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Remick, Daniel G.

doi: 10.1097/shk.0b013e31811ff139

Boston University School of Medicine, Boston, Massachusetts

One of the principal functions when preparing "What's new in Shock" is to find overriding themes that draw the journal together and make it more than a collection of outstanding papers. September is the time of the fall harvest, so it is appropriate that 10 of the 15 papers in this issue of Shock deal with H subjects-heart function, hemorrhagic shock/hypoperfusion, or hypoxia. The common theme of H stretches the imagination, just as these papers stretch our scientific horizons.

There are four heart-related papers, two in the review section and two original papers. Many Shock investigators are interested in "two-hit" animal models where one injury alters cell and organ function, so that the response to a second injury is exacerbated. The biological relevance of the events drives scientific interest in these models. One of Shock's leading investigators and a former president of the Society, Jureta Horton, describes heart dysfunction developing after a burn injury that is complicated by pneumonia (1). The clinical importance of the model is readily apparent to any physician who has worked in a burn unit or any scientist attending a Shock Society meeting. The data show that the two-hit model produces a significantly greater inflammatory response and substantially more myocardial depression. The study design involves a 40% burn injury, followed by pneumonia after 7 days and sacrifice at 8 days (i.e., 24 h after the onset of pneumonia). Although there was no increase in mortality in the model, the study was not designed to address this question. The two-hit model of burn followed by infection did significantly increase both myocardial inflammation and dysfunction, with defects observed in myocardial contraction and relaxation. The importance of sepsis-induced myocardial dysfunction is emphasized in the review article by Sharma (2). In this review, he discusses the signal transduction mechanisms that have been reported to mediate myocardial depression. The paper contains a figure to provide a visual overview of the changes. Investigators looking for future trends would be well advised to carefully read both these papers, in the opinion of this commentator.

A mini-review by Law et al. (3) discusses cardiac purine metabolism in sepsis. This mini-review article follows closely on the Symposium on Adenosine Receptors at the 2007 Shock Society meeting in Baltimore. Please notice the diligence by the editorial staff to write a commentary in April linking a symposium to be held in June to a paper to be published in September. The mini-review by Law focuses on the role of purines in autocrine and paracrine communication. Particular attention is paid to purines located in the extracellular space that, of course, would be the location for these molecules to serve as communication molecules.

The paper by Sato et al. (4) gets double H credit because it deals with hemorrhagic shock and the heart. In this paper, the authors provide data that p38 MAP kinase plays an important role in modulating the inflammatory response and subsequent heart dysfunction.

Hemorrhagic shock represents the second of the H topics this month with three papers. The first by Feinman et al. (5) looked at the pulmonary molecular profile after hemorrhagic shock. An interesting approach was used in this paper to specifically address which genes within the lung are upregulated in response to the injury. This group has previously reported that diversion of the mesenteric lymph would prevent lung injury after trauma-hemorrhage. Two experimental groups were created, hemorrhagic shock with lung injury compared with hemorrhagic shock without lung injury-the second group generated by dividing the mesenteric lymph duct. The gene expression profiles from the lung indicated that IL-1β was a critical central mediator of the lung injury. The results from the gene expression profiles were verified by polymerase chain reaction.

Therapies for the treatment of hemorrhagic shock were examined in two separate manuscripts. The paper by Stennett et al. (6) evaluated the oxygen radical-scavenging ability and pharmacokinetics of trans-sodium crocetinate, a compound that has been shown in previous reports to reduce the symptoms of hemorrhagic shock. The data in the paper indicate that the beneficial effects of the compound may occur by a mechanism other than scavenging of oxygen free radicals. Another treatment for hemorrhagic shock was evaluated in the paper by Nöt et al. (7). Rats subjected to laparotomy and hemorrhage were treated with glucosamine without resuscitation. This therapy doubled the survival in addition to increasing mean arterial blood pressure, which was associated with an increase in protein O-glycosylation.

Another H paper examines hypoperfusion that occurs in traumatic brain injury. In an interesting study by Chio et al. (8), they examined the potential cerebral protective effects of brain cooling after traumatic brain injury. A number of parameters were measured including several that are clinically relevant such as intracranial hypertension, cerebral hypoperfusion, and motor and proprioception deficits. All of these parameters were significantly improved with brain cooling.

Rounding out our H papers are two reports on hypoxia. Signal transduction events induced by hypoxia as a result of hemorrhage were examined in a paper by Mollen et al. (9). They evaluated events in an in vivo setting by looking at the liver and also looked at an in vitro setting to test the hypothesis that hypoxia would activate c-Jun N-terminal kinase through Rac-1-dependent reactive oxygen signaling. Using a combination of in vivo correlations and in vitro precise experiments, the authors provide convincing evidence that production of reactive oxygen species during hepatic hypoxia results in c-Jun N-terminal kinase activation through a Rac-1-dependent process. Hemodynamics and hypoxia were also evaluated in the work by Al-Salam et al. (10) that evaluated the effects of dobutamine in a piglet model of neonatal asphyxia. Their data showed improvements in hemodynamics and other parameters at the highest dose of dobutamine.

