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OBJECTIVES: To investigate the relationship between the serum levels of NLRP3 and HMGB-1 and the prognosis of patients with severe blunt abdominal trauma. METHODS: In total, 299 patients were included in the current study from July 2014 to December 2015. All patients were divided into the mild/moderate blunt abdominal trauma group and the severe blunt abdominal trauma group according to their injury severity scores. Serum levels of NLRP3 and HMGB-1 were measured upon admission (0 h) and at 12 h, 24 h, 48 h, 72 h and 7 days after admission. RESULTS: Compared with the healthy controls, both the mild/moderate and severe blunt abdominal trauma groups had higher serum levels of NLRP3 and HMGB-1 at admission. At all points, the serum levels of NLRP3 and HMGB-1 were significantly higher in the severe group than in the mild/moderate group. The serum levels of both NLRP3 and HMGB-1 were significantly higher in the deceased patients than in the living patients. The Kaplan-Meier curve showed that compared with patients with higher levels of NLRP3 or HMGB-1, those with lower levels had longer survival times. The serum levels of both NLRP3 and HMGB-1 were independent risk factors for 6-month mortality in severe blunt abdominal trauma patients. CONCLUSION: The serum levels of NLRP3 and HMGB-1 were significantly elevated in severe blunt abdominal trauma patients, and the serum levels of both NLRP3 and HMGB-1 were correlated with 6-month mortality in severe blunt abdominal trauma patients.

Background: Ex vivo lung perfusion (EVLP) enables assessment of marginal donor lungs for transplantation, with similar clinical outcomes to conventional lung transplantation. We investigated whether cell death-related proteins in the EVLP perfusate could predict primary graft dysfunction (PGD) after transplantation., Methods: M30 (indicating epithelial apoptosis), M65 (indicating total epithelial cell death), and high mobility group box 1 (HMGB-1, related to cell death and inflammation) protein levels in EVLP perfusate were measured by enzyme-linked immunosorbent assay and correlated with clinical outcomes., Results: From 100 sequential EVLP patients, 79 lungs were transplanted. Patients who were bridged with extracorporeal life support (ECLS, n = 6) or who received lobar/single lung (n = 25) were excluded. PGD grade 3 (partial pressure of arterial oxygen/fraction of inspired oxygen <200 or need for ECLS) developed in 11 at any time within 72 hours after transplantation (PGD Group). PGD grade 3 did not develop in 34 patients (Control Group). M30 was significantly higher in the PGD Group than in the Control Group at 1 hour (PGD: 73.3 ± 24.9, control: 53.9 ± 15.9 U/liter; p < 0.01) and at 4 hours (PGD: 137.0 ± 146.6, Control: 72.4 ± 40.0 U/liter; p = 0.046) of EVLP. The increase of HMGB-1 from 1 to 4 hours of EVLP was significantly greater in the PGD Group (PGD: 37.0 ± 25.4, Control: 7.2 ± 16.8 ng/ml; p < 0.001). Higher levels of or a greater increase in M30 and a greater increase in HMGB-1 were associated with higher mortality in Cox regression., Conclusions: Levels of M30 and HMGB-1 in the EVLP perfusate correlate with PGD after lung transplantation and might therefore be useful biomarkers to improve donor lung assessment during EVLP., (Copyright © 2017 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background & Objective: Since its initial discovery, current understanding on the functional role of the Receptor for Advanced Glycation End-products (RAGE) in physiology and in pathology has impressively grown, especially in consideration of its large ligand repertoire (AGEs, HMGB-1, β amyloid, S100B/S100A12) and its potential involvement in the pathophysiology of several chronic human disorders. Downstream RAGE engagement by its ligands, NF-κB signaling activation has been demonstrated in several cell phenotypes, including neurons and glia. Based on the observation that in Alzheimer's Disease (AD) brain expression of RAGE and its ligands is upregulated and that RAGE/NF-κB axis activation can trigger an autoregulatory loop which further amplifies neuroinflammation and neurodegeneration, this signaling pathway has been hypothesized to greatly contribute to AD pathophysiology. Herein we review the vast array of information supporting a detrimental role of RAGE/NF-κB axis activation in AD brain and discuss those data in the context of recent findings obtained in our laboratory pointing to an unexpected effect elicited by this signaling pathway which may rather contribute to reparative mechanisms in AD, namely positive modulation of adult neurogenesis. Interestingly, the proneurogenic effect resulting from RAGE/NF-κB axis activation could be induced by molecules which are commonly considered as mediators of toxicity, like Aβ oligomers and HMGB-1., Conclusion: Altogether, despite a large set of data suggesting that RAGE may represent an interesting target for the pharmacological treatment of AD, the complex functional roles of the receptor would require the use of molecules able to counteract RAGE negative effects without altering the positive ones such as the promotion of adult neurogenesis., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Introduction: High-mobility group box 1 protein (HMGB-1) has been implicated in the pathogenesis of lupus nephritis (LN). There is increased HMGB-1 expression in the kidneys and increased levels are observed in serum and urine of patients with LN. This study was performed to determine whether the increased urinary HMGB-1 was specific for active lupus or secondary to renal damage., Methods: Urine from 61 lupus patients (32 had active LN and 29 had systemic lupus erythematosus (SLE) with no evidence of LN) and 14 control proteinuric patients (all with hypertension and eight also with diabetes) were included in this study. HMGB-1 was detected by Western blot. Urine protein was normalized to urine creatinine to account for volume of the specimen., Results: Median normalized urine HMGB-1 levels were significantly elevated in LN patients compared to lupus patients without kidney disease (53.81 vs 9.46, p < 0.001). A difference in median levels was seen between LN classes, with a significant difference between proliferative and membranous disease (33.4 vs 138.8, p = 0.003). Urine protein to urine creatinine ratio (P/C) correlated with urinary HMGB-1 (r = 0.52, p < 0.001), but across the classes this was true only for membranous disease (r = 0.71, p = 0.022, proliferative, p = 0.63; mixed, p = 0.34)., Conclusions: HMGB-1 is elevated in the urine of patients with active LN. Levels are associated with LN class, and higher levels of urinary HMGB-1 are seen in patients with class V when compared to both proliferative and mixed classes. Therefore, urinary HMGB-1 may be suggestive of membranous LN and warrants further evaluation in a large lupus cohort., Competing Interests: statement The Authors declare that there is no conflict of interest, (© The Author(s) 2016.)

