Skip Navigation LinksHome > November 2012 - Volume 38 - Issue 5 > What’s New in Shock, November 2012?
Text sizing:
A
A
A
Shock:
doi: 10.1097/SHK.0b013e31827486cf
Commentary

What’s New in Shock, November 2012?

Lederer, James A. PhD

Free Access
Article Outline
Collapse Box

Author Information

Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts

Articles presented in this issue of Shock contribute several new insights into long-standing questions associated with the host response to trauma, sepsis, pneumonia, and pulmonary function after injury. Subjects include approaches to the diagnosis of sepsis and hemorrhagic shock, treatment strategies for sepsis and hemorrhagic shock, cellular immune mechanisms involving the host response to sepsis and trauma, and cell signaling response mechanisms in organ responses to inflammation. In addition, Maegele et al. (1) provide an insightful overview of acute coagulopathy of trauma that highlights current ways to diagnose which patients might require massive transfusion and damage control resuscitation. The authors discuss why point-of-care technology is needed. They provide an argument for using viscoelastic testing as a way to predict which patients might be at risk of developing acute coagulopathy following trauma.

The clinical aspects section provides reports on genomics, diagnostic approaches to detecting hemorrhagic shock in trauma patients, resuscitation for sepsis and shock, and clinical complications associated with subarachnoid hemorrhage. A genomic study performed by Sponholz et al. (2) addresses the heme degradation pathway as a genetic factor influencing sepsis outcome in patients. These authors tested the hypothesis that polymorphisms in heme oxygenase 1 (HMOX1) and biliverdin reductases (BLVRA/B) genes might influence the clinical trajectory of sepsis patients. The authors demonstrate that patients with polymorphisms in the HMOX1 gene showed significantly higher 28-day mortality rates, whereas polymorphisms in the BLVRA/B genes did not affect sepsis mortality. Although the HMOX1 gene polymorphism showed higher 28-day mortality, the authors did not finding a significant difference in heme oxygenase 1 plasma levels in these patients. This observation is clinically relevant given the ongoing interest in the heme oxygenase 1 pathway as being protective in sepsis. The findings suggest that HMOX1 polymorphisms should be measured in patients in clinical trials testing factors that influence the heme degradation pathway. In addition, future work by this group and others interested in the HO-1 pathway should focus on understanding the phenotypic nature of this HMOX1 polymorphism on the cellular response to sepsis. Outcome studies by Corradi et al. (3) and Watanabe et al. (4) in this issue of Shock suggest that using splenic Doppler resistive index could be used to predict hemorrhagic shock in trauma patients and that end-diastolic volume is associated with the development of cerebral ischemia and pulmonary edema after subarachnoid hemorrhage. These are clearly important advances in the diagnosis of complications from hemorrhage that will aid in the development of clinical trials for treating hemorrhagic shock. In this issue, a retrospective outcomes study by Kang et al. (5) evaluated the factors that influence the Surviving Sepsis Campaign guidelines for early resuscitation of patients with severe sepsis and septic shock. This study included 317 patients. Not surprisingly, they found that hyperthermia and experience were factors influencing outcome in a high-compliance group of patients, whereas low-compliance factors were cryptic shock and higher serum lactate levels.

