• coagulopathy
• damage control
• hemorrhagic shock
• inflammation
• trauma resuscitation

• K08GM134185 National Institutes of Health, (NIH); National Institute of General Medical Sciences (NIGMS)
• 1R01GM153949 National Institutes of Health, (NIH); National Institute of General Medical Sciences (NIGMS)

• Global health
• Intraperitoneal sepsis
• Laparotomy
• Multiple organ dysfunction
• Open abdomen
• Peritonitis
• Randomized controlled trial
• Septic shock

• Humans
• Abdomen
• Inflammation
• Laparotomy/adverse effects
• Multiple Organ Failure/etiology
• Prospective Studies
• United States

• Global health
• Intraperitoneal sepsis
• Laparotomy
• Multiple organ dysfunction
• Open abdomen
• Peritonitis
• Randomized controlled trial
• Septic shock

• Humans
• Abdomen
• Inflammation
• Laparotomy/adverse effects
• Multiple Organ Failure/etiology
• Prospective Studies
• United States

• 3M/Acelity Corporation
• Abdominal Compartment Society
• Andrew W Kirkpatrick Professional Corporation

• Antibacterial implants
• Charge transfer
• Intestinal disinfection
• Piezoelectric nanofiber film
• Ultrasound treatment

• Rats
• Animals
• Intestinal Perforation
• Disinfection
• Biofilms
• Anti-Bacterial Agents/pharmacology
• Bacterial Infections
• Bacteria

• peptidylarginine deiminase
• neutrophil extracellular trap
• citrullinated histone h3
• trauma
• inflammation
• traumatic brain injury
• burn
• hemorrhage

• Protein-Arginine Deiminases/genetics
• Protein-Arginine Deiminases/metabolism
• Extracellular Traps/metabolism
• Citrullination
• Neutrophils/metabolism
• Histones/metabolism

• F32 HL162378 NHLBI NIH HHS
• R01 HL155116 NHLBI NIH HHS

Assessment of immune status in critically ill patients is often based on serial tracking of systemic cytokine levels and clinical laboratory values. Exosomes are extracellular vesicles that can be secreted and internalized by cells to transport important cellular cargo in the regulation of numerous physiological and pathological processes. Here, we characterize the early compartmentalization profile of key proinflammatory mediators in serum exosomes in the steady state and following trauma. Adult male Sprague-Dawley rats (91 including naïve) were divided into one of four traumatic injury model groups incorporating whole-body blast, fracture, soft-tissue crush injury, tourniquet-induced ischemia, and limb amputation. Serum was collected at 1, 3, 6, and 24 h, and 3- and 7-day post-injury. Electrochemiluminescence-based immunoassays for 9 key proinflammatory mediators in whole serum, isolated serum exosomes, and exosome depleted serum were analyzed and compared between naïve and injured rats. Serum clinical chemistry analysis was performed to determine pathological changes.

In naïve animals, substantial amounts of IL-1β, IL-10, and TNF-α were encapsulated, IL-6 was completely encapsulated, and CXCL1 freely circulating. One hour after blast injury alone, levels of exosome encapsulated IFN-γ, IL-10, IL-6, IL-13, IL-4, and TNF-α increased, whereas freely circulating and membrane-associated levels remained undetectable or low. Rats with the most severe polytraumatic injuries with end organ complications had the earliest rise and most pronounced concentration of IL-1β, IL-10, TNF-α, and IL-6 across all serum compartments. Moreover, CXCL1 levels increased in relation to injury severity, but remained almost entirely freely circulating at all timepoints.

These findings highlight that conventional ELISA-based assessments, which detect only free circulating and exosome membrane-bound mediators, underestimate the full immunoinflammatory response to trauma. Inclusion of exosome encapsulated mediators may be a better, more accurate and clinically useful early strategy to identify, diagnose, and monitor patients at highest risk for post-traumatic inflammation-associated complications.

