SHOCK, Vol. 41, No. 4, pp. 267Y268, 2014
Commentary WHAT’S NEW IN SHOCK? APRIL 2014 Mark G. Clemens University of North Carolina at Charlotte, Charlotte, North Carolina
The April issue of Shock leads off with a very interesting clinical study by Perez et al. (1), examining the safety and efficacy of increasing mean arterial pressure during resuscitation of patients with cardiogenic shock resulting from myocardial infarction. This two-edged sword of increased perfusion pressure but with increased afterload imposed on an already damaged heart generated controversy as indicated by the Letter to the Editor (2) and Editorial Comment (3) that it stimulated. The authors concluded that increasing mean arterial pressure improves microcirculation and cardiac performance; however, the commentaries addressed controversies with respect to both the clinical approach and the ethics of oral consent used in the patients. The reader is highly advised to read this robust exchange. In a second clinical study, Liang et al. (4) examined the relationship between tumor necrosis factor ! and microvascular endothelial cell dysfunction in septic patients. They found that tissue factor and von Willebrand factor from endothelial cells and tumor necrosis factor were elevated in septic patients compared with controls and that the levels correlated with injury score. Moreover, treatment of human umbilical vein endothelial cells with septic plasma increased tissue factor and von Willebrand factor expression, which correlated with activation of the p38 mitogen-activated kinase and nuclear factor .B pathways, suggesting that these pathways are involved in microvascular dysfunction in sepsis. In the basic science aspects, this month’s issue offers organspecific reports relevant to lung, heart, and liver. Lung injury is a common component of shock and sepsis; as such, three reports this month address lung injury. Dolgachev et al. (5) used transgenic mice with a lung-specific overexpression of interleukin 10 (IL-10 OE) in a combined lung contusionYtracheal instillation of Klebsiella pneumoniae model. The IL-10 OE mice showed higher lung bacterial counts and bacteremia along with increases in M2 macrophages. This resulted in higher mortality. Thus, while the anti-inflammatory effects of IL-10 may be protective, excessive expression impairs macrophage bacterial killing, increasing the severity of sepsis. Another common mode of lung injury is that induced by mechanical ventilation. Li et al. (6) investigated another antiinflammatory strategy on ventilator-induced lung injury in a high-tidal-volume model in rats. Lipoxin is an endogenous negative regulator of inflammation. These investigators thus used a stable lipoxin agonist BML-111 to test whether this anti-inflammatory strategy might attenuate lung injury. BL111 given at the beginning of ventilation resulted in decreased bronchoalveolar lavage fluid proinflammatory cytokines and lung injury. This was associated with decreased activation of nuclear factor .B, suggesting that its action is via modulation
of this pathway. The final lung article by Emr et al. (7) examines the effect of inflammatory mediators in ascites in a swine peritonitis model with in silico analysis. Their results showed that active removal of ascites by suction interrupted the proinflammatory cycle, resulting in a decrease in remote lung injury. Another important organ in shock-related conditions is the heart, resulting in two basic science articles this month. Wang et al. (8) studied possible mediators of protection by postconditioning after myocardial ischemia. Postconditioning resulted in decreased expression of inflammatory mediators that correlated with prevention of the upregulation of early growth response 1, an activator of inflammation. Although the experimental design does not clearly indicate causality, this study does suggest that upregulated early growth response 1 might be an important factor for the inflammatory response following myocardial ischemia and that prevention of its upregulation may contribute to protection by post conditioning. In addition to being a target for injury, the heart plays a regulatory role in hypovolemia. Cardiac mechanoreceptors respond to changes in atrial and ventricular filling, and the afferent output from these receptors contributes to compensation and decompensation in hemorrhage. Troy et al. (9) examined the respective role of vagal and spinal afferent pathways from the heart in a rat hemorrhage model. To do this, they compared the response of rats to hemorrhage following surgical transection of the nerves. Their results showed that it is the spinal afferents rather than the vagal afferents that contribute to the progression of decompensation following hemorrhage. The liver is not only a target of injury in shock, but also an important organ for protective mechanisms. One important function is in the regulation of body iron stores. This is particularly important during the acute-phase response during which plasma iron is decreased while hepatic iron is increased. Ahmad et al. (10) studied the relationship between iron levels and acute-phase cytokines in regulating hepatic iron uptake in isolated rat hepatocytes. Their results showed a significant regulation by media iron levels as well as by some acute-phase cytokines but a particularly significant effect of combined iron plus IL-1 on increasing iron uptake. This effect was due largely to change in expression of hepatic iron regulatory genes including lipocalin 2. Nutritional support is an important component of management of critically ill patients. Two articles this month address issues of nutritional support. Hu et al. (11) compared pyruvate to lactate as the substrate in a hyperosmolar peritoneal resuscitation fluid. In general, peritoneal resuscitation with hyperosmolar 267
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SHOCK VOL. 41, NO. 4
solutions improved splanchnic perfusion and decreased injury; however, solutions with pyruvate were found to be superior to those with lactate. Although the mechanism is not clear, it may be related to the differential effects on cellular redox potential. In addition to macronutrients, trace elements can also play an important role in modulating the inflammatory response. Slinko et al. (12) examined the effect of zinc supplementation before sepsis on the beneficial effect of proinsulin C-peptide (a cleavage product of insulin activation). There results showed that zinc significantly potentiated the effect of C-peptide apparently through restoration of peroxisome proliferator-activated receptor + expression in lung nuclei. Although pretreatment was required, given the cost and over-the-counter availability of zinc supplements, this does not detract from its potential clinical relevance. In addition to conventional nutritional supplements, extracts from plants used in traditional medicine have been found to have some beneficial activity in inflammation. Baicalin is one such root extract. Wang and Liu (13) investigated the potential mechanisms of its action in a mouse model of sepsis and with endotoxin in cell cultures. Posttreatment with baicalin improved survival in vivo and decreased the release of high mobility group box 1 and cytokines from macrophages. The effect on high mobility group box 1 appeared to be mediated by decreased translocation from the nucleus rather than increased expression. The final article in this month’s issue addresses a novel branch of the renin-angiotensin system. Ang(1Y7) is an alternative proteolytic product of angiotensin I that has recently been found to be biologically active through its receptor Mas. Although this has been studied in the cardiovascular system, little is known about its role in inflammation. Souza et al. (14) used Masj/j mice to study this system in an endotoxin model. Masj/j showed increased levels of IL-6, CXCL-1, and CXCL-2 following endotoxin as well as increased mortality. In addition, Masj/j mice showed a more profound hypothermia compared with wild-type mice. These results suggest that Ang(1Y7) plays a protective role in endotoxemia suppressing
proinflammatory cytokine production and preventing severe hypothermia. REFERENCES 1. Perez P, Kimmoun A, Blime V, Levy B: Increasing mean arterial pressure in cardiogenic shock secondary to myocardial infarction: effects on hemodynamics and tissue oxygenation. Shock 41:269Y274, 2014. 2. Jakob S: Increasing mean arterial pressure in cardiogenic shock secondary to myocardial infarction: effects on hemodynamics and tissue oxygenation [letter to the editor]. Shock 41:362, 2014. 3. Pereira AJ, De Backer D: Should we aim at high blood pressure targets in patients with cardiogenic shock? Shock 41:367Y368, 2014. 4. Liang Y, Li X, Zhang X, Li Z, Wang L, Sun Y, Liu Z, Ma X: Elevated levels of plasma TNF-! are associated with microvascular endothelial dysfunction in patients with sepsis through activating the NF-WB and p38 mitogen-activated protein kinase in endothelial cells. Shock 41:275Y281, 2014. 5. Dolgachev VA, Yu B, Sun L, Shanley TP, Raghavendran K, Hemmila MR: IL-10 overexpression alters survival in the setting of gram negative pneumonia following lung contusion. Shock 41:301Y310, 2014. 6. Li H, Wu Z, Feng D, Gong J, Yao C, Wang Y, Yuan S, Yao S, Shang Y: BML111, a lipoxin receptor agonist, attenuates ventilator-induced lung injury in rats. Shock 41:311Y316, 2014. 7. Emr B, Sadowsky D, Azhar N, Gatto LA, An G, Nieman G, Vodovotz Y: Removal of inflammatory ascites is associated with dynamic modification of local and systemic inflammation along with prevention of acute lung injury: in vivo and in silico studies. Shock 41:317Y323, 2014. 8. Wang N-P, Pang X-F, Zhang L-H, Tootle S, Harmouche S, Zhao Z-Q: Attenuation of inflammatory response and reduction in infarct size by postconditioning are associated with downregulation of early growth response 1 during reperfusion in rat heart. Shock 41:346Y354, 2014. 9. Troy BP, Hopkins DA, Keay KA: The hemodynamic response to blood loss in the conscious rat: contributions of cardiac vagal and cardiac spinal signals. Shock 41:282Y291, 2014. 10. Ahmad S, Sultan S, Naz N, Ahmad G, Alwahsh SM, Cameron S, Moriconi F, Ramadori G, Malik IA: Regulation of iron uptake in primary culture rat hepatocytes: the role of acute-phase cytokines. Shock 41:337Y345, 2014. 11. Hu S, Ma L, Luo H-M, Lin Z-L, Wang X-Q, Jia Y-H, Bai X-D, Zhou F-Q, Sheng Z-Y: Pyruvate is superior to reverse visceral hypoperfusion in peritoneal resuscitation from hemorrhagic shock in rats. Shock 41:355Y361, 2014. 12. Slinko S, Piraino G, Hake PW, Ledford JR, O’Connor M, Lahni P, Solan PD, Wong HR, Zingarelli B: Combined zinc supplementation with proinsulin Cpeptide treatment decreases the inflammatory response and mortality in murine polymicrobial sepsis. Shock 41:292Y300, 2014. 13. Wang H, Liu D: Baicalin inhibits high-mobility group box 1 release and improves survival in experimental sepsis. Shock 41:324Y330, 2014. 14. Souza LL, Duchene J, Todiras M, Azevedo LCP, Costa-Neto CM, Alenina N, Santos RA, Bader M: Receptor Mas protects mice against hypothermia and mortality induced by endotoxemia. Shock 41:331Y336, 2014.
Copyright © 2014 by the Shock Society. Unauthorized reproduction of this article is prohibited.