Although there are many new basic science contributions in this issue, there are several reports that provide some unique and timely information about the effects of trauma and complex injury responses on the immune system. Darwiche et al. (6) reexamined the role of inducible nitric oxide synthase (iNOS) as a factor that influences the response to injury in mice. Rather than focus on innate immunity such as prior iNOS work, this report examines the effect of iNOS on adaptive immune responses. Specifically, these authors use a recently established pseudofracture model to study the relationship between immune cell populations in the spleen and iNOS expression. The authors show that a macrophage population expressing the cell surface markers, GR-1 and CD11b, increased in the spleen after performing their pseudofracture procedure. These cells, which resemble myeloid-derived suppressor cells, showed high iNOS expression at 1 day after pseudofracture. A reduction in T-cell proliferation and TH1-type cytokine production accompanied the increase in iNOS-expressing GR-1+CD11b+ cells, suggesting a role for iNOS in suppressed T-cell reactivity after trauma. Next, iNOS−/− mice and the iNOS inhibitor drug, 1400W, were used to demonstrate a contribution of iNOS to suppressed T-cell responses at early time points after trauma. Although the observation that GR-1+ macrophages increase in mice following trauma has been reported by other groups, these investigators provide new insights into the potential that GR-1+ macrophages suppress T-cell responses by an iNOS-dependent mechanism following trauma. Mendoza et al. (7) also show that a complex traumatic injury caused by radiation with combined burn injury in mice leads to a significant increase in a GR-1+ immature macrophage-like population with phenotypic similarity to those described in the report by Darwiche et al. (6). This mouse model, which was developed to mimic the response to a radionuclear event, represents an applied animal model that will be useful for developing new information about the immunophysiological and pathophysiological effects of radiation-combined injury in humans. The authors show that a moderate radiation dose exposure of 5 Gy (500 rad) with 20% scald burn injury induces a significant and sustained increase in GR-1+CD11b+ cells in burn-injured and radiation-combined burn–injured mice. In contrast to the study by Darwiche et al., they show that these cells are long-lived and may not be immune suppressive. They provide data suggesting that they enhance innate immune function in mice up to 14 days after burn or radiation-combined burn injury. This report as well as the report by Darwiche et al. clearly demonstrate that cells with seemingly similar cell marker profiles can function differently, depending on the severity or type of traumatic injury that occurs. If the GR-1+CD11b+ cells induced by burn or radiation-combined burn injury mediate a beneficial effect by an iNOS-dependent mechanism as described in the pseudofracture mouse model, then iNOS inhibition could be detrimental following burn or radiation-combined burn injury.

Two other studies contribute new information on how sepsis affects T-cell function. In one study by Zhang et al., the authors show that treating mice with statin (simvastatin) prior to cecal ligation and puncture (CLP) sepsis reduces CLP-induced CD4 T-cell apoptosis and blocked CD4+ regulatory T-cell expansion (8). Simvastatin treatment also reduced systemic HMGB1 and IL-6 levels, which suggests that statin treatment also has counterinflammatory activity in sepsis. Although the contribution of statins to trauma and sepsis outcome remains controversial, these findings support the idea that statins could be used therapeutically to modulate immune system function in sepsis. The development of sepsis-induced predisposition to infection is a clinically important complication of sepsis. In the report by Mukherjee et al. (9), the authors use a “two-hit” mouse model of CLP sepsis followed by respiratory syncytial virus infection to demonstrate heightened immune pathology in the lungs of sepsis mice versus normal mice. The authors demonstrate that the heightened lung response in sepsis mice correlates with increased IL-17 levels in the lungs and that IL-17–producing CD4+ T cells appear to be the primary cell responsible for the two-hit response phenotype in respiratory syncytial virus–challenged mice. These TH17-like T cells are primed to produce IL-17 by a STAT3-mediated mechanism. This report contributes a novel observation about how IL-17–producing CD4 T cells might amplify and mediate the two-hit response phenotype in sepsis.

In another mouse sepsis report by Fox et al. (10), the authors address whether having a normal microbial flora influences sepsis responses in a Pseudomonas aeruginosa pneumonia model. In this straightforward study, the group compared the pneumonia response in conventional and germ-free mice and showed that germ-free mice showed lower resistance to infection and reduced inflammation in the lung. Germ-free mice also showed lesser gut apoptosis than conventional mice. The authors suspected that the difference in gut epithelial response between germ-free mice and conventional mice may be due to lymphocyte control of apoptosis because Rag1−/− mice that lack B and T cells showed higher gut apoptosis following sepsis than did wild-type mice. However, when the same comparison in gut epithelial apoptosis was performed in germ-free Rag1−/− and wild-type mice, they found similar-level gut apoptosis. The authors conclude from these studies that colonization with commensal bacteria significantly influences lymphocyte control of gut apoptosis. This work highlights the importance of the microbiome to controlling the pathophysiological response to sepsis.

