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WHAT'S NEW IN SHOCK, AUGUST 2007?

Lowry, Stephen F.

doi: 10.1097/SHK.0b013e3181238792
Commentary
Free

Department of Surgery, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey

The days of summer may not be as lazy as they used to be, but it is still a great opportunity to catch up on that pile of journals beside you. This month's Shock might be a reasonable place to start because there are several interesting and informative contributions.

This issue includes a review article from Malleo and colleagues (1) that provides a thorough overview of the experimental and clinical data suggesting a role for tumor necrosis factor in the pathogenesis of pancreatitis. Although we do not often attribute the pathology of this process to TNF-driven mechanisms, this comprehensive review nicely summarizes this evidence and also discusses the important themes of genetic predisposition and treatment opportunities.

The theme of genetic contribution to clinical susceptibility and responsiveness is apparent in two studies derived from volunteer Han Chinese. The first, from Lin and colleagues (2), studied the controversial relationship of a single nucleotide polymorphism (SNP) within the CD14 promoter (CD14-159 C/T) because this SNP may relate to the risk and inflammatory consequences of infection. They observed that subjects bearing -159 TT alleles exhibit an LPS-induced imbalance of pro- (TNF-α) and anti- (IL-10) inflammatory cytokine appearance in ex vivo studies. This study supports the analysis of this, and other contributory SNPs, when interpreting the results of clinical observational and therapy-directed studies of infection susceptibility and outcome.

The importance of population-based genetic description is also confirmed by an article from Duan and colleagues (3) who have identified what they believe is an important functional SNP within the 3′ untranslated region of the TLR4 receptor that is consequential to the Han Chinese population. The more widely reported TLR4/A896G and T1196C SNPs noted in Western populations are rare in Asiatic peoples. This article outlines an alternative SNP (TLR4/G11367C) that may also alter endotoxin responsiveness in the Han Chinese population. We must be mindful that ex vivo studies in unstressed subjects also may miss other important contributory mechanisms of severe injury/inflammation. As analysis of genetic variation is considered within these contexts, there will doubtless be further fascinating observations.

The importance of injury- and therapy-related context is evident in several contributions within this issue. Ruttinger and his associates (4) report their analysis of 3037 prospectively studied intensive care unit (ICU) patients to determine the impact of red blood cell transfusion upon ICU and hospital duration as well as outcome. They note that controlling for the effect of organ failure development during the ICU stay eliminated red cell transfusion as an independent predictor of mortality. This observation is consistent with prior meta-analyses. A severe inflammatory context also influences the distribution of endogenous and exogenously administered agents. Aibiki and colleagues (5) have applied a two-compartment model of antithrombin (AT) III kinetics in an analysis of AT infusion in critically ill patients. They observed a significant increase in the volume of distribution of this agent in such patients.

This issue also contains articles discussing age and sex variables that are known to influence inflammatory risk and response. An analysis of hepatomegaly, liver function, and acute phase reactant appearance among pediatric burn patients is reported by Jeschke and his associates (6) from the Galveston group. They note an early increase in hepatic size in these patients and suggest that a defect in hepatic protein synthesis may persist for up to 9 months in these children. Given the consequences of fatty infiltration and associated hepatic cell damage in children, they recommend that efforts to limit this hepatomegaly are warranted. What those interventions may be remains open to question.

Hussein and colleagues (7) provide a unique perspective on sex dimorphism by analysis of cerebrospinal fluid neuron-specific enolase, total hydroperoxide, and cytokine levels derived from normal and asphyxiated newborns. They observed sex-related differences in IL-8 and antioxidant levels among male and female babies leading to speculation that enhanced activation of brain protective Nrf2/antioxidant pathway(s) may occur among female infants. One might speculate as to the durability of this influence among sexually immature populations.

Xing and Remick (8) provide us with another perspective on the complex responses to reactive oxygen intermediates by assessing the production of monocyte chemoattractant protein 1 using both ex vivo whole blood and isolated monocyte assays. They observed that antioxidants reduced monocyte chemoattractant protein 1 messenger RNA and protein production in vitro and confirmed this effect in an endotoxin-challenged murine model pretreated with dimethyl sulfoxide. This antioxidant did not, however, reduce the production of TNF-α or IL-6 in vitro. This study further confirms the complex relationships between induced oxidant species and cytokines confirming that reactive oxygen intermediate activity may exert some beneficial effects in the injury/inflammation setting.

