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What's New in Shock, January 2011?

Clemens, Mark G. PhD

doi: 10.1097/SHK.0b013e3182023933
Commentary
Free

University of North Carolina at Charlotte, Charlotte, North Carolina

The January 2011 issue of Shock provides another excellent selection of clinical and laboratory studies. Three clinical studies provide insights into the treatment of patients following surgery or trauma. Chen et al. (1) identified haplotype tag single-nucleotide polymorphisms (SNPs) in the TLR 2 gene in peripheral blood cells of 410 Chinese trauma patients and tested whether they correlated with morbidity. They identified three SNPs as haplotype tag SNPs for TLR2; two of them were significantly associated with cytokine production, but only one was found to correlate with increased morbidity. These results suggest that these SNPs in TLR2 may be important determinants of response in at least this population of patients.

Bacterial translocation is considered to be an important event in the propagation of the inflammatory response. Diepenhorst et al. (2) thus tested whether modulating bacterial translocation by either probiotics or selective decontamination would affect outcome in patients after pancreatic surgery. They tested for bacterial translocation by polymerase chain reaction of mesenteric lymph nodes before and after surgery and permeability by polyethylene glycol recovery. Interestingly, neither probiotics nor decontamination affected intestinal permeability or translocation, nor was there a significant increase in bacteria in lymph nodes after surgery. Thus, in this patient group, bacterial translocation does not seem to be a significant event. Another factor often affecting outcome in trauma patients is the amount of blood transfused. Hassan et al. (3) examined the effect of storage time of blood used for transfusion on outcome of 820 trauma patients. The amount of blood more than 14 days old was compared with clinical outcome in trauma patients who received at least 1 U of blood within 24 h of admission. Patients who died as well as those who developed complicated sepsis received older blood than those received by survivors and those with uncomplicated courses. The authors conclude that avoiding transfusion of multiple units of older blood may help prevent transfusion-associated morbidity in trauma patients. One way to avoid transfusion of large amounts of older stored blood is to use blood substitutes. Shono et al. (4) examined the use of liposome-encapsulated hemoglobin (LEH) administered via an intraosseous route for treatment of hypohemoglobinemic shock. They exchanged blood with 5% albumin solution or hemorrhaged mice and then resuscitated the mice with LEH or red blood cells intravenously or infused into the femur. Red blood cells intravenously administered were more effective in hypohemoglobinemia, whereas red blood cells and LEH intravenously administered were about equally effective after hemorrhage. However, LEH was more effective in preventing mortality when given intraosseously. Thus LEH may be useful in prehospital intraosseous resuscitation when venous access is not possible.

An alternative to blood for initial resuscitation is the use of hypertonic saline (HS). Although HS has been shown to have some anti-inflammatory effects, the full mechanisms are not well understood. Chen et al. (5) studied the response to HS in burned mice using both wild-type and C3H/HeJ mice with nonfunctional TLR4. They found that HS decreased bacterial translocation and bacterial clearance and upregulated nuclear factor κB in peritoneal cells with subsequent increased expression of TLR4 and decreased apoptosis. These responses were not seen in C3H/HeJ mice, suggesting that HS might have beneficial effects after burn injury through upregulation of TLR4. It would be interesting to compare this model to one in which overactivation of TLR4 is detrimental. Another approach for resuscitation is to produce hypothermia. Some studies have shown that the gaseous mediator H2S may induce hypothermia by decreasing metabolism. Therefore, Drabek et al. (6) tested whether inhaled H2S might induce hypothermia and protect from hemorrhagic shock in a pig model. Their results showed no effect of H2S on hypothermia hemodynamics or markers of injury in this model, suggesting possible species differences. Plasma H2S levels were not reported, so it is difficult to determine whether the failure to respond is a failure of delivery or local response.

