indeed be biologically and functionally different from the iatrogenic hypothermia that results from bleeding and resuscitation. Finishing up on the topic of hemorrhagic shock, Richter et al. (4) examined the novel role of macrophage-derived chemokine (MDC/CCL22) in mediating pulmonary inflammation following hemorrhage and resuscitation with Ringer’s lactate solution. Both systemic and pulmonary levels of MDC after resuscitation correlated with infiltration of inflammatory cells and lung inflammation. These effects were mitigated by pretreatment with neutralizing antibodies to MDC and worsened by recombinant MDC. Their results suggested that alterations in MDC levels correlated with pulmonary levels of the chemoattractant cytokines KC, MIP-2, and MIP-1α. It would be interesting to know how alternative fluids or blood products would alter this important chemokine. The next set of articles focused on sepsis. Continuing with the ongoing “omic” theme of this month’s Shock, Kamisoglu et al. (5) integrated transcriptional data from circulating leukocytes and metabolic profiling from plasma obtained from normal healthy individuals who received a dose of endotoxin. The goal of this study was to assess the transcriptional regulation specifically of metabolic processes to detect metabolism-specific transcripts. The authors therefore filtered the transcriptome to negate the pronounced influence of early inflammatory genes. Changes in metabolism occurred at later time points compared with transcriptomic alterations, and there were differential alterations in lipids and proteins across time. The authors highlighted the potential clinical application of this technique as “omic” analysis becomes increasingly available. The liver seemed like a lovely organ to study for several authors. Starting off, Hsu et al. (6) examined the role of exogenous heat shock protein 70 in a rodent model of lipopolysaccharide (LPS). The constitutive heat shock cognate protein 70 was used in this proof-of-concept study to demonstrate its important role in attenuating both myocardial and hepatic dysfunction after endotoxemia. Heat shock cognate protein 70 lessened systemic signs of sepsis and attenuated a number of proinflammatory mediators via the MAPK/NF-κB pathway. In another proof-of-concept article, Shirozu et al. (7) used a galactosamine/LPS model of acute liver failure to examine the role of farnesyltransferase (FTase) inhibition in mitigating liver failure. The authors extended their work on FTase inhibitors in LPS-induced liver damage to now looking at liver failure. They demonstrated that the FTase inhibitor tipifarnib prevented acute liver failure and thus lessened mortality. In addition, liver injury was attenuated and apoptotic changes lessened. The mechanisms responsible for these effects in their galactosamine/LPS model of liver failure were inhibition of JNK activation and upregulation of the liver antiapoptotic molecules Bcl-2 and Bcl-xL. Lastly, Kwok and Clemens (8) delved into the molecular mechanisms of Rho-kinase (ROCK-2) inhibition of endothelin-1–induced nitric oxide and its subsequent effect on liver microcirculation. RhoA is a small GTPase that binds GTP and interacts with caveolin-1 in the caveolae of endothelial cells when activated. RhoA then binds to the Rho-binding domain of ROCK-2 to increase its activity. Rho-kinase ROCK-2 regulates both cell contractility and assembly of the actin cytoskeleton. Using liver sinusoidal endothelial cells and LPS administration to mimic endotoxemia, they tested the effects of ROCK-2 inhibition. Lipopolysaccharide induced the Rho/ROCK signaling pathway and disrupted endothelin-1–mediated eNOS activation. These effects were restored by ROCK-2 inhibition, in part, via an increase in actin depolymerization. Kwok and Clemens really ROCK! The next article highlights the complexity of sepsis-related research by pointing out the conflicting role of macrophage 1 antigen (Mac-1), a leukocyte adhesion molecule, on lung injury after sepsis. Liu et al. (9) used Mac-1–null mice in a severe model of abdominal sepsis. They found that Mac-1–deficient mice had increased mortality that was associated with a higher systemic bacterial load and more severe inflammation. However, they found no attenuation of lung neutrophil recruitment, contrary to earlier reports. Bijli et al. (10) also rolled down the path of lung leukocyte recruitment, focusing on the role of transglutaminase 2 (TG2) in endothelial cell inflammation and pulmonary leukocyte infiltration. Transglutaminase 2 is a calcium-dependent enzyme that catalyzes cross-linking of proteins (10). In vitro, TG2 mediated thrombin-induced endothelial cell inflammation by promoting NF-κB signaling via phosphorylation and DNA binding of RelA/p65. The authors confirmed these findings in vivo in a mouse model of endotoxemia, and further studies suggested a role for TG2 in adhesion molecule expression and lung leukocyte infiltration. Boisrame-Helms et al. (11) investigated the differential effect of two lipid emulsions used in parenteral nutrition on membrane remodeling and associated inflammation. The combination of medium-chain triglycerides and long-chain triglycerides, but not long-chain triglycerides alone, exacerbated sepsis-induced hemodynamic instability and enhanced endothelial cell activation, as shown by increased procoagulant microparticle generation from platelets, leukocytes, and endothelial cell origin. Microparticle generation was also associated with markers of inflammation, including phosphorylated IκB. These findings occurred in septic, but not sham, rats, suggesting that the choice of lipid emulsion may be important when administered to septic patients. Lastly, a hot article by Yu et al. (12) on burn-induced hyperglycemia completes this month’s Shock. MiRNAs regulate gene expression at the translational level. They are involved in glucose metabolism, and their expression is altered in burn wound tissue. In the current article, the authors identified a novel function of miR-194 in modulating burn-induced hyperglycemia via suppression of insulin-like growth factor receptor (IGF-IR). In an elegant set of experiments, the authors demonstrated a significant increase in miR-194 expression that was accompanied by a reduction in IGF-IR/Akt signaling in the skeletal muscle of burned rats. Overexpression of miRNA attenuated IGF-IR/Akt activation and promoted hyperglycemia. The important role of miR-194 may pave the way to a better understanding and treatment of burn-induced hyperglycemia and its detrimental effects on outcome.