Acetaminophen (APAP) is one of the most common antipyretic and analgesic drugs. Despite various precautions patients use APAP in amounts exceeding acceptable daily doses. APAP overdosing contributes to APAP intoxication, which leads to acute liver injury or necessity of exigent liver transplantation. Biomarkers that can be helpful in early diagnosis of liver injury during APAP overdosing are studied worldwide. This review presents recent reports on new potential biomarkers and their prospective application in clinical practice., (Copyright © 2016 Medical University of Bialystok. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.)

Objectives: Increased Toll like receptors (TLRs) especially 2 and 4 have been demonstrated in obesity, metabolic syndrome (MetS) and diabetes resulting in increased cellular inflammation. Since we have shown increased TLR2 and 4 activities in both T1DM and T2DM and MetS, we wanted to elucidate the mechanisms of this sterile inflammation. In T1DM, T2DM and MetS we have shown that high mobility group box 1 protein (HMGB-1), a non-histone DNA binding protein is increased and could be a potential activator of TLRs since it has previously shown to activate TLR2, 4 and 9. We examined the role of HMGB-1 in patients and animal models of diabetes and MetS to determine how important it is as an activator of TLR mediated inflammation and its role in diabetic vascular complications., Methods: A Medline search was conducted using the terms HMGB-1, TLRs and diabetes., Results: HMGB-1 levels are increased in patients with diabetes and MetS, and associated with increased biomediators of inflammation. Furthermore data supported a role of HMGB-1 in both diabetic microvascular and macrovascular complications., Conclusions: HMGB-1 interaction with TLRs is implicated in diabetic complications and could be important therapeutic target., (Published by Elsevier Inc.)