Recent studies have highlighted the importance of neural mechanisms in the response to shock. Acute alcohol intoxication may blunt the sympathetic response to hemorrhage, thus decreasing the ability to sustain blood pressure. Sulzer and Molina (7) tested whether the acetylcholinesterase inhibitor physostigmine might enhance compensation after hemorrhage in intoxicated rats by potentiating sympathetic neurotransmission. They showed that physostigmine improved blood pressure when added to crystalloid resuscitation; however, when resuscitation was delayed, physostigmine exacerbated organ damage despite improved arterial pressure. Thus, potentiation of the sympathetic may improve blood pressure but at the expense of organ perfusion in acute alcohol intoxication. Baroreflex function may also be altered in brain trauma. McMahon et al. (8) used a rat model of mild or moderate brain trauma to test the effect on sensitivity of the baroreceptor reflex. Their results showed that moderate but not mild brain trauma resulted in an increased sensitivity of the baroreceptor reflex. Although they did not determine whether this altered the ability to respond to a stress such as hemorrhage, these findings warrant further investigation.

Nitric oxide (NO) is well recognized as both a promoter and preventer of injury in shock. Although high levels may be injurious, animal studies have shown that intact local production is required to support the microcirculation. Engelberger et al. (9) tested whether endotoxemia results in impaired NO mechanisms in the microcirculation in humans. A bolus dose of endotoxin produced typical inflammatory response and also impaired NO-dependent cutaneous dilation in response to heating. This was not correlated with changes in plasma l-arginine or asymmetric dimethylarginine. These results demonstrate in a human model that impaired local NO production or response may lead to heterogeneous microvascular flow in endotoxemia or sepsis. In addition to its effects on the microcirculation, NO can act on other tissues by activating guanylyl cyclase. Paula-Neto et al. (10) investigated whether NO activation of guanylyl cyclase in neutrophils might contribute to impaired function. They found that activation of guanylyl cyclase after LPS stimulation downregulated chemotactic receptors on human neutrophils and impaired their migration response. In addition, they showed that, in a mouse model of sepsis (cecal ligation and puncture), severe sepsis resulted in impaired neutrophil migration into the peritoneum, which was prevented by treatment with a guanylyl cyclase inhibitor. This also improved survival. Thus, the guanylyl cyclase pathway seems to be critical for the suppression of neutrophil function in severe sepsis.

Sepsis is associated with increases in serum protease activity, resulting in part from suppression of endogenous protease inhibitor activity. Opal et al. (11) noted that assembly of key endotoxins from anthrax requires protease activity that might be inhibited by inter-α-inhibitor proteins (IαIPs), an endogenous serine protease inhibitor. They therefore tested whether this human protease inhibitor might be protective against anthrax infection in a mouse model. Mice were treated with anthrax spores and then with IαIP and antibiotic 1 or 24 h later. At both time points, IαIP was significantly protective compared with antibiotic alone with earlier treatment being more successful. These results provide the intriguing possibility of using such protease inhibitors as adjunctive therapy for anthrax infection.

In addition to their role in thrombus formation, platelets are also known to contribute inflammation via mediator release and interaction with neutrophils. M1 protein, an important virulence factor Streptococcus pyrogenes, has been reported to bind to both neutrophils and platelets. Therefore, Zhang et al. (12) evaluated the relative contribution of neutrophils and platelets on lung damage resulting from M1 protein. Mice were treated with M1 protein and a neutralizing antibody to either neutrophils or platelets. M1 protein had no effect on adhesion molecule expression on platelets, and deletion of platelets had no effect on lung injury. In contrast, deletion of neutrophils protected against M1-dependent lung injury, indicating that neutrophils but not platelets were key mediators of M1-induced lung injury. Another blood cell that is key in the inflammatory response in shock is the macrophage. Signaling in macrophages occurs largely in membrane subdomains called caveolae, which are dependent on the structural protein caveolin for their function. Tsai et al. (13) thus tested whether deletion of caveolin 1 (cav-1) might alter signaling in macrophages. Macrophages from cav-1/ mice were found to be deficient in TLR4 and MyD88 expression, phagocytosis, bacterial killing, and iNOS induction. Inflammatory cytokine production was also decreased. These results suggest that modulation of cav-1 in macrophages may be a promising direction for the development of therapeutic approaches to modulate macrophage activity.

The final article in this month's issue by Kasper et al. (14) addresses mechanisms of skeletal muscle insulin resistance in burn injury. The renin angiotensin system is well known to be upregulated after burn injury with elevated plasma levels of angiotensin II (AII). Because there is significant cross talk between the AII and insulin signaling pathways, these investigators hypothesized that the amelioration of insulin resistance in skeletal muscle by losartan, an AII type 1 receptor antagonist, was due the effects on insulin receptor signaling. They found that losartan had no direct effect on glucose uptake or PI3 kinase phosphorylation, but enhanced the response to insulin. This was associated with increased AKT phosphorylation and GLUT-4 translocation to the plasma membrane. Thus, increased AII seems to contribute to insulin resistance by interfering with insulin signaling, and blocking the AII type 1 receptor may be an effective adjunct for the prevention of insulin resistance in burn patients.