• Blast
• Exosomes
• Inflammation
• Traumatic injury

• Immune
• P53
• TNFAIP8
• Th17 cells

Background: Nitric oxide is a small gaseous molecule with significant bioactivity. It has been observed that NO may have a dual role dependent on its production and concentrations in the bone microenvironment. The objective of the study was to assess the concentration of total nitric oxide malonyldialdehyde, nitrotyrosine, and asymmetric dimethylarginine in the serum of patients with mandibular fractures and to understand the relationship between these compounds, in order to expand the knowledge base of the role of nitric oxide and its activity indicators in the process of bone fracture healing. Material and Methods: The study included 20 patients with mandibular fractures who were undergoing inpatient and outpatient treatments and a control group of 15 healthy people. Results were analyzed with respect to the measurement time. Total nitric oxide concentration in the blood serum was determined according to the Griess reaction, while the concentration of malonyldialdehyde, nitrotyrosine, and asymmetric dimethylarginine was estimated using the immunoenzymatic method (i.e., enzyme-linked immunosorbent assay). Results: Before the procedure, as well as on the first day and 2 and 6 weeks after the procedure, higher concentrations of total nitric oxide and lower concentrations of malonyldialdehyde were observed in the blood serum of patients with mandibular fractures compared to the control group. No statistically significant differences were found in nitrotyrosine concentrations in the blood serum of patients throughout the measurement period. However, a significantly higher asymmetric dimethylarginine concentration was observed in the patient serum before the procedure and on the first day of operation as compared with the control group. Analysis of the results observed in patient serum with respect to the number of fractures within the mandible demonstrated the same trend of concentrations for the tested compounds for the entire study group. Conclusions: In summary, our results revealed that the intensity of local processes resulting from mandibular fractures is associated with the concentration of nitric oxide, confirming its significant role, as well as that of its indicators, in the process of bone fracture healing in this patient population.

• asymmetric dimethylarginine (ADMA)
• malonyldialdehyde (MDA)
• mandibular fractures
• nitric oxide (NO)
• nitrotyrosine (NT)

• exosomes
• extracellular vesicles
• inflammation
• intercellular communication
• trauma

• Alarmins/metabolism
• Cytokines/metabolism
• Cytoskeletal Proteins/metabolism
• Exosomes/metabolism
• Heat-Shock Proteins/metabolism
• Humans
• Inflammation/etiology
• Inflammation/metabolism
• MicroRNAs/metabolism
• Reperfusion Injury/complications
• Reperfusion Injury/pathology
• Wounds and Injuries/complications

• Interscalene nerve block
• arthroscopic shoulder surgery
• balanced general anesthesia
• inflammatory response
• postoperative pain
• shoulder surgery

• Kidney injury
• LPS
• Nrf2
• TNF-α

• acute physiology and chronic health evaluation II
• continuous blood purification
• cytokine
• endotoxin
• inflammatory
• interleukin-6
• interleukin-8
• retrospective study

• Bio-mediators
• Intra-peritoneal sepsis
• Laparotomy
• Multiple organ dysfunction
• Open-abdomen
• Peritonitis
• Randomized trial
• Septic shock

• Aged
• Female
• Humans
• Male
• Middle Aged
• Abdomen/surgery
• APACHE
• Incidence
• Interleukin-10/analysis
• Interleukin-10/blood
• Interleukin-6/analysis
• Interleukin-6/blood
• Laparotomy/methods
• Organ Dysfunction Scores
• Procalcitonin/analysis
• Procalcitonin/blood
• Protein C/analysis
• Sepsis/mortality
• Sepsis/surgery
• Randomized Controlled Trials as Topic

• Acelity

Polymorphonuclear granulocytes (PMN) play a crucial role in host defense. Physiologically, exposure of PMN to the complement activation product C5a results in a protective response against pathogens, whereas in the case of systemic inflammation, excessive C5a substantially impairs neutrophil functions. To further elucidate the inability of PMN to properly respond to C5a, this study investigates the role of the cellular membrane potential of PMN in response to C5a.

Electrophysiological changes in cellular and mitochondrial membrane potential and intracellular pH of PMN from human healthy volunteers were determined by flow cytometry after exposure to C5a. Furthermore, PMN from male Bretoncelles-Meishan-Willebrand cross-bred pigs before and three hours after severe hemorrhagic shock were analyzed for their electrophysiological response.

PMN showed a significant dose- and time-dependent depolarization in response to C5a with a strong response after one minute. The chemotactic peptide fMLP also evoked a significant shift in the membrane potential of PMN. Acidification of the cellular microenvironment significantly enhanced depolarization of PMN. In a clinically relevant model of porcine hemorrhagic shock, the C5a-induced changes in membrane potential of PMN were markedly diminished compared to healthy littermates. Overall, these membrane potential changes may contribute to PMN dysfunction in an inflammatory environment.

• (Centr Eur Immunol 2018
• 42-49)
• 43 (1)
• CRP
• cytokines
• infectious complications
• inflammation
• multiple injuries

The protective potential of lazaroids has been reported in previous studies on ischemia/reperfusion and induced hemorrhagic shock protocols.

The present study is the first experimental protocol on the effects of the antioxidant factor U-74389G on the small intestine of swine models in a hemorrhagic shock protocol and resuscitation with 3 different types of fluids.