Early recovery from shock improves prognosis in patients with severe sepsis and septic shock. During this period, cytokine imbalances mediate the development of organ damage and mortality. In Japan, we have access to hemoperfusion using an immobilized polymyxin B fiber column for endotoxin removal (PMX-DHP) and continuous hemodiafiltration (CHDF) as artificial support for patients with septic shock, with the aim of improving hemodynamics and organ dysfunction caused by elevated inflammatory cytokines and mediators. In this Short communication, we discuss recent findings showing anti-inflammatory treatment following these continuous renal replacement therapies in sepsis., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Asthma is a chronic disorder of the airways characterized by cellular infiltration, airway hyper-responsive and airway inflammation. Innate immune cells are the first line of defense against endogenous and exogenous signals in the airways and as such possess a diverse array of pattern recognition receptors. Toll-like receptors are crucial sentinels which when activated, can either promote or ameliorate the inflammatory response in predisposed individuals. The recently discovered triggering receptor expressed on myeloid cells family members are emerging mediators of inflammation. These receptors are believed to modulate inflammatory responses by collaborating with classic PRRs. Endogenous signals like HMGB-1, signaling through the receptor for advanced glycation end products, also promotes inflammation, however, its contribution to inflammation in the airways is not well known. Here, we discuss the role of each receptor in airway inflammation and highlight potential synergistic mechanisms, which contribute to disease pathogenesis in allergic asthma.

Purpose: Traumatic insults result in an altered inflammatory response, in which alarmins release has a central role. The impact of haemorrhagic shock intensity on the long-term kinetics of alarmins is not yet fully elucidated. We investigated these aspects in a combined trauma (chest, abdominal, and extremities injury) porcine model with different severities and durations of haemorrhagic shock., Methods: After induction of combined trauma (tibia fracture, lung contusion, and liver laceration), haemorrhagic shock was induced at different intensities: moderate haemorrhage (MH; n = 15): mean arterial pressure (MAP) <30 ± 5 mmHg [maximum loss of total blood volume (TBVmax): 45 %] for 90 min, and severe haemorrhage (SH; n = 10): MAP <25 ± 5 mmHg (TBVmax 50 %) for 120 min. Resuscitation was performed using a standardized crystalloid infusion protocol. Animals were mechanically ventilated and underwent ICU-monitoring for 48 h (MH) and 48.5 h (SH). Blood samples were collected over the clinical time course, and systemic levels of serum alarmins [High-Mobility Group Protein B-1 (HMGB-1) and Heat Shock Protein 70 (HSP70)] were measured using an ELISA kit., Results: Heart rate, systemic blood pressure, lactate, and base excess were significantly altered as a function of haemorrhagic shock in both trauma groups (MH and SH). Systemic HMGB-1 levels were significantly elevated in both trauma groups when compared to the sham group. Haemorrhagic shock severity and duration were positively correlated with HMGB-1 levels and compared to baseline values, concentrations remained significantly increased in SH when compared to MH. On the other hand, we observed a significant decrease in the systemic HSP70 levels of trauma groups (MH, and SH) when compared to the sham group, which was significantly decreased compared to baseline values in SH over the entire time course., Conclusion: Our data show that haemorrhagic shock duration and severity affect the systemic levels of HMGB-1 and HSP70. This early alarmins release after trauma can be used to guide the treatment strategies (e.g. surgical procedures) of polytrauma patients.

The evaluation of the inflammasome activation usually addresses the presence of extracellular IL-1β and IL-18 or the secretion of danger signal proteins such as HMGB-1 through their quantification using an enzyme-linked immunosorbent assay (ELISA). The ELISA is a routine laboratory technique that uses antibodies and colorimetric changes to identify a substance of interest. ELISA uses a solid-phase enzyme immunoassay to detect the presence of a substance, usually an antigen, in a liquid or wet sample. Using 96 well plates, the ELISA technique enables to quantify the concentration of a single cytokine in multiple samples. However, a limitation of IL-1β and IL-18 ELISA is the absence of discrimination between active and non-active form of the proteins, parameter critical, for example, to distinguish the biologically relevant IL-1β from its poorly active form pro-IL-1β. This issue can be solved using western blots or immunoblots (IB), a common analytical procedure to detect the presence of different proteins in biological samples. Using denaturating conditions, IB allows the visualization of different sizes of the proteins of choice and is a commonly used technique in the inflammasome field to evaluate, for instance, the maturation of pro-IL-1β, pro-IL-18, and pro-caspase-1 into mature IL-1β, mature IL-18, and mature caspase-1, respectively. Moreover inflammasome activation may lead to the release of inflammasome particles outside the cell through caspase-1- or caspase-11-dependent cell death mechanism termed pyroptosis. In this case, NLR, ASC, and caspase-1 components are detectable outside the cell using IB analysis. ELISA and IB can be performed on cell culture supernatant or cell extract and on ex vivo samples from organ homogenates or biological fluids such as serum and plasma or bronchoalveolar lavages.

We herein clarified the time course of changes in the serum high mobility group box chromosomal protein-1 (HMGB-1) concentrations in esophageal cancer patients after esophagectomy, and investigated whether the perioperative serum HMGB-1 levels correlate with the administration of neoadjuvant chemoradiation therapy (NACRT) and the postoperative clinical course, especially the occurrence of pulmonary complications, in such patients. Sixty patients who underwent right transthoracic esophagectomy for esophageal cancer were enrolled in this study. The relationship between the perioperative serum HMGB-1 levels and NACRT, and the postoperative severe pulmonary complications were evaluated. Patients with severe pulmonary complications (n = 44) tended to have undergone NACRT more often than those without severe pulmonary complications (n = 16). The preoperative and postoperative day 7 serum HMGB-1 concentrations were significantly higher in patients with severe pulmonary complications than those in patients without severe pulmonary complications. In the univariate and multivariate analyses, the use of NACRT and the preoperative elevations in the serum HMGB-1 levels (>4.2 ng/mL) were found to be significantly associated with pulmonary dysfunction. Furthermore, the response to NACRT was found to be significantly associated with the preoperative serum HMGB-1 levels. The use of NACRT contributes to preoperative serum HMGB-1 elevation, and these were risk factors for the occurrence of severe postoperative pulmonary complications in patients with esophageal cancer after thoracic esophagectomy., (© 2014 International Society for Diseases of the Esophagus.)

Studies have shown that LPS-preconditioned tolerant state could protect against brain injury to subsequent challenges. We hypothesized astrocytes were directly involved in the readjustment to confer neuroprotective effects with LPS pretreatment. High-mobility group box 1(HMGB-1) from LPS-preconditioned astrocytes, presumably serving as a positive regulator, might contribute to the favorable preconditioned effects. Furthermore, a potential cellular pathway (PI3K/AKT pathway), has been proposed for the active regulation of LPS-primed reactive astrocytes to secrete HMGB-1. In the present study, we used a low concentration of LPS to directly prime the astrocytes in vitro, and the subsequent astrocytic reactions, including cytokine secretion, the expression of transcription factors, and the release of HMGB-1 were examined after the blockade of the PI3K pathway. The data showed that LPS preconditioning could reduce some capacity of astrocytes to subsequent challenge in vitro. PI3K/AKT pathway was partially involved in the modulation of the release HMGB-1 from reactive astrocytes. These findings offer direct evidence supporting the flexible roles of astrocytes in mediating LPS-primed neuroprotection, and highlight additional targets for future attempts to modify the protective effects of astrocytes through LPS preconditioning.

Background: Acute gastrointestinal disease occurs commonly in horses. Novel biomarkers might improve the understanding of SIRS and aid diagnosis and determination of prognosis., Hypotheses: Increased plasma concentrations of the biomarkers HMGB-1 and nucleosomes are associated with severity of gastrointestinal lesions in horses; concentrations of these biomarkers will be greater in horses with lesions more likely to cause SIRS; and will provide additional information compared with standard biomarkers fibrinogen and SAA., Animals: Thirty horses with gastrointestinal disease, 22 healthy horses., Methods: Prospective study. Plasma samples taken on admission were used for measurement of HMGB-1, nucleosomes, fibrinogen, and SAA. Values were compared between healthy horses and those with gastrointestinal disease, and between horses with gastrointestinal disease grouped by lesion type (inflammatory, strangulating, and nonstrangulating). Correlations between biomarkers were assessed., Results: Plasma concentrations of all biomarkers were significantly higher in horses with gastrointestinal disease compared to healthy horses (P ≤ .001). HMGB-1 and nucleosomes were significantly higher in inflammatory and strangulating groups compared to healthy horses (3.5-fold and 5.4-fold increases, respectively, for HMGB-1 (P < .05) and 4.8-fold and 5.6-fold increases for nucleosomes (P < .05)), but concentrations in the group with nonstrangulating disease did not differ from healthy horses. There was significant correlation between HMGB-1 and nucleosomes (Spearman's r = 0.623; P < .001), and fibrinogen and SAA (Spearman's r = 0.801; P < .001) but not between other biomarkers., Conclusions and Clinical Importance: High mobility group box-1 and nucleosomes might have use as biomarkers for horses with gastrointestinal disease. Further studies are required to determine kinetics and prognostic value of serial measurements of these biomarkers in horses., (Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Stress and glucocorticoids (GCs) have universally been considered to be anti-inflammatory, however in recent years, stress and GCs have been found to exert permissive effects (immunological priming) on neuroinflammatory processes. This phenomenon of priming is characterized by prior stress or GC exposure potentiating the neuroinflammatory response to a subsequent immune challenge. A considerable body of evidence is discussed here that supports this permissive effect of stress and GCs. In light of this evidence, a mechanism of neuroinflammatory priming is proposed involving a signal cascade in the brain involving danger-associated molecular patterns (HMGB-1) and inflammasomes (NLRP3), which results in an exaggerated or amplified neuroinflammatory response and subsequently, the amplification of the physiological and behavioral sequelae of this response (i.e. sickness). Finally, we explore the notion that stressor-induced sensitization of the neuroimmune microenvironment may predispose individuals to psychiatric disorders, in which exaggerated innate immune/inflammatory responses in the brain are now thought to play a key role.

The receptor for advanced glycation endproducts (RAGE) can engage a diverse class of ligands and contribute to the immune and inflammatory response to infection and injury. It is known to be a pathogenic receptor in many inflammatory diseases, including ischemia/reperfusion (IR) injuries in several tissues; however, its role has not been investigated in IR injuries of the intestine to date. Mesenteric (or intestinal) IR leads to recruitment of inflammatory cells into intestinal interstitial spaces, which markedly disrupts intestinal mucosa. IR-induced mucosal injury is accompanied by the development of a local and systemic inflammatory response and remote organ injury, and results in high mortality in the clinic. We hypothesized that elimination of RAGE signaling using RAGE(-/-) mice would result in decreased local and remote organ injury and reduced inflammation in a mesenteric IR model, and thus be a target for therapeutic intervention. We found that RAGE ligands including HMGB-1 and C3a were elevated after mesenteric IR indicating the potential for enhanced RAGE activation in this model. However despite this, wild-type and RAGE(-/-) mice both displayed similar degrees of mesenteric injury, neutrophil infiltration, intestinal edema, cytokine generation, neutrophil mobilization, and remote organ injury after mesenteric IR. We, therefore, conclude that despite its role in other organ IR injuries, and the robust production of RAGE ligands after intestinal ischemia, RAGE itself does not directly influence tissue injury and the inflammatory response in mesenteric IR.

Objective: Acupuncture at ST36 can produce anti-inflammatory effects, which might be associated with vagus nerve activity. This study explored the effects of electroacupuncture (EA) at ST36 on severe thermal injury-induced remote acute lung injury in rats., Interventions: Forty male Sprague-Dawley (SD) rats were randomly divided into five groups: (1) the sham (S) group, (2) the thermal injury (TEM) group subjected to 30% total body surface area (30% TBSA) third-degree scald, (3) the EA at ST36 group subjected to EA stimulation at ST36 (3V, 2ms, and 3Hz) after 30% TBSA scald, (4) the EA at non-acupoint group subjected to EA stimulation at non-acupoint after 30% TBSA scald, and (5) the α-bungarotoxin (α7 nicotinic acetylcholine receptor subunit antagonist) group administered 1.0 μg kg(-1) α-bungarotoxin before EA at ST36., Measurements and Main Results: Thermal injury of 30% TBSA induced leukocytosis in the alveolar space, interstitial edema, and the pro-inflammatory cytokines interleukin (IL)-1β, IL-6, and high-mobility group box 1 (HMGB-1); the expression of both HMGB-1 messenger RNA (mRNA) and protein in lung tissue was significantly enhanced. EA at ST36 significantly downregulated the levels of inflammatory cytokines and improved lung tissue injury. However, pretreatment with α-bungarotoxin reversed the effects of electrical stimulation of ST36., Conclusions: EA at ST36 might have a potential protective effect on severe thermal injury-induced remote acute lung injury via limitation of inflammatory responses in rats., (Copyright © 2015 Elsevier Ltd and ISBI. All rights reserved.)

We previously reported the promising effect of dioscin against hepatic ischemia/reperfusion (I/R) injury, but its effect on cerebral I/R injury remains unknown. In this work, an in vitro oxygen-glucose deprivation and reoxygenation (OGD/R) model and an in vivo middle cerebral artery occlusion (MCAO) model were used. The results indicated that dioscin clearly protected PC12 cells and primary cortical neurons against OGD/R insult and significantly prevented cerebral I/R injury. Further research demonstrated that dioscin-induced neuroprotection was accompanied by a significant inhibition in the expression and the nuclear to cytosolic translocation of HMGB-1, reflected by decreased TLR4 expression. Blockade of the TLR4/MyD88/TRAF6 signaling pathway by dioscin inhibited NF-κB and AP-1 transcriptional activities, MAPK and STAT3 phosphorylation, and pro-inflammatory cytokine responses, and upregulated the levels of anti-inflammatory factors. In addition, small interfering RNA (siRNA) and overexpressed genes of HMGB-1 and TLR4 were applied in in vitro experiments, respectively, and the results further confirmed that dioscin showed an efficient neuroprotection because of its inhibiting effects on HMGB-1/TLR4 signaling and subsequent suppressing inflammation. These findings provide new insights that will aid in elucidating the effect of dioscin against cerebral I/R injury and support the development of dioscin as a potential treatment for ischemic stroke., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Diabetic Retinopathy (DR) is one of the most common complications of the late phase diabetes, and also a common cause of blindness. High mobility group box 1 (HMGB-1) is considered to be an inflammatory mediator in the late phase that promotes inflammation and neovascularization in diabetes. Therefore, this paper discussed the role of HMGB-1 in diabetic retinopathy inflammation and neovascularization. 96 adult SD rats were randomly divided into control and diabetes group. The diabetic rat model was established by intraperitoneal injection of streptomycin (0.1 mol/L). Western blot was applied to determine HMGB-1 and its receptor RAGE and TLR2 protein expression in the serum. TUNEL was used to detect retinal apoptosis. Immunofluorescence was performed to test HMGB1 protein expression in retina. HBGM-1 and RAGE expression in diabetic rat retina was significantly higher than the control (P < 0.05), while TLR2 expression was lower (P < 0.05). TUNEL detection showed that diabetic rat retinal cells presented obviously higher apoptosis rate (P < 0.05). Immunofluorescence test revealed that HMGB1 largely expressed in the diabetic rat retinal cells (P < 0.05). HMGB1 may involve in the pathogenesis of diabetic retinopathy by binding with RAGE receptor to accelerate rat retinal cells apoptosis.

Introduction: The innate immune response molecules and their use as a predictor of mortality in cancer patients with severe sepsis and septic shock are poorly investigated., Objective: To analyze the value of interleukin (IL)-1ß, IL-6, IL-8, IL-10, IL-12, tumor necrosis factor α (TNF-α), soluble triggering receptor expressed on myeloid cells 1 (sTREM-1), and high-mobility group box 1 (HMGB-1) as predictors of mortality in cancer patients with severe sepsis and septic shock compared with septic patients without malignancies., Design: Prospective, observational cohort study., Setting: Tertiary level adult intensive care unit (ICU)., Subjects: Seventy-five patients with severe sepsis or septic shock, 40 with cancer and 35 without., Interventions and Measurements: Laboratory data were collected at ICU admission, 24 and 48 hours after. Plasma concentrations of HMGB-1 and sTREM-1 were measured by enzyme-linked immunosorbent assay, whereas cytokines were measured by cytometric bead array., Results: Intensive care unit mortality in cancer and noncancer patients was 40% and 28.6% (P = .29), and 28-day mortality was 45% and 34.3% (P = .34). Proinflammatory cytokines IL-1ß, IL-6, IL-8, IL-12, and TNF-α showed significantly higher values in the cancer group. Interleukin-10 at 48 hours (P = .01), sTREM-1 in all measurements (P < .01) and HMGB-1 at 24 hours (P < .01) showed significantly lower values in the cancer group. In addition, for the cancer group, sTREM-1 at 24 hours (P = .02) and 48 hours (P = .01) showed higher levels in nonsurvivors patients. The area under the receiver operating characteristic curve for predicting ICU mortality for sTREM-1 was 0.73 (95% confidence interval, 0.57-0.89; P = .01). Multivariate logistic analysis showed that the days spent in mechanical ventilation and levels of sTREM-1 and IL-1ß at 48 hours were independent predictors of ICU mortality; corticosteroids requirement and levels of sTREM-1 and TNF-α at 24 hours were independent predictors of 28-day mortality., Conclusions: Patients with cancer have different immune profile in sepsis when compared with patients without cancer, as demonstrated for levels of cytokines, sTREM-1 and HMGB-1. sTREM-1 and days spent in mechanical ventilation proved to be good predictors of ICU and 28-day mortality in cancer patients., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Exposure to acute and chronic stressors sensitizes the proinflammatory response of microglia to a subsequent immune challenge. However, the proximal signal by which stressors prime microglia remains unclear. Here, high mobility group box-1 (HMGB-1) protein was explored as a potential mediator of stress-induced microglial priming and whether HMGB-1 does so via the nucleotide-binding domain, leucine-rich repeat, pyrin domain containing protein 3 (NLRP3) inflammasome. Exposure to 100 inescapable tail shocks (ISs) increased HMGB-1 and NLRP3 protein in the hippocampus and led isolated microglia to release HMGB-1 ex vivo. To determine whether HMGB-1 signaling is necessary for stress-induced sensitization of microglia, the HMGB-1 antagonist BoxA was injected into the cisterna magna before IS. Hippocampal microglia were isolated 24 h later and stimulated with LPS ex vivo to probe for stress-induced sensitization of proinflammatory responses. Previous IS potentiated gene expression of NLRP3 and proinflammatory cytokines to LPS, that is, microglia were sensitized. Treatment with BoxA abolished this effect. To determine whether HMGB-1 is sufficient to prime microglia, IS was replaced with intracerebral administration of disulfide or fully reduced HMGB-1. Intracerebral disulfide HMGB-1 mimicked the effect of the stressor, because microglia isolated from HMGB-1-treated rats expressed exaggerated NLRP3 and proinflammatory cytokine expression after LPS treatment, whereas fully reduced HMGB-1 had no effect. The present results suggest that the CNS innate immune system can respond to an acute stressor as if it were cellular damage, thereby releasing the danger signal HMGB-1 in the brain to prime microglia by acting on the NLRP3 inflammasome, in preparation for a later immune challenge., (Copyright © 2015 the authors 0270-6474/15/350316-09$15.00/0.)

Objective: To clarify the time course of changes in the serum HMGB-1 concentrations in patients undergoing major gastrointestinal surgery, and to investigate whether the serum HMGB-1 levels correlate with the postoperative clinical course of the patients. Methods: Twenty-eight patients with alimentary tract carcinoma who underwent elective gastrointestinal surgery were enrolled in this study. The correlation between the serum HMGB-1 levels and the postoperative clinical course were evaluated. Results: Serum HMGB-1 concentrations in patients who underwent surgery for gastrointestinal cancer increased gradually during postoperative days, and reached peak concentrations on postoperative day 3 (POD3). There was a statistically significant positive correlation between the serum HMGB-1 levels on POD3 or POD5 and the duration of SIRS (r = 0.68, P < 0.001, r = 0.45, P < 0.05, respectively). A significantly positive correlation was found between the