Three reports in this issue address the mechanisms of action of treatments to control pulmonary inflammation and damage. The report by Hamahata et al. (11) used a clinically relevant sheep model for burn injury and smoke inhalation to test whether lung delivery of a drug called WW-85 that degrades peroxynitrite might lessen lung injury in combined burn and smoke inhalation model. The authors found that WW-85 treatment given at 1 h after burn and smoke injury attenuated the pulmonary injury response in sheep. This finding supports a direct involvement of peroxynitrite as a mediator of early lung injury from smoke inhalation with burn and suggests that this drug could be translated for clinical use. Another study examined pulmonary injury using the popular mouse bleomycin-induced lung damage and fibrosis model. In this report by Meng et al. (12), the authors tested the effectiveness of fluorofenidone (FD) treatment as an anti-inflammatory and antifibrotic treatment for idiopathic pulmonary fibrosis as modeled in mice. The authors found that daily treatment with FD significantly reduced lung fibrosis and inflammation. The beneficial effect of FD treatment was found to be associated with inhibition of ERK, P38, and JNK phosphorylation and an increase in or restoration of caveolin 1 protein expression to normal levels in FD-treated mice. It is hoped that future work will unravel the specific mechanisms of action of this potentially useful anti-inflammatory and antifibrotic drug. Another report by Strunden et al. (13) in this issue used an ex vivo lung perfusion model to test whether a hydroxyethyl starch preparation could prevent glycocalyx damage. The authors used an innovative approach to show that hydroxyethyl starch 130/0.4 pretreatment of lungs given heparinase to damage the glycocalyx protected the pulmonary microcirculation.

Hemorrhagic shock is a major component of traumatic injuries, and articles in this issue address signaling mechanisms in shock-induced liver damage and the effects of vasopressin treatment on the microcirculation following hemorrhagic shock. In the first report by Korff et al. (14), the authors use an elegant tool, cis-NF-κB transgenic reporter mice, to measure nuclear factor κB (NF-κB) activation in the liver at time points after hemorrhagic shock. Their findings revealed a clear time-dependent activation of NF-κB in the liver and that the most intense NF-κB activation occurred in regions within the liver showing necrotic and oxidative damage. In this sterile organ injury mouse model, the authors build on the idea that necrotic cell death and damage can initiate strong inflammatory reactivity and in this case via the activation of NF-κB–dependent genes and proteins. The other study on hemorrhagic shock by Lima et al. (15) tested the hypothesis that vasopressin treatment could modulate microcirculatory changes from hemorrhagic shock. The authors report that vasopressin treatment could prevent many of the microcirculatory changes induced by shock including vessel diameter and red blood cell velocity. They also report better survival from shock in the vasopressin-treated animals. Collectively, they conclude that vasopressin plus fluid resuscitation could be an effective treatment to restore tissue perfusion following hemorrhagic shock.

The article by Chien et al. (16) presents a detailed examination of mechanisms for how prostaglandins (PGs) inhibit bacterial lipopolysaccharide-, lipoteichoic acid–, and peptidoglycan-stimulated iNOS and nitric oxide production by a macrophage-like cell line. They also examine the effects of PGs on HO-1 and cyclooxygenase 2 protein induction. The authors compared the activities of PGJ2, Δ12-PGJ2, 15-deoxy-Δ12,14-PGJ2, PGE2, and PGF. They found that PGJ2, Δ12-PGJ2, and 15-deoxy-Δ12,14-PGJ2 induced HO-1 protein expression in the macrophage cell line, and these same PGs inhibited lipopolysaccharide-, lipoteichoic acid–, and peptidoglycan-induced iNOS and nitric oxide. The other PGs tested did not have this activity. The group then used a variety of pharmacological inhibitors to demonstrate that the inhibitory action of these PGs was likely mediated by a PG-induced increase in HO-1 expression. This study contributes new molecular pathway information linking the anti-inflammatory activity of PGs to increased expression of HO-1 in macrophages. It is hoped that this group or other investigators interested in PGs as immune response modifiers will extend these observations to a relevant in vivo animal model to test the functional importance of their findings.

Back to Top | Article Outline

REFERENCES

1. Maegele M, Spinella PC, Schoechl H: The acute coagulopathy of trauma: mechanisms and tools for risk stratification. Shock 38: 450–458, 2012.

2. Sponholz C, Huse K, Kramer M, Giamarellos-Bourboulis EJ, Claus RA, Kern A, Engel C, Kuhnt E, Kiehntopf M, Routsi C, et al.: Gene polymorphisms in the heme degradation pathway and outcome of severe human sepsis. Shock 38: 459–465, 2012.

