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Moldawer, Lyle L. PhD

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doi: 10.1097/01.shk.0000228802.63846.b5
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For those of you who have attended the past Annual Conference on Shock held at Marco Island, you know that Florida summers can be indescribably hot. August is even more unbearable, and many of us who are able to do so flee the near-Equatorial sun for cooler locales. For myself, come the first of August, I pack my briefcase full of journals and head to the downeast coast of Maine to await the cooler days of September and the return of Gator football season. Overlooking Frenchman's Bay, I have the opportunity to peruse my favorite journal, Shock, at leisure and ponder the future directions of my own research.

This month's issue of Shock will reward me with a comprehensive review and an outstanding blend of 14 clinical, translational, and basic science reports. Several will undoubtedly send me inside to my laptop and PubMed for a quick exploration; and as happens quite frequently with Shock, several articles will shake me of my summer complacency and fill me with admiration for the authors and their work. There will also be a few articles in this month's issue that will require a terse e-mail or phone call to the laboratory making sure this article is read and discussed at the next laboratory's journal club.

In this month's issue, 3 clinical reports are focused on the measurement of novel analytes in patients with infections and septic shock. Many of us in the shock field continue to search for one of our "holy grails," that single analyte (or multiplex of analytes) that can identify or predict clinical trajectories in trauma, shock, and sepsis. Matsumoto and colleagues from Mie University in Japan and the Oklahoma Medical Research Foundation examined proteinase-3 expression on neutrophils from patients with infectious disease (1). Proteinase-3 is of particular interest in inflammation biology because it is a serine protease, structurally similar to elastase, but also membrane-associated and responsible for the cleavage of a number of important cell-associated cytokines and their receptors. What is particularly interesting to me is the extreme intersubject variability in expression that was observed, which varied from 0.2% to 84% of the neutrophils expressing this protein after TNF and FMLP stimulation. What is the biological significance of these dramatic differences? Regardless of the subject variation, neutrophil expression of proteinase-3 was increased in infected patients and was even more elevated in patients with systemic inflammatory response syndrome. Although this report was not designed to test whether increased expression could be used for prognostication, the results clearly show that expression of neutrophil proteinase-3 is labile and induced during infectious states.

Along the same lines, Ueda and his colleagues from the Nara Medical University in Japan examined brain natriuretic peptide and atrial natriuretic peptide levels in 33 patients with severe sepsis or septic shock, and compared the levels with those of 20 healthy subjects (2). Although the sample sizes in this study were not large, there was clear evidence that both brain and atrial natriuretic peptide concentrations were dramatically (50- to 100-fold) increased in patients with severe sepsis and septic shock. Concentrations were further elevated in nonsurviving patients. Receiver operating characteristic curves that discriminated survivors from nonsurvivors (650 pg/mL) were constructed with a sensitivity of 92% and a specificity of 80%, impressive numbers. Further studies will need to verify these findings prospectively in larger patient populations. Furthermore, because there are large numbers of plasma analytes that have been demonstrated to predict clinical outcome from severe sepsis and septic shock, future studies will need to test whether brain and atrial natriuretic peptides have better predictive capabilities than other prospective mediators. Only time and larger clinical studies will tell, but the authors are to be complimented on an important clinical observation.

In the third clinical report, Maier and colleagues from Germany examined plasma and cerebrospinal fluid sTNFR1 (p55) and sTNFR2 (p75) in patients after traumatic brain injury (3). Almost 15 years ago, Van Zee et al. first reported that plasma p55 and p75 levels were increased in septic shock and endotoxemia, and could bind and neutralize excess TNF (4). Since then, there have been numerous reports demonstrating elevated shed receptor levels in a variety of inflammatory states. The present report extends these earlier findings to traumatic brain injury and demonstrates that both p55 and p75 levels are increased in plasma and cerebrospinal fluid. Interestingly, however, the increased appearance in the cerebrospinal fluid is delayed by several days relative to the increases in plasma. This differential appearance raises important questions about the sources of the increased plasma and cerebrospinal fluid concentrations after traumatic brain injury. It seems unlikely that the increased plasma TNF receptor concentrations are derived from the injured brain or the cerebrospinal fluid, but rather may be a secondary systemic response to the traumatic brain injury.