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REFERENCES

1. Chen K, Gu W, Zeng L, Jiang D, Zhang L, Zhou J, Du D, Hu P, Liu Q, Huang S, et al: Identification of haplotype tag SNPS within the entire TLR2 gene and their clinical relevance in patients with major trauma. Shock 35:35-41, 2011.
2. Diepenhorst GMP, van Ruler O, Besselink MGH, van Santvoort HC, Wijnandts PR, Renooij W, Gouma DJ, Gooszen HG, Boermeester MA: Influence of prophylactic probiotics and selective decontamination on bacterial translocation in patients undergoing pancreatic surgery: a randomized controlled trial. Shock 35:9-16, 2011.
3. Hassan M, Pham TN, Cuschieri J, Warner KJ, Nester T, Maier RV, Shalhub S, O'Keefe GE: The association between the transfusion of older blood and outcomes after trauma. Shock 35:3-8, 2011.
4. Shono S, Kinoshita M, Takase B, Nogami Y, Kaneda S, Ishihara M, Saitoh D, Kikuchi M, Seki S: Intraosseous transfusion with liposome-encapsulated hemoglobin improves mouse survival after hypohemoglobinemic shock without scavenging nitric oxide. Shock 35:45-52, 2011.
5. Chen LW, Su MT, Chen PH, Liu WC, Hsu CM: Hypertonic saline enhances host defense and reduces apoptosis in burn mice by increasing toll-like receptors. Shock 35:59-66, 2011.
6. Drabek T, Kochanek PM, Stezoski J, Wu X, Bayir H, Morhard RC, Stezoski SW, Tisherman SA: Intravenous hydrogen sulfide does not induce hypothermia or improve survival from hemorrhagic shock in pigs. Shock 35:67-73, 2011.
7. Sulzer JK, Molina PE: Delayed resuscitation with physostigmine increases end organ damage in alcohol intoxicated rats. Shock 35:74-79, 2011.
8. McMahon CG, Kenny RA, Bennett K, Little R, Kirkman M: Effect of acute traumatic brain injury on baroreflex function. Shock 35:53-58, 2011.
9. Engelberger RP, Pittet YK, Henry H, Delodder F, Hayoz D, Chioléro RL, Waeber B, Liaudet L, Berger MM, Feihl F: Acute endotoxemia inhibits microvascular nitric oxide-dependent vasodilation in humans. Shock 35:28-34, 2011.
10. Paula-Neto HA, Alves-Filho JC, Souto FO, Spiller F, Amendola RS, Freitas A, Cunha FQ, Barja-Fidalgo B: Inhibition of guanylyl cyclase restores neutrophil migration and maintains bactericidal activity increasing survival in sepsis. Shock 35:17-27, 2011.
11. Opal SM, Lim YP, Cristsofaro P, Artenstein AW, Kessimian N, DelSesto D, Parejo N, Palardy JE, Siryaporn E: Inter-α inhibitor proteins: a novel therapeutic strategy for experimental anthrax infection. Shock 35:42-44, 2011.
12. Zhang S, Zhang S, Rahman M, Herwald H, Thorlacius H: Streptococcal M1 protein-induced lung injury is independent of platelets in mice. Shock 35:86-91, 2011.
13. Tsai TH, Chen SF, Huang TY, Tzeng CF, Chiang AS, Kou YR, Lee TS, Shyue SK: Impaired CD14 and CD36 expression, bacterial clearance, and toll-like receptor 4-MyDD88 signaling in caveolin-1-deleted macrophages and mice. Shock 35:92-99, 2011.
14. Kasper SO, Phillips EE, Castle SM, Daley BJ, Enderson BL, Karlstad MD: Blockade of the rennin-angiotensin system improves insulin receptor signaling and insulin-stimulated skeletal muscle glucose transport in burn injury. Shock 35:80-85, 2011.
©2011The Shock Society