3. Corradi F, Brusasco C, Garlaschi A, Santori G, Vezzani A, Moscatelli P, Pelosi P: Splenic Doppler resistive index for early detection of occult hemorrhagic shock after polytrauma in adult patients. Shock 38: 466–473, 2012.

4. Watanabe A, Tagami T, Yokobori S, Matsumoto G, Igarashi Y, Suzuki G, Onda H, Fuse A, Yokota H: Global end-diastolic volume is associated with the occurrence of delayed cerebral ischemia and pulmonary edema after subarachnoid hemorrhage. Shock 38: 480–485, 2012.

5. Kang MJ, Shin TG, Jo IJ, Jeon K, Suh GY, Sim MS, Lim SY, Song KJ, Jeong YK: Factors influencing compliance with early resuscitation bundle in the management of severe sepsis and septic shock, Shock 38: 474–479, 2012.

6. Darwiche SS, Pfeifer R, Menzel C, Ruan X, Hoffman M, Cai C, Chanthaphovong RS, Loughran P, Pitt BR, Hoffman R, et al.: Inducible nitric oxide synthase contributes to immune dysfunction following trauma. Shock 38: 499–507, 2012.

7. Mendoza AE, Neely CJ, Charles AG, Kartchner LB, Brickey WJ, Khoury AL, Sempowski GD, Ting JPY, Cairns BA, Maile R: Radiation combined with thermal injury induces immature myeloid cells. Shock 38: 532–542, 2012.

8. Zhang S, Luo L, Wang Y, Rahman M, Lepsenyi M, Syk I, Jeppsson B, Thorlacius H: Simvastatin protects against T-cell immune dysfunction in abdominal sepsis. Shock 38: 524–531, 2012.

9. Mukherjee S, Allen RM, Lukacs NW, Kunkel SL, Carson WF IV: STAT3 mediated IL-17 production by post-septic T cells exacerbates viral immunopathology of the lung. Shock 38: 515–523, 2012.

10. Fox AC, McConnell KW, Yoseph BP, Breed E, Liang Z, Clark AT, O’Donnell D, Zee-Cheng B, Jung E, Dominguez JA, et al.: The endogenous bacteria alter gut epithelial apoptosis and decrease mortality following pseudomonas aeruginosa pneumonia. Shock 38: 508–514, 2012.

11. Hamahata A, Enkhbaatar P, Lange M, Yamaki T, Nakazawa H, Nozaki M, Sakurai H, Traber LD, Traber DL: Administration of a peroxynitrite decomposition catalyst into the bronchial artery attenuates pulmonary dysfunction after smoke inhalation and burn injury in sheep. Shock 38: 543–548, 2012.

12. Meng J, Zou Y, Hu C, Zhu Y, Peng Z, Hu G, Wang Z, Tao L: Fluorofenidone attenuates bleomycin-induced pulmonary inflammation and fibrosis in mice via restoring caveolin-1 expression and inhibiting MAPK signaling pathway. Shock 38: 567–573, 2012.

13. Strunden MS, Bornscheuer A, Schuster A, Kiefmann R, Goetz AE, Heckel K: Glycocalyx degradation causes microvascular perfusion failure in the ex vivo perfused mouse lung. Hydroxyethyl starch 130/0.4 pretreatment attenuates this response. Shock 38: 559–566, 2012.

14. Korff S, Falsafi R, Czerny C, Jobin C, Nau C, Jakob H, Marzi I, Lehnert M: Time dependency and topography of hepatic nuclear factor κB activation after hemorrhagic shock and resuscitation in mice. Shock 38: 486–492, 2012.

15. Lima R, Villella N, Bouskela E: Microcirculatory effects of selective receptor blockade during hemorrhagic shock treatment with vasopressin: experimental study in the hamster dorsal chamber. Shock 38: 493–498, 2012.

16. Chien C-C, Shen S-C, Yang L-Y, Chen Y-C: Prostaglandins as negative regulators against lipopolysaccharide, lipoteichoic acid, and peptidoglycan induced inducible nitric oxide synthase/nitric oxide production through reactive oxygen species-dependent heme oxygenase 1 expression in macrophages. Shock 38: 549–558, 2012.

©2012The Shock Society

Follow Us

Login

Article Tools

Share