The study included 49 Landrace breed swine that were divided into groups of 7 each. Hemorrhage was provoked 45 minutes after starting the surgical protocol (0 minutes), followed by resuscitation starting 30 minutes after haemorrhage ceased by using 3 different fluids. Three groups (Group A, resuscitation using blood; Group B, resuscitation with Ringer’s lactate solution; and Group C, resuscitation with hypertonic saline solution) underwent resuscitation with fluid alone, and another 3 groups (named A', B,' and C') were administered lazaroid U-74389G in addition to fluid. Control Group S underwent all the surgical procedures without hemorrhagic shock. Vital signs, complete blood count, and biochemical markers were analyzed, and tissue samples of the small intestine were collected from all animals. Further, malondialdehyde, tumor necrosis factor-α, and levels of inflammation in the tissue sample were measured.

In Group S-A-A' and Group S-C-C', the analysis did not show statistically significant differences in the percentage changes of histopathology, malondialdehyde, and tumor necrosis factor-α through time. In Group S-B-B', the malondialdehyde levels in the small intestine were reduced in both the B and B' groups, without lazaroid (Group B) (P = 0.038) and lazaroid (Group B') (P = 0.011), compared with Group S (control), but the group without lazaroid (Group B) had greater reduction in malondialdehyde levels than the group treated with lazaroid (Group B'). With regard to the biochemistry results, 24% reduction was observed for alkaline phosphatase (P = 0.022) in Group A' treated with lazaroid compared with that in the untreated group. Lastly, for the complete blood count parameters, a 14% reduction in white blood cells was observed in Group B', which was treated with lazaroid in all phases (P = 0.015) (absolute value = 6.23) compared with Group B (absolute value = 13.74).

Despite few initial findings of this study suggesting that administration of lazaroid U-74389G may have some potential in attenuation of the effects of hemorrhagic shock in the small intestine of swine models, no differences remained after correction for multiple comparisons was made. Therefore, further research is required to investigate this result thoroughly.

• Chiu score
• inflammation
• ischemia-reperfusion
• lazaroid
• lipid peroxidation
• malondialdehyde
• tumor necrosis factor-α

To evaluate the effects of mineralocorticoid receptor (MR) antagonists on mortality and inflammatory responses after hemorrhagic shock (HS) in rats.

One hundred and two male Sprague–Dawley rats were randomly assigned to one of the following three groups: Control, spironolactone (SPL), and eplerenone (EP) groups. HS was induced by the removal of blood. One half of rats were evaluated to determine mortality, hemodynamics, plasma tumor necrosis factor-alpha (TNF-α) concentrations, and arterial blood gas at 8 h after HS recovery. In the remainder of rats, the expression levels of genes encoding cytokines were evaluated in liver tissue samples at 1 h after HS recovery.

The survival rates 8 h after HS recovery were 71%, 94%, and 82% in the control, SPL, and EP groups, respectively. There were no significant differences in survival rates among the three groups (P = 0.219). Furthermore, there were no significant differences in gene expression levels in the liver or plasma TNF-α concentrations among the three groups (P = 0.888).

Pretreatment with MR antagonists did not improve mortality or cytokine responses in the liver after HS recovery in rats.

• Hemorrhagic shock
• Mortality
• Inflammatory response
• Mineralocorticoid receptor antagonist
• Cytokine

Sepsis is a condition associated with a dysregulated inflammatory response to infection with significant morbidity. Recent advances have elucidated the vital role that the short chain fatty acid glycoprotein receptor 43 (FFA2/GPR43) plays in inflammatory and immunomodulatory pathways. We hypothesized that elevated whole blood GPR43 RNA expression would be associated with increased 30-day survival in patients admitted with sepsis. Patients (n = 93) admitted to the intensive care unit with the diagnosis of sepsis underwent quantitative real time PCR within 48 h of intensive care unit admission. Clinical and demographical parameters were retrospectively extracted from the chart and compared to quantitative measurements of GPR43 RNA expression.

Utilizing logistic regression, we found that the odds of mortality decreased for every one-unit increase in GPR43 RNA expression for patients that survived to 30 days [OR = 0.71; 95% CI (0.50, 0.99) p = 0.049]. Using linear regression, we determined that the increase in whole blood GPR43 expression was not associated with whole blood white cell count [r = 0.04; 95% CI (−0.16, 0.24); p = 0.70] or body mass index [r = − 0.07; 95% CI (− 0.23, 0.18); p = 0.81]. We conclude that the GPR43 receptor plays an integral role in survival during and after sepsis.

