What’s New in Shock? October 2013 (2013)

This month’s issue of Shock again presents an outstanding selection of review and original articles with both clinical and basic science approaches. Two review articles reevaluate an old player in mechanisms of shock and evaluate hemorrhage/trauma models. De Maio and Vasquez (1) revisit heat shock proteins. Although well known to be induced following stress, the authors present recent evidence indicating that heat shock proteins also have an important extracellular role. This novel role may provide additional insight into the mechanisms by which the immune system becomes aware of tissue stress. In another review, Hildebrand et al. (2) summarize the current status of porcine models of trauma and hemorrhage. They point out that although there are many models reported in the literature, they tend to focus on a very short time course after injury. They conclude that there is a need for more long-term models to examine clinically relevant delayed impairment in organ function. In the same vein of combined injury models, Chai et al. (3) report of model of combined burn and blast injury followed up to 7 days after injury. They found that rats exposed to the combined injury had more severe injury and that this was particularly so for lung injury and coagulopathies. This model may be useful for the study of battlefield casualties in which these injuries may be combined. Another important area of shock research is in the discovery of markers of severity of injury. Two articles this month address this. Stamataki et al. (4) report a clinical study examining serum levels of S100B protein, a biomarker of brain injury in the context of hemorrhage. They compared serum S100B with interleukin 6 levels in 64 patients with severe hemorrhage. S100B was elevated in the hemorrhage patients and correlated with interleukin 6 as well as lactate, pH, and bicarbonate. It also significantly predicted mortality, suggesting that it may be a useful biomarker in hemorrhage patients without brain injury. In an animal (swine) study, Noel-Morgan et al. (5) examined the utility of pulse pressure variation as a parameter to guide resuscitation in a combined hemorrhage/endotoxin model. Pulse pressure variation was found to be comparable to central venous pressure in guiding resuscitation but superior to mean arterial pressure or mixed venous oxygen saturation. Although the investigators reported limitations to both pulse pressure variation and central venous pressure, they suggest that combining the two may provide a superior method for guiding resuscitation. This month’s issue also provides two articles addressing mechanisms of injury in shock-related states. Carter et al. (6) studied the potential role for increased gut permeability in the increased mortality associated with combined radiation and burn injury in excess of what is seen in either injury alone. In a mouse model, they found that the combined injury results in increased bacterial translocation associated with disruption of intestinal tight junctions and epithelial cell apoptosis, suggesting a focus on gut function as an important mechanism in this combined injury. Toll-like receptors (TLRs) are well known to contribute to injury response, but the full mechanisms by which they are regulated are not fully known. Blok et al. (7) tested the role of interleukin 1 receptor-like 1 (ST2), a negative regulator to TLR signaling, on the cytokine response to a gram-positive and gram-negative pathogen. They isolated total leukocytes and splenocytes from wild-type or ST2−/− mice and stimulated them in vitro with Streptococcus pneumoniae and Klebsiella pneumoniae. Unexpectedly, deletion of the negative regulator decreased cytokine production. Moreover, in vivo, there was little effect of induced cytokine production. The authors conclude that ST2 is proinflammatory but of little effect with infection. It is also possible that the effects are from compensatory mechanisms in the knockout mice, making them unrepresentative. The remaining articles this month address potential therapeutic approaches. Two focus on cardiac injury, two on lung injury, and one on wound infection. Liu et al. (8) tested the effect of an extract of ginseng (Panax quinquefolium saponin) on cardiac remodeling after myocardial infarction in a rat model. Panax quinquefolium saponin decreased infarct size and improved ventricular function after myocardial infarction. This was associated with decreased endoplasmic reticulum stress and apoptosis. This effect was similar to that seen with taurine supplementation, which has also been shown to decrease endoplasmic reticulum stress, suggesting that this may be the mechanism of the P. quinquefolium saponin effect. Pelletier et al. (9) also addressed myocardial injury, but in a swine model of neonatal hypoxia. Cardiac depression is a major cause of mortality and morbidity in hypoxic neonates. They tested whether vasopressin infusion might be effective in ameliorating cardiac depression and compared it with dobutamine. Both treatments significantly decreased cardiac dysfunction and ameliorated ischemic intestinal injury. Although there was no difference between vasopressin and dobutamine, the authors suggest that vasopressin may be an attractive alternative to prevent the adverse effects of high-dose catecholamine. It is well known that the lung is an important target of injury in systemic inflammation. Tuinman et al. (10) tested the efficacy of modulation of platelet function with either high- or low-dose aspirin compared with clopidogrel or clopidogrel plus low-dose aspirin in a mouse model of intranasal endotoxin instillation. All treatments reduced neutrophil infiltration and protein in bronchoalveolar lavage fluid, but the high-dose aspirin was significantly more effective than the other treatments, suggesting promise for modulation of platelet activation in acute lung injury. It is becoming ever more evident that pathways important for embryonic and cell development are also important modulators of inflammation. One of these is notch whose pathway interacts with TLR signaling. Han et al. (11) investigated the contribution of notch signaling to acute lung injury in a zymosan inflammation model in mice. Either pretreatment or posttreatment with the notch inhibitor DAPT reduced multiple markers of lung injury, suggesting that notch signaling may amplify the inflammatory response to zymosan. Wound healing and infection continue to be an important clinical problem, especially in older patients. Brubaker and Kovacs (12) studied the potential ability of granulocyte-macrophage colony-stimulating factor (GM-CSF) to aid in wound closure and resistance to infection in a mouse model of Staphylococcus aureus wound infection in mice. Older mice showed impaired healing of infected wounds compared with younger mice. Whereas GM-CSF did not have an effect on wound healing in younger mice, it significantly improved wound closure in aged mice, and this was associated with increased neutrophil infiltration and reduced wound infection. They conclude that GM-CSF may be a useful therapeutic approach in elderly patients with infected wounds. The final offering in this month’s Shock is a summary by Dan Remick (13) of the special session held at the 2013 Shock Conference on the recent controversy regarding the relevance of mouse models to human disease in burn, blunt trauma, and endotoxin. This has become a very important issue for Shock researchers largely because of the not always accurate coverage in the lay press. Dr. Remick presents a very accurate and balanced summary of the debate and ends with a call to the Shock Society to take a leadership role in “to help address these issues through thoughtful dialog.” This summary does an excellent job of starting that dialog.