What’s New in Shock? April 2013

Field: Medicine (Health Sciences)

This issue of Shock covers again a wide area of trauma- and sepsis-related, important entities. Four articles deal with the heart (1–4). Two articles deal with the lung (5, 6), and three with liver and the intestinal barrier (7–9). The remaining two articles deal with the complement system related to biofilms (10) and fluid resuscitation guided by sublingual PCO2 (11). Schmittinger et al. (1) deal with the myocardium in septic shock. Histopathologic changes are described as observed in a postmortem study upon clinical evaluation. Twenty patients dying of septic shock were included to try to partly unravel the pathophysiologic genesis of sepsis-induced cardiac dysfunction. In almost all patients, stress-induced pathologies such as contraction band necrosis and myocytolysis were observed. The maximum epinephrine dose was associated with mononuclear infiltrates and myocytolysis. Thus, the authors conclude that epinephrine is responsible for the stress-induced cytotoxicity as all patients received catecholamine therapy. However, it is not clear how these pathologies contribute to the septic cardiomyopathy, as commented by Radermacher et al. (2). They point out that the study by Schmittinger et al. (1) is a well-designed one, but a control group is missing. Moreover, a “hen and egg” problem is encountered. Radermacher et al. (2) point out that the study adds to our knowledge, but still open questions remain. The loss of cardiomyocytes (as in myocytolysis) can also be caused by apoptosis. Yeh et al. (3) investigated whether carvedilol, a β-blocking agent, treatment could decrease cardiomyocytic apoptosis upon induction of a myocardial infarct. This was investigated both in vivo and in vitro. In the in vivo study, the left anterior descending coronary artery was ligated in rats. Twenty-four hours thereafter, treatment with three different doses of carvedilol was initiated. Treatment with carvedilol showed a decrease in tumor necrosis factor α (TNF-α) on protein and mRNA level as well as in troponin I levels. On the other hand, interleukin 10 (IL-10) levels were dose-dependently increased. Investigating the periinfarct zone revealed increased transcription of inducible nitric oxide synthase in a dose-dependent way. Apoptosis was decreased with increasing carvedilol doses, and this was associated with decreases in caspase 3 levels. These results could be reproduced in HL-1 myocytic cell cultures. Moreover, inhibition studies could show that PI3K and MEK are important signal transductors mediating the carvedilol effects. Besides carvedilol treatment, Ebelt et al. (4) found that bone morphogenic protein 2 (BMP-2) administration can limit infarct size after myocardial infarct also by decreasing apoptosis. Bone morphogenic protein 2 is mainly known as an osteogenic promoter. However, during embryologic development, it protects neonatal cardiomyocytes from ischemia/reperfusion injury. This study, like the previous one discussed, also comprised an in vivo and an in vitro part. The in vivo study induced myocardial infarct in mice by ligating the left anterior descending coronary artery. The animals were treated with an intravenous injection of BMP-2, and after 7 days apoptotic cells were determined, whereas after 21 days a histomorphometric analysis was performed. It was shown that upon administration of BMP-2 less apoptosis of cardiomyocytes occurred. This resulted into a reduced infarct size. Unfortunately, no effects on survival or functional parameters in the electrocardiogram were found. The in vitro study showed that BMP-2 increased the phosphorylation of Smad1/5/8 without activation of the transforming growth factor β pathway. The latter was shown by using specific ALK4/5/7 inhibitors. This is a positive result as the transforming growth factor β pathway would elicit detrimental effects. The beating frequency and contractile performance were increased by BMP-2 in this in vitro setting. Sartorius et al. (10) deal with the clinical problem of the innate reaction to Staphylococcus epidermidis biofilms on indwelling catheters. This microorganism is an important cause of nosocomial infection. However, patients’ reactions are very modest, and therefore, clinically this infection often remains hidden. A potential reason may lie in the formation of a biofilm. The authors determined that polysaccharide intercellular adhesion molecule (PIA) is necessary for C5a production. This was detected by, on the one hand, removing PIA and, on the other, adding PIA alone on beads. The amount of biofilm produced was correlated with C5a production. However, using clinical samples of S. epidermidis, this correlation could not be shown. Thus, simple biofilm production does not determine C5a production. Based on these results, a mathematical model was constructed. This model indeed revealed that C5a levels were lower than detected in “normal” patients. Thus, these amounts of C5a would not be enough to elicit an adequate immune response. Another clinical problem is fluid resuscitation in hemorrhagic shock. Xu et al. (11) were guiding fluid resuscitation by sublingual PCO2 measurements in a porcine hemorrhagic shock model. They induced a volume-controlled hemorrhagic shock. In the sublingual PCO2-guided group, resuscitation was started at values greater than 70 mmHg and stopped when they were less than 50 mmHg. In the blood pressure–guided group, resuscitation was initiated when the mean arterial pressure was less than 60 mmHg and stopped at values greater than 90 mmHg. In the group that was guided by sublingual PCO2, only 40% of the animals required fluid resuscitation compared with 100% in the blood pressure–guided group. Furthermore, resuscitations volumes were lower in the first group compared with the latter. However, no effects on the outcome were observed. Sublingual PCO2 measurements may help to prevent overresuscitation in certain cases. To place this study in the right clinical context, patient studies need to be performed. Resuscitation regimens in hemorrhagic shock also comprise the use of hypertonic saline (HTS), and ameliorating effects on the immune system and concomitant multiple organ dysfunction have been known. To further investigate the mechanism, Banerjee et al. (5) investigated the effects of HTS on polymorphonuclear granulocytes (PMN) interactions with human pulmonary microvascular endothelial cells. Hypertonic saline did not change the expression of the adhesion molecule intercellular adhesion molecule 1 per se. However, TNF-α–induced intercellular adhesion molecule 1 expression was dose-dependently attenuated by HTS. Moreover, IL-8 levels and PMN–human pulmonary microvascular endothelial cell interactions were decreased as well. The latter was associated with decreased nuclear factor κB and increased p38 activity. These in vitro studies support the observed beneficial effects in the clinic with HTS therapy. Decreasing PMN activity may, however, be detrimental in the setting of sepsis as bacteria cannot be cleared well enough. In these cases, increasing PMN activity may be worthwhile. This was investigated by Czaikoski et al. (6) in a murine model of pneumonia-induced sepsis. After intratracheal induction of pneumonia by Klebsiella pneumoniae, animals received a heme oxygenase (HO) inhibitor. This led to increased PMN numbers in the intra-alveolar space with concomitant decreased bacterial load. This resulted in less lung damage and less alveolar collapse with improved gas exchange and lung mechanics. Overall, HO inhibition resulted in better survival rates. Unfortunately, HO inhibition was performed in a pretreatment setting in this study. Long-lasting, complete HO inhibition may be detrimental as observed in HO-knockout mice. Thus, timing and duration may be important and need further elucidation. Heme oxygenase 1 also plays a role in hepatic ischemia/reperfusion injury, especially regarding TNF-mediated apoptosis. Kim et al. (8) used a model of liver ischemia/reperfusion, in which HO-1 levels were increased to investigate the effects of elevated HO-1 induction. Increasing HO-1 levels by hemin were associated with lower apoptosis rates. This was mainly due to effects found in the mitochondria. Here, caspase 8 levels and TNF receptor 1–associated caspase 8 levels were significantly decreased. In whole cell lysates, TRADD and FADD were less present as well. Thus, increasing HO-1 levels may protect against hepatic ischemia/reperfusion–induced cell loss. Another possibility to attenuate liver damage after hepatic ischemia/reperfusion may be treatment with Bβ15-42, as investigated by Liu et al. (9). Bβ15-42 decreased alanine aminotransferase and aspartate aminotransferase levels after hepatic ischemia/reperfusion. This may be caused by less hepatic damage as reflected by decreased leukocyte infiltration and concomitant less hepatic cytokines. Especially, a decrease in translocation and release of high mobility group box 1 and mitogen-activated protein kinase activation was observed. The last article deals with the intestinal barrier upon binge ethanol exposure and burn injury (7). The role of IL-6 was in focus. Blocking IL-6 using an antibody resulted in less histopathologic alterations in the ileum and less bacterial translocation to the mesenteric lymph nodes. Moreover, zonula occludens 1 and occludin were relocated to their “normal” positions. Using IL-6–knockout mice, less intestinal damage was likewise observed. However, all the other parameters did not show similarities to those upon IL-6 blockade with an antibody. The difference between these two models is that IL-6–antibody treatment lowers IL-6 levels, but IL-6 is still present. In IL-6–knockout mice, absolutely no IL-6 can be detected. Thus, too much and too less IL-6 are detrimental. Or as Paracelsus said, “the dose makes the poison.”