• FFA2
• GPR43
• Multiple organ dysfunction
• Sepsis
• Short-chain fatty acids

• Complement
• Inflammation
• Inhibition
• Macaca mulatta
• Shock
• Trauma

• Endotoxins shock
• Immunosuppression
• Injuries

Liver failure induced by systemic inflammatory response (SIRS) is often associated with mitochondrial dysfunction but the mechanism linking SIRS and mitochondria-mediated liver failure is still a matter of discussion. Current hypotheses suggest that causative events could be a drop in ATP synthesis, opening of mitochondrial permeability transition pore, specific changes in mitochondrial morphology, impaired Ca²⁺ uptake, generation of mitochondrial reactive oxygen species (mtROS), turnover of mitochondria and imbalance in electron supply to the respiratory chain. The aim of this review is to critically analyze existing hypotheses, in order to highlight the most promising research lines helping to prevent liver failure induced by SIRS. Evaluation of the literature shows that there is no consistent support that impaired Ca⁺⁺ metabolism, electron transport chain function and ultrastructure of mitochondria substantially contribute to liver failure. Moreover, our analysis suggests that the drop in ATP levels has protective rather than a deleterious character. Recent data suggest that the most critical mitochondrial event occurring upon SIRS is the release of mtROS in cytoplasm, which can activate two specific intracellular signaling cascades. The first is the mtROS-mediated activation of NADPH-oxidase in liver macrophages and endothelial cells; the second is the acceleration of the expression of inflammatory genes in hepatocytes. The signaling action of mtROS is strictly controlled in mitochondria at three points, (i) at the site of ROS generation at complex I, (ii) the site of mtROS release in cytoplasm via permeability transition pore, and (iii) interaction with specific kinases in cytoplasm. The systems controlling mtROS-signaling include pro- and anti-inflammatory mediators, nitric oxide, Ca²⁺ and NADPH-oxidase. Analysis of the literature suggests that further research should be focused on the impact of mtROS on organ failure induced by inflammation and simultaneously providing a new theoretical basis for a targeted therapy of overwhelmed inflammatory response.

•

Relationship between mitochondrial dysfunction and high lethality upon sepsis.

• Inflammation
• Liver failure
• Mitochondria
• Reactive oxygen species
• Signaling

• LPS
• NF-κB
• chloroquine
• protéase spécifique à l’ubiquitine 25
• sepsie
• sepsis
• ubiquitin-specific protease 25

• Cytokine
• Inflammation
• Outcome
• Sevoflurane

• Hemorrhagic shock
• Inflammation
• Peptidylarginine deiminase inhibitor
• Rat
• Survival

Supplemental Digital Content is Available in the Text.

This randomized trial observed a survival difference between patients randomized to the ABThera versus Barker's vacuum pack after abbreviated laparotomy. As this difference did not seem to be mediated by improved peritoneal fluid drainage, fascial closure rates, or markers of systemic inflammation, it should be confirmed by a multicenter trial.

To determine whether active negative pressure peritoneal therapy with the ABThera temporary abdominal closure device reduces systemic inflammation after abbreviated laparotomy.

Excessive systemic inflammation after abdominal injury or intra-abdominal sepsis is associated with poor outcomes.

We conducted a single-center, randomized controlled trial. Forty-five adults with abdominal injury (46.7%) or intra-abdominal sepsis (52.3%) were randomly allocated to the ABThera (n = 23) or Barker's vacuum pack (n = 22). On study days 1, 2, 3, 7, and 28, blood and peritoneal fluid were collected. The primary endpoint was the difference in the plasma concentration of interleukin-6 (IL-6) 24 and 48 hours after temporary abdominal closure application.

There was a significantly lower peritoneal fluid drainage from the ABThera at 48 hours after randomization. Despite this, there was no difference in plasma concentration of IL-6 at baseline versus 24 (P = 0.52) or 48 hours (P = 0.82) between the groups. There was also no significant intergroup difference in the plasma concentrations of IL-1β, −8, −10, or −12 p70 or tumor necrosis factor α between these time points. The cumulative incidence of primary fascial closure at 90 days was similar between groups (hazard ratio, 1.6; 95% confidence interval, 0.82–3.0; P = 0.17). However, 90-day mortality was improved in the ABThera group (hazard ratio, 0.32; 95% confidence interval, 0.11–0.93; P = 0.04).

This trial observed a survival difference between patients randomized to the ABThera versus Barker's vacuum pack that did not seem to be mediated by an improvement in peritoneal fluid drainage, fascial closure rates, or markers of systemic inflammation.

ClinicalTrials.gov identifier NCT01355094.

• anesthesia
• cytokines
• immunosuppression
• surgery
• systemic inflammation