Morgenthaler and colleagues (9) provide updated information regarding the potential prognostic value of the C-terminal arginine vasopressor precursor, copeptin, in a primate hemorrhagic shock model and from critically ill patients. As previously reported for native arginine vasopressor responses, copeptin levels increase dramatically and in relative concordance with the degree of septic insult and mortality risk. Receiver operating characteristic analysis comparing copeptin levels with other "standard" physiological scores and biomarker levels confirms this outcome prediction relationship. It remains to be seen, however, if determinations of copeptin levels will prove useful in directing the initiation or assessment of nonstandard therapeutic strategies.

Two studies related to peroxisome proliferator-activated receptor(s) (PPAR) appear in this issue. Monroy and her colleagues (10) have used the well-described PPAR-γ agonist 15D-PGJ2 to confirm that this agent protects from cecal ligation and puncture (CLP) mortality in vivo and reduces nuclear factor κβ translocation and proinflammatory gene transcription in splenic macrophages. This study also points out the variable tissue PPAR-γ expression elicited by various stimulants-the expression may be dependent upon the nature of the inflammatory ligand and context. Mazzon and Cuzzocrea (11) describe the potential importance of PPAR-α activation in limiting the evolution of experimental colitis, noting a significant enhancement of epithelial tight junction dysfunction and enhanced apoptosis in a PPAR-α knockout model.

A very nice study addressing the important role of tissue immunocyte cross talk and oxidant injury is provided by Fan and colleagues from Pittsburgh (12). Shock-activated polymorphonuclear leukocyte from animals lacking a core enzyme of the nicotinamide adenine dinucleotide phosphate oxidase [NAD(P)H] membrane complex (gp91 phox/−) in coculture promoted a reduced alveolar macrophage TLR2 after subsequent LPS exposure. They further defined a role for MyD88 in this oxidant-signaling pathway and, perhaps most importantly, suggested that IRAK-4 is crucial for the redox-regulated response. It will be interesting to follow the pursuit of NAD(P)H signaling and the therapeutic implications for various systemic and tissue-specific oxidant-induced injuries.

The importance of cell cross talk is further underscored in an article by Bashenko and colleagues (13) who describe a protective influence of heparanase in the setting of endotoxin-induced lung injury. Importantly, they note that this protective effect is mediated by monocytes and, presumably, by heparanase released IL-10 in this model. This study further expands the implications for heparanase-influenced signaling pathways and its anti-inflammatory potential.

Injury-associated intestinal dysfunction has long been a quandary for clinicians and, in recent years, has become an increasingly fruitful area of investigation for inflammation biologists. There have been many efforts to define the relevant signaling mechanisms for "ileus;" in the current issue, Uray and her associates (14) have used their unique mesenteric venous hypertension (VH) model to dissect the consequences of STAT-3 activation. In the presence of a STAT-3 inhibitor (AG490), they note an attenuation of VH-induced contractile dysfunction and myosin light chain phosphorylation. Interestingly, these partially modulated consequences of VH occurred against an unaltered inflammatory milieu, including IL-6. This raises some question as to the reported influence of IL-6 in STAT-3-associated intestinal dysfunction.

The cellular modus exodus within solid organs after inflammatory insult also remains open to question. This unresolved issue has both mechanistic and therapeutic consequences. In this issue, Mura and colleagues (15) used a murine model of brief intestinal ischemia/reperfusion (IIR) followed by hyperoxic ventilation to determine the cell fate within the lung and other solid organs. This model of IIR/organ support promotes remote injury in several tissues, and based upon the investigators' analysis of target tissues, they propose that oncotic cell death may be a prominent feature of IIR-induced organ dysfunction. Indeed, if this is the case, and their observed correlation of enhanced heme-oxygenase expression in such cells is mechanistically involved, alternative therapeutic strategies need to be used.

One unique new therapeutic approach is suggested by the report of Barut and colleagues (16) who used the antiepileptic agent lamotrigine in a rodent IIR model. Given previous observations that lamotrigine reduced NO generation and lipid peroxidation in brain ischemia models, the authors hypothesized that such effects may occur in IIR. Indeed, they did observe reduced intestinal malondialdehyde and myeloperoxidase production in their model and enhanced activity of several inducible antioxidants. Unfortunately, we are not provided with a survival analysis resulting from this intervention, and as a consequence, the robustness of these observations remains in doubt.