While examining some of the articles focusing on basic and translational aspects of shock research, there are 2 reports focused on inflammatory mediators/cytokines that catch my attention. Both macrophage migration inhibitory factor (MIF) and high mobility group protein B1 (HMGB1) keep me humble and belie the common tenet that cytokines are not stored preformed in appreciable quantities but are only rapidly synthesized and released upon cell activation. Unlike more traditional cytokines (like TNF and IL-1), appreciable quantities of both preformed HMGB1 and MIF are found in unstimulated myeloid cells and are released upon cell activation. However, MIF has also been an anomaly because corticosteroids, which are potent inhibitors of most cytokine expression, are known to induce MIF expression. Bruhn and colleagues in Jean-Louis Vincent's laboratory in Belgium evaluated plasma and peritoneal MIF concentrations in septic mice administered dexamethasone (5). Although sepsis increases plasma and peritoneal MIF levels, pretreatment of the mice with dexamethasone does not further increase MIF concentrations in the plasma, peritoneal cavity, or organs of the reticuloendothelial system. Thus, dexamethasone administration does not seem to stimulate MIF production in murine sepsis.

HMGB1 is equally perplexing. Studies from the laboratories of Haichao Wang and Kevin Tracey have unequivocally shown that blocking HMGB1 can improve outcome in murine models of sepsis, whereas administration of HMGB1 to a healthy animal can induce inflammation and organ injury. One of the many questions surrounding this unorthodox mediator is how signaling is achieved. Studies by Yu and colleagues in the present issue of Shock have now resolved the issue and show that HMGB1 signals at least in part through toll-like receptor (TLR) 4 and TLR2 (6). These findings are important for several reasons, suggesting that the TLR receptors, in addition to their role as sensors of microbial infection, are also involved in sensing endogenous danger signals, of which HMGB1 may be one. The findings also reveal how HMGB1 can propagate the systemic inflammatory response, being released in response to microbial infection or proximal inflammatory cytokines and then sustaining nuclear factor kappa B (NF-κB) activation through MyD88- and TRIF-dependent signaling pathways. The HMGB1 and MIF stories continue to enthrall me.

Doughty et al. ask an interesting question whether preexisting viral infections alter the inflammatory response to polymicrobial sepsis (7). They recapitulated a chronic viral infection by administering the TLR3 agonist, polyinosinic:polycytidylic acid, and saw a dramatic plasma type I interferon response. Animals pretreated with the TLR3 agonist have an exaggerated inflammatory response to a subsequent cecal ligation and puncture, and heightened lethality. Animals lacking a type I interferon receptor or blockade of NF-κB prevent this increased lethality. One wonders whether other TLR agonists (primarily TLR7/8 or TLR9) also known to induce a type I interferon response (although to a lesser extent) also promote lethality in this model, and what the cell types (presumably dendritic cells, B cells, fibroblasts, and macrophages) responsible for this dramatic interferon response are.

Ipaktchi et al. from the laboratories of Stewart Wang, Dan Remick, and Saman Arbabi used topical administration of a p38 MAPkinase inhibitor on a partial thickness scald burn and dramatically suppressed neutrophil infiltration and microvascular damage in the wounded tissue (8). Interestingly, the same treatment also reduces apoptosis of hair follicles. The studies clearly reveal the potential benefit to this local approach at treating the inflammatory and apoptotic responses to a partial thickness burn. Although the rat may not be the optimal animal model to ask these questions, I wondered what the consequences of local p38 MAPkinase inhibition would be on the healing process, and importantly, on the systemic manifestations of a large burn injury. For example, does suppression of the local inflammatory response with a topical p38 MAPkinase inhibitor alter the infiltration of inflammatory cells into the lung and/or other distant organs, or the increased bacterial translocation in the gut? Is wound healing promoted?

