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Clemens, Mark G.

doi: 10.1097/SHK.0b013e3181eb458f

Department of Biology, University of North Carolina, Charlotte, North Carolina

The September 2010 issue of Shock offers a selection of articles pertinent to clinical and laboratory investigations in shock. The one clinical investigation introduces a theme in this month's issue related to nitric oxide (NO). Rather than address NO as a mediator of either protection from or contribution to the development of shock, Tadie et al. (1) looked at NO in breath as a predictor of the development of nosocomial infections in mechanically ventilated intensive care unit patients. This was based on their previous observation that decreased NO in breath was associated with immune suppression. In 15 of the 45 patients who developed nosocomial infections, nasal NO was the only significant predictor, with an odds ratio of 2.7. This suggests that monitoring NO may be useful to guide treatment based on the prediction of probable ventilator-assisted pneumonia. Continuing in the NO theme, Su et al. (2) tested the effect of a selective inducible NO synthase (iNOS) inhibitor in combination in a sheep sepsis model. Inhibition of NOS in septic shock has been controversial (see also editorial comment in this issue by Stahl et al.), but this is at least in part caused by the different roles of NO from iNOS versus endothelial NOS (NOS3). Using a new and very selective iNOS inhibitor, BYK191023, in combination with norepinephrine, these investigators examined the hemodynamic response to peritonitis in a sheep model. BYK191023 alone was superior to norepinephrine in correcting pulmonary hemodynamics and blood oxygenation. The combination of drugs, but neither alone, corrected arterial pressure and renal blood flow. These results suggest that careful use of very selective iNOS inhibitors may be a useful adjunct pressor therapy in sepsis.

Unlike iNOS, NOS3 is generally considered to be protective in shock. Although the mechanism is largely through maintenance of microcirculation, direct anti-inflammatory effects have also been reported. Bougaki et al. (3) tested this anti-inflammatory effect using a septic peritonitis model in wild-type or NOS3-knockout mice. They showed that NOS3 deficiency was associated with increased inflammation in heart, lung, and liver, as well as more myocardial dysfunction. This myocardial dysfunction was at least associated with decreased mitochondrial function in the NOS3-deficient mice, suggesting an effect that may be distinct from the vasodilatory action of NOS3-derived NO.

One aspect of inflammation that is controlled by NO is vascular permeability, but multiple other factors are also involved. And 17β-estradiol (estrogen) is one such factor. Childs et al. (4) report that the mechanism of estrogen effects on preserving vascular permeability in a hemorrhagic shock model in rats involves decreased reactive oxygen production and preserved mitochondrial function in vascular endothelial cells. This led to decreased cytochrome c release and subsequent decreased apoptosis. Chu et al. (5) also studied the mechanisms that produce increased vascular permeability but in a burn mode. Monolayers of human umbilical vein endothelial cells were cultured with burn serum that caused an increase in albumin permeability. This increased permeability was accompanied by rearrangement of the actin cytoskeleton. Actin polymerization is regulated in part by caldesmon phosphorylation of which was also increased by burn serum in a p38 mitogen-activated protein kinase manner. These results suggest that modulation of mitogen-activated protein kinase activity may provide a novel approach to inhibiting vascular permeability increase in burn injury.

Tumor necrosis factor (TNF) is well recognized as an important mediator in many shock states, however, its exact role is complex. This month's issue offers two articles addressing this complex role. Recent reports indicate that mesenchymal stem cells transplantation can contribute to repair of ischemic myocardium. Tan et al. (6) investigated whether TNF is involved in this beneficial effect. Using mesenchymal stem cells from wild-type or knockouts for one or both TNF receptors transplanted into rats with myocardial ischemia/reperfusion, they found that the two receptors mediated distinct responses, with TNF receptor 1 knockouts showing increased protection, but TNF receptor 2 knockouts showing decreased protection. These results indicate that TNF has divergent effects mediated by its two different receptors. This could provide a more focused strategy for therapy by targeting specific receptors. Soares et al. (7) also studied TNF but as a potential mediator of remote lung injury after intestinal ischemia/reperfusion (I/R). They found that intestinal I/R caused remote lung injury but did not find increased serum or intestinal TNF. In addition, TNF neutralization did not affect injury, and injury was also seen in TNF receptor-knockout mice. Toll-like receptor 4-knockout mice were, however, protected, indicating an important role for Toll-like receptor 4 but not TNF.