Injection of lipopolysaccharide causes significant acute inflammation including alterations in circulating leukocytes. The effects of hydroxyethyl starch on leukocytes within the pulmonary vasculature were examined by direct visualization in work by Küpper et al. (11). Lipopolysaccharide caused a significant decrease in cell velocity coupled with an increase in cell adhesion within the lung of both platelets and leukocytes, and hydroxyethyl starch prevented the decrease in platelet sticking. Further parameters of the lipopolysaccharide model were elucidated in the work by Yang et al. (12) when they demonstrated that pentobarbital decreased the production of tumor necrosis factor and tissue damage. In addition to the reduced plasma levels of TNF, several indices of organ injury were also decreased by pentobarbital.

Treatment of sepsis induced by cecal ligation and puncture was examined in the paper by Wheeler et al. (13). Treatment with the major polyphenolic flavonoid found in green tea, epigallocatechin-3-gallate, yielded an improvement in the hypotension observed in rats and an improvement in survival observed in mice subjected to cecal ligation and puncture-induced sepsis. In vitro studies with smooth muscle cells showed that the compound inhibited nuclear factor κB and NOS2 gene expression, suggesting a probable mechanism for the observed beneficial effects.

Lipid rafts are an important component of the cell membrane that serve multiple functions and do not exist merely as a docking station for receptors. In a study by Solomkin et al. (14), the authors examined lipid raft function in human neutrophils. Surprisingly, depletion of membrane cholesterol resulted in a priming of the neutrophils with enhanced production of reactive oxygen intermediates. This priming was also associated with recruitment of CD11b and CD66b rich raft domains from the specific granules.

In the final excellent manuscript in this month's issue, Daniel et al. (15) describe the regulation of the inflammatory response in burn wounds by λδ T-cells. In wild-type mice, burn induces an increase in cytokines coupled with an influx in inflammatory cells. In contrast, in knockout mice lacking the λδ T-cell receptor, there was a 6-fold reduction in the recruitment of inflammatory cells, and the burn injury did not increase the wound content of cytokines.

Please enjoy the excellent papers in this month's issue of Shock.

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1. Horton JW: A model of myocardial inflammation and dysfunction in burn complicated by sepsis. Shock 28:326-333, 2007.
2. Sharma AC: Sepsis-induced myocardial dysfunction. Shock 28:265-269, 2007.
3. Law WR, Conlon BA, Ross JD: The extracellular cardiac purine metabolome in sepsis. Shock 28:259-264, 2007.
4. Sato H, Tanaka T, Kasai K, Kita T, Tanaka N: Role of p38 mitogen-activated protein kinase on cardiac dysfunction after hemorrhagic shock in rats. Shock 28:291-299, 2007.
5. Feinman R, Deitch EA, Aris V, Chu HB, Abungu B, Caputo FJ, Galante A, Xu DZ, Lu Q, Colorado I, et al.: Molecular signatures of trauma-hemorrhagic shock-induced lung injury: hemorrhage- and injury-associated genes. Shock 28:360-368, 2007.
6. Stennett AK, Murray RJ, Roy JW, Gainer JL: Trans-sodium crocetinate and hemorrhagic shock. Shock 28:339-344, 2007.
7. Nöt LG, Marchase RB, Fulop N, Brocks CA, Chatham JC: Glucosamine administration improves survival rate after severe hemorrhagic shock combined with trauma in rats. Shock 28:345-352, 2007.
8. Chio C-C, Kuo J-R, Hsiao S-H, Chang C-P, Lin M-T: Effect of brain cooling on brain ischemia and damage markers after fluid percussion brain injury in rats. Shock 28:284-290, 2007.
9. Mollen KP, McCloskey CA, Tanaka H, Prince JM, Levy RM, Zuckerbraun BS, Billiar TR: Hypoxia activates c-Jun N-terminal kinase via Rac1-dependent reactive oxygen species production in hepatocytes. Shock 28:270-277, 2007.
10. Al-Salam Z, Johnson S, Abozaid S, Bigam D, Cheung P-Y: The hemodynamic effects of dobutamine during reoxygenation after hypoxia: a dose-response study in newborn pigs. Shock 28:317-325, 2007.
11. Küpper S, Mees ST, Gassmann P, Brodde MF, Kehrel B, Haier J: Hydroxyethyl starch normalizes platelet and leukocyte adhesion within pulmonary microcirculation during LPS-induced endotoxemia. Shock 28:300-308, 2007.
12. Yang FL, Li CH, Hsu BG, Tsai N-M, Lin SZ, Harn HJ, Chen HI, Liao KW, Lee RP: The reduction of tumor necrosis factor-α release and tissue damages by pentobarbital in the experimental endotoxemia model. Shock 28:309-316, 2007.
13. Wheeler DS, Lahni PM, Hake PW, Denenberg AG, Wong HR, Snead C, Catravas JD, Zingarelli B: The green tea polyphenol epigallocatechin-3-gallate improves systemic hemodynamics and survival in rodent models of polymicrobial sepsis. Shock 28:353-359, 2007.
14. Solomkin JS, Robinson CT, Cave CM, Ehmer B, Lentsch AB: Alterations in membrane cholesterol cause mobilization of lipid rafts from specific granules and prime human neutrophils for enhanced adherence-dependent oxidant production. Shock 28:334-338, 2007.
15. Daniel T, Thobe BM, Chaudry IH, Choudhry MA, Hubbard WJ, Schwacha MG: Regulation of the postburn wound inflammatory response by γδ T-cells. Shock 28:278-283, 2007.
©2007The Shock Society