There are several articles whose primary goal is simply to unravel pathogenic mechanisms. These studies seem deceptively straightforward, but the more time you spend with them, the more they reveal their complexity and the more satisfying they become. I thoroughly enjoyed the article of Yanagida et al. examining the factors that regulate inducible NO synthetase expression after hepatic I/R injury (9). Hepatocytes from rats subjected to I/R injury are stimulated with IL-1 and respond with markedly increased NO production. What did a prior I/R event do to increase this responsiveness to an inflammatory stimulus? Apparently, a great deal! Hepatocytes from these rats respond to an IL-1 challenge with a markedly increased activation of NF-κB, increased phosphorylation of Akt, and upregulation of the type I IL-1 receptor. The authors speculate that I/R upregulates IL-1 signaling pathways and makes the cells more responsive to a subsequent IL-1 stimulation.

Piraino et al. from Basilia Zingarelli's laboratory examined the role of the peroxisome proliferator activated receptor-γ (PPARγ) and liver X receptor-α (LXAα) ligands on the response by a murine macrophage cell line to endotoxin stimulation (10). PPARγ is presumed to play a central role in the inflammatory response, and its ligands (e.g. 15-deoxyprostaglandin J2) are notably anti-inflammatory. Less is known about the LXAα receptor, although its natural ligands are also thought to be anti-inflammatory. In a series of well-designed studies, Piraino et al. demonstrate that both PPARγ and LXAα agonists suppress NO and TNF production in response to endotoxin, and importantly, do so through common cell signaling pathways (NF-κB). Importantly, the authors conclude, and I am inclined to agree, that the anti-inflammatory signaling by these 2 receptors is likely through common intracellular signaling mechanisms.

Sivarajah et al. in Chris Thiemermann's laboratory in London taught me about "gasotransmitters" (i.e. physiologically active endogenous gases of small molecular weight) and the protective effects of hydrogen sulfide during myocardial infarction (11). When rats are pretreated with a hydrogen sulfide donor, their myocardial injury to an ischemic event is dramatically reduced. Interestingly, endogenous hydrogen sulfide production also plays a role in reducing myocardial ischemic injury because inhibiting 1 of the 2 enzymes responsible for endogenous generation, cystathionine-γ-lyase, increases infarct size. Thus, hydrogen sulfide seems to be produced in sufficient quantities during myocardial I/R injury to regulate myocardial injury. The question that immediately comes to mind is how is this feat accomplished? What are the mechanisms by which this gasotransmitter limits cellular death in the injured myocardium? This is an important report that will clearly lead to additional mechanistic studies.

Nakagawa et al. used intravital microscopy to examine endothelial-leukocyte interactions in the mesenteric circulation of rats after hemorrhagic shock and/or a cecal ligation and puncture (12). Interestingly, the authors stepped in, 24 h after the cecal ligation and puncture, to surgically remove the devitalized cecum and irrigate the intraperitoneal cavity. Cecal ligation and puncture increase leukocyte rolling, adherence, and emigration, all of which could be restored by the surgical removal of the necrotic cecum. However, when cecal ligation and puncture are performed in rats subjected to a prior hemorrhagic shock, surgical removal of the necrotic tissue does not fully restore normal microcirculation and leukocyte adherence. This article highlights an important consideration of the commonly used cecal ligation and puncture model of sepsis. Removal of the devitalized cecum can alter the trajectory and be a useful model for studying the successful dissolution of the septic response. It is my opinion that we study this component of the septic response too infrequently, in large part because we do not have good experimental models. Rodents that survive cecal ligation and puncture without intervention convert into a chronic abscess/infection model, and Nakagawa et al. have convincingly demonstrated the utility and clinical relevance of this surgical intervention to create a useful sepsis recovery model.