Management of aberrant hemodynamic responses in shock remains an important problem. In particular, providing for the combined need for vasodilation and inotropic support is problematic. Two studies this month address the use of a calcium-sensitizing drug, levosimendan. This offers the possible combined effect of increased myocardial contractility plus vasodilation through activation of KATP channels. Garcia-Septiem et al. (8) used a porcine bacteremia model to study the effect of levosimendan on pulmonary hemodynamics and splanchnic hemodynamics and oxygenation. Levosimendan decreased pulmonary hypertension, improved splanchnic flow and oxygenation, and attenuated oliguria, suggesting effective treatment of impaired hemodynamics in this model. Zausig et al. (9) looked at the direct effects of levosimendan, as well as dobutamine, dopamine, and epinephrine on isolated hearts from septic rats. In this study, all drugs, except levosimendan, improved depressed myocardial performance in septic hearts. Combined, these studies suggest that levosimendan may be effective on the peripheral circulation but less so as a direct inotrope in animals with sepsis-induced myocardial depression.

This month's issue of Shock also provides two articles on basic pathophysiology of shock and one on novel treatment. Ventilation at high fraction of inspired oxygen is commonly used in cerebral ischemia, but hyperoxia may have deleterious effects through increased free radical production. Fujita et al. (10) addressed this problem in a forebrain ischemia model. Ventilating with a fraction of inspired oxygen of 1.0 rather than 0.4 resulted in a decrease on reactive oxygen production in the brain and appearance in jugular vein blood. This was associated with a generalized decrease in inflammatory response. Although the mechanism of this seemingly paradoxical effect is unclear, the results suggest that normobaric hyperoxia may be a useful adjunct in preventing cerebral reperfusion injury. Moving south in the anatomy, Fang et al. (11) examined potential mediators of systemic injury mediated by mesenteric lymph components after hemorrhagic shock. They used a proteomic analysis to screen for changes in mesenteric lymph between preshock and 3 h of resuscitation. The analysis showed four proteins that were consistently upregulated and two that were consistently downregulated. Although this study is not conclusive regarding mechanisms, it is an important step in determining the many changes in mesenteric lymph in shock that may contribute to systemic inflammation. In the area of novel treatment, Liu et al. (12) tested the effect of the active ingredient notoginsenoside R1 (NR1) isolated from the traditional Chinese herb Panax notoginseng in a renal I/R model. Treatment with NR1 just before reperfusion and then daily for 3 days significantly improved serum creatinine level, kidney histological appearance, and markers of inflammation. This suggests that NR1 may have clinically relevant anti-inflammatory actions that could be useful in the treatment of renal ischemia.

Finally, this month's issue of Shock provides two important articles related to the use of animal models. The issue of the use of anesthetics and analgesics is very important and controversial in shock research. Although appropriate alleviation of pain and suffering is an ethical imperative, there is valid concern that some analgesics or anesthetics may fundamentally alter the physiological response, thus making the findings invalid. Hugunin et al. (13) directly addressed the effect of two commonly used analgesics, tramadol and buprenorphine, on the immunologic markers in a cecal ligation and puncture model. Although some differences were found between the treatment groups, the differences were fairly minor and not consistent across the study with the use of analgesics. However, some of the differences found suggest that caution must be exercised in comparing studies using different analgesics. In another study, Al-Mousawi et al. (14) examined the influence of anesthesia, analgesia, and method of euthanasia on cytokines in a rat burn model. They compared isoflurane, ketamine-xylazine, and pentobarbital with or without analgesia with buprenorphine on a wide variety of cytokines 72 h after burn injury. Although all treatments had significant effects on the levels of specific cytokines for short procedures, isoflurane followed by euthanasia followed by decapitation (compared with exsanguination) produced the fewest changes, whereas ketamine-xylazine seemed to produce the fewest changes in longer procedures. As in the report by Hugunin et al. (13), these authors stressed the importance of paying careful attention to the conditions of anesthesia and analgesia as well as euthanasia both when designing experiments and when interpreting the results of experiments using different conditions.