Finally, the effects of chronic ethanol ingestion upon LPS-induced pulmonary alveolar tight junction protein expression and permeability is reported by Zhang and colleagues (17). They observed that glutamine (Gln) supplementation improved the expression of occludin, zona occludens 1, and adherens junction E-cadherin in an endotoxin-challenged rodent model of chronic ethanol ingestion. As has been demonstrated in intestinal injury models, this Gln supplementation may act to maintain cellular glutathione activity. Although supplementation of Gln is not indicated in all seriously ill subjects, some high-risk patients with comorbidities associated with reduced endogenous antioxidant activity may benefit from such therapy.

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REFERENCES

1. Malleo G, Mazzon E, Siriwardena AK, Cuzzocrea S: Role of tumor necrosis factor-α in acute pancreatitis: from biological basis to clinical evidence. Shock 28:130-140, 2007.
2. Lin J, Yao Y-M, Yu Y, Chai J-K, Huang Z-H, Dong N, Sheng Z-Y: Effects of CD14-159 C/T polymorphism on CD14 expression and the balance between proinflammatory and anti-inflammatory cytokines in whole blood culture. Shock 28:148-153, 2007.
3. Duan Z-X, Zhu P-F, Dong H, Gu W, Yang C, Liu Q, Wang Z-G, Jiang J-X: Functional significance of the TLR4/11367 polymorphism identified in Chinese Han population. Shock 28:160-164, 2007.
4. Rüttinger D, Wolf H, Küchenhoff H, Jauch K-W, Hartl WH: Red cell transfusion: an essential factor for patient prognosis in surgical critical illness? Shock 28:165-171, 2007.
5. Aibiki M, Fukuoka N, Nishiyama T, Maekawa S, Shirakawa Y: Differences in antithrombin III activities by administration method in critical patients with disseminated intravascular coagulation: a pharmacokinetic study. Shock 28:141-147, 2007.
6. Jeschke MG, Mlcak RP, Finnerty CC, Herndon DN: Changes in liver function and size after a severe thermal injury. Shock 28:172-177, 2007.
7. Hussein MH, Daoud GA, Kakita H, Hattori A, Murai H, Yasuda M, Mizuno K, Goto K, Ozaki Y, Tetsuya I, et al.: The sex differences of cerebrospinal fluid levels of interleukin 8 and antioxidants in asphyxiated newborns. Shock 28:154-159, 2007.
8. Xing L, Remick DG: Mechanism of oxidant regulation of monocyte chemotactic protein 1 production in human whole blood and isolated mononuclear cells. Shock 28:178-185, 2007.
9. Morgenthaler NG, Müller B, Struck J, Bergmann A, Redl H, Christ-Crain M: Copeptin, a stable peptide of the arginine vasopressin precursor is elevated in hemorrhagic and septic shock. Shock 28:219-226, 2007.
10. Monroy MA, Opperman KK, Pucciarelli M, Yerrum S, Berg DA, Daly JM: The PPARγ Ligand 15d-PGJ2 modulates macrophage activation after injury in a murine trauma model. Shock 28:186-191, 2007.
11. Mazzon E, Cuzzocrea S: Absence of functional peroxisome proliferator-activated receptor-α enhanced ileum permeability during experimental colitis. Shock 28:192-201, 2007.
12. Fan J, Li Y, Vodovotz Y, Billiar TR, Wilson MA: Neutrophil NAD(P)H oxidase is required for hemorrhagic shock-enhanced TLR2 up-regulation in alveolar macrophages in response to LPS. Shock 28:213-218, 2007.
13. Bashenko Y, Ilan N, Krausz MM, Vlodavsky I, Hirsh MI: Heparanase pretreatment attenuates endotoxin-induced acute lung injury in rats. Shock 28:207-212, 2007.
14. Uray KS, Laine GA, Xue H, Allen SJ, Cox CS Jr: Edema-induced intestinal dysfunction is mediated by STAT3 activation. Shock 28:239-244, 2007.
15. Mura M, Andrade CF, Han B, Seth R, Zhang Y, Bai X-H, Waddell TK, Hwang D, Keshavjee S, Liu M: Intestinal ischemia-reperfusion-induced acute lung injury and oncotic cell death in multiple organs. Shock 28:227-238, 2007.
16. Barut I, Tarhan OR, Kapucuoglu N, Sutcu R, Akdeniz Y: Lamotrigine reduces intestinal I/R injury in the rat. Shock 28:202-206, 2007.
17. Zhang Y-L, Li Q-Q, Guo W, Huang Y, Yang J: Effects of chronic ethanol ingestion on tight junction proteins and barrier function of alveolar epithelium in the rat. Shock 28:245-252, 2007.
©2007The Shock Society