There are 2 articles, one a clinical investigation and the second a comprehensive review, that explore components of fluid responsiveness and resuscitation in critically ill patients. Westphal and colleagues from Brazil (13) examined whether a dynamic evaluation of central venous pressure amplitude could be a reliable measure of responsiveness to fluids in patients on mechanical ventilation. The investigators speculate that in patients on mechanical ventilation, the dynamic evaluation of central venous pressure tracings could be used as a marker of fluid responsiveness. The studies are conducted in 30 postcardiac patients and reveal that the changes in the central venous pressure amplitude induced by mechanical ventilation are in general agreement with the variations in pulse arterial pressure.

In a comprehensive review, Cotton et al. have summarized some of the physiological consequences of aggressive fluid resuscitation (14). As a basic scientist, I tackled this article with some trepidation, concerned that I would find little of interest to my own research. However, like much of Dr Abumrad's previous writings, I was immediately drawn into the article. Statements like "the focus of this review is on the literature…condemning aggressive volume administration" immediately grab your attention. When referring to Tom Shire's editorial from 1967 stressing the need for moderation, Cotton et al. put it succinctly, "To this day, however, their pleas have been, for the most part, ignored." The article starts with a helpful historical context, but rapidly tackles the immunological consequences of fluid resuscitation and moves into the difficulties associated with organ injury. It is an enjoyable read, suitable for clinicians and basic scientists alike.

The last 2 articles in this month's issue are in their own categories. Ghiselli and his colleagues from Ancona, Italy, explored the effectiveness of ertapenem combined with the cathelicidin tritrpticin in 2 rat models of septic shock (15). Tritrpticin is a member of a class of small antimicrobial peptides that can bind to bacterial endotoxin and other cell surface proteins on bacteria, killing the organisms. More importantly, they can, by binding to endotoxin, suppress the inflammatory response while still being antimicrobial. In models of bacteremic shock and cecal ligation and puncture, both ertapenem and tritrpticin had antimicrobial properties, but ertapenem increased the inflammatory response, whereas tritrpticin suppressed it. Combined therapies were most effective at increasing antimicrobial activities, improving survival, and suppressing the inflammatory response. The authors conclude that addition of these small antimicrobial peptides can improve the efficacy of standard approaches and alter the inflammatory response.

With the August heat in Florida, the last article to be discussed in this issue is most apropos; after all, it deals with heat stroke and its treatment with the retrograde jugular vein infusions of cold saline. Heat stroke in the rat produces systemic inflammation characterized by thrombocytopenia, D-dimer appearance, loss of protein C, and increased TNF production, as well as organ injury (16). Retrograde jugular vein infusion of cold saline improves survival and reduces the magnitude of the inflammatory response. The authors speculate that the rapid cooling of the brain is protective through reducing oxidative stress and the inflammatory state. The authors to their credit lay out a credible experimental plan for future studies, using interventions focusing on specific free radicals and individual cytokines to resolve the underlying mechanism.

August is generally associated with the summer doldrums, and life slows down appreciably in Gainesville while all of the students are on summer break. The coast of Maine is a great alternative to Florida's summer heat, and this month's issue of Shock is an optimal way to spend an afternoon immersed in shock, trauma, and sepsis research. Wherever your summer holidays may take you, even if it is only the library of your institution, take this month's issue of Shock with you, and enjoy the depth and diversity of shock research. There is much to enjoy and learn.