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1. Tadié J-M, Trinquart L, Janniére-Nartey C, Guerot E, Louis B, Fagon J-Y, Diehl J-L, Delclaux C: Prediction of nosocomial infection acquisition in ventilated patients by nasal nitric oxide: proof-of-concept study. Shock 34:217-221, 2010.
2. Su F, Huang H, Kazuki A, Occhipinti G, Donadello K, Piagnerelli M, De Backer D, Vincent J-L: Effects of a selective iNOS inhibitor versus norepinephrine in the treatment of septic shock. Shock 34:243-249, 2010.
3. Bougaki M, Searles RJ, Kida K, Yu JD, Buys ES, Ichinose F: NOS3 protects against systemic inflammation and myocardial dysfunction in murine polymicrobial sepsis. Shock 34:281-290, 2010.
4. Childs EW, Tharakan B, Hunter FA, Smythe WR: 17β-Estradiol mediated protection against vascular leak after hemorrhagic shock: role of estrogen receptors and apoptotic signaling. Shock 34:229-235, 2010.
5. Chu Z, Zhang J, Song H, Hu J, Zhang Q, Xiang F, Huang Y: p38 MAP kinase mediates burn serum-induced endothelial barrier dysfunction: involvement of F-actin rearrangement and L-caldesmon phosphorylation. Shock 34:222-228, 2010.
6. Tan J, Weil BR, Abarbanell AM, Wang Y, Herrmann JL, Dake ML, Meldrum DR: Ablation of TNF-α receptors influences mesenchymal stem cell-mediated cardiac protection against ischemia. Shock 34:236-242, 2010.
7. Soares AL, Coelho FR, Guabiraba R, Kamal M, Vargaftig BB, Li L, Li J, Tavares-de-Lima W, Ryffel B: Tumor necrosis factor is not associated with intestinal ischemia/reperfusion-induced lung inflammation. Shock 34:306-313, 2010.
8. García-Septiem J, Lorente JA, Delgado MA, de Paula M, Nin N, Moscoso A, Sánchez-Ferrer A, Perez-Vizcaino F, Esteban A: Levosimendan increases portal blood flow and attenuates intestinal intramucosal acidosis in experimental septic shock. Shock 34:275-280, 2010.
9. Zausig YA, Geilfus D, Missler G, Sinner B, Graf BM, Zink W: Direct cardiac effects of dobutamine, dopamine, epinephrine, and levosimendan in isolated septic rat hearts. Shock 34:269-274, 2010.
10. Fujita M, Tsurata R, Kaneko T, Otsuka Y, Kutsuna S, Izumi T, Aoki T, Shitara M, Kasaoka S, Maruyama I, et al: Hyperoxia suppresses excessive superoxide anion radical generation in blood, oxidative stress, early inflammation, and endothelial injury in forebrain ischemia/reperfusion rats: laboratory study. Shock 34:299-305, 2010.
11. Fang J-F, Shih L-Y, Yuan K-C, Fang K-Y, Hwang T-L, Hsieh S-Y: Proteomic analysis of post-hemorrhagic shock mesenteric lymph. Shock 34:291-298, 2010.
12. Liu W-J, Tang H-T, Jia Y-T, Ma B, Fu J-F, Wang Y, Lv K-Y, Xia Z-F: Notoginsenoside R1 attenuates renal ischemia-reperfusion injury in rats. Shock 34:314-320, 2010.
13. Hugunin KMS, Fry C, Shuster K, Nemzek JA: Effects of tramadol and buprenorphine on select immunologic factors in a cecal ligation and puncture model. Shock 34:250-260, 2010.
14. Al-Mousawi AM, Kulp GA, Branski LK, Kraft R, Mecott GA, Williams FN, Herndon DN, Jeschke MG: Impact of anesthesia, analgesia, and euthanasia technique on the inflammatory cytokine profile in a rodent model of severe burn injury. Shock 34:261-268, 2010.
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