1. Matsumoto T, Kaneko T, Wada H, Kobayashi T, Abe Y, Nobori T, Shiku H, Stearns-Kurosawa DH, Kurosawa S: Proteinase 3 expression on neutrophil membranes from patients with infectious disease. Shock 26:128-133, 2006.
2. Ueda S, Nishio K, Akai Y, Fukushima H, Ueyama T, Masui K, Yoshioka A, Okuchi K: Prognostic value of increased plasma levels of brain natriuretic peptide in patients with septic shock. Shock 26:134-169, 2006.
3. Maier B, Lehnert M, Laurer HL, Mautes AE, Steudel W-I, Marzi I: Delayed elevation of soluble TNF-receptors p75 and p55 in cerebrospinal fluid and plasma following traumatic brain injury. Shock 26:122-127, 2006.
4. Van Zee KJ, Kohno T, Fischer E, Rock CS, Moldawer LL, Lowry SF: Tumor necrosis factor soluble receptors circulate during experimental and clinical inflammation and can protect against excessive tumor necrosis factor alpha in vitro and in vivo. Proc Natl Acad Sci U S A 89:4845-4849, 1992.
5. Bruhn A, Verdant C, Vercruysse V, Su F, Vray B, Vincent J-L: Effects of dexamethasone on macrophage migration inhibitory factor production in sepsis. Shock 26:169-173, 2006.
6. Yu M, Wang H, Ding A, Golenbock DT, Latz E, Czura CJ, Fenton MJ, Tracey KJ, Yang H: HMGB1 signals through toll-like receptor (TLR) 4 and TLR2. Shock 26:174-179, 2006.
7. Doughty LA, Carlton S, Galen B, Cooma-Ramberan I, Chung C-S, Ayala A: Activation of common antiviral pathways can potentiate inflammatory responses to septic shock. Shock 26:187-194, 2006.
8. Ipaktchi K, Mattar A, Niederbichler AD, Hoesel LM, Hemmila MR, Su GL, Remick DG, Wang SC, Arbabi S: Topical p38 MAPK inhibition reduces dermal inflammation and epithelial apoptosis in burn wounds. Shock 26:201-209, 2006.
9. Yanagida H, Kaibori M, Yoshida K, Habara K, Yamada M, Kamiyama Y, Okumura T: Hepatic ischemia-reperfusion upregulates the susceptibility of hepatocytes to confer the induction of iNOS gene expression. Shock 26:162-168, 2006.
10. Piraino G, Cook JA, O'Connor M, Hake PW, Burroughs TJ, Teti D, Zingarelli B: Synergistic effect of peroxisome proliferator activated receptor γ (PPAR γ) and liver X receptor-α (LXR α) in the regulation of inflammation in macrophages. Shock 26:146-153, 2006.
11. Sivarajah A, McDonald MC, Thiemermann C: The production of hydrogen sulfide limits myocardial ischemia and reperfusion injury and contributes to the cardioprotective effects of preconditioning with endotoxin, but not ischemia in the rat. Shock 26:154-161, 2006.
12. Nakagawa NK, Nogueira RA, Correia CJ, Shiwa SR, Miranda Costa Cruz JW, Poli de Figueiredo LF, Rocha e Silva M, Sannomiya P: Leukocyte-endothelium interactions after hemorrhagic shock/reperfusion and cecal ligation/puncture: an intravital microscopic study in rat mesentery. Shock 26:180-186, 2006.
13. Westphal GA, Silva E, Caldeira Filho M, Roman Goncalves AR, Poli de Figueiredo LF: Variation in amplitude of central venous pressure curve induced by respiration is a useful tool to reveal fluid responsiveness in post-cardiac surgery patients. Shock 26:140-145, 2006.
14. Cotton BA, Guy JS, Morris JA Jr, Abumrad NN: The cellular, metabolic, and systemic consequences of aggressive fluid resuscitation strategies. Shock 26:115-121, 2006.
15. Ghiselli R, Cirioni O, Giacometti A, Mocchegiani F, Orlando F, Silvestri C, Licci A, Vittoria AD, Scalise G, Saba V: The cathelicidin-derived tritrpticin enhances the efficacy of ertapenem in experimental rat models of septic shock. Shock 26:195-200, 2006.
16. Hsu S-F, Niu K-C, Lin C-L, Lin M-T: Brain cooling causes attenuation of cerebral oxidative stress, systemic inflammation, activated coagulation, and tissue ischemia/injury during heat stroke. Shock 26:210-220, 2006.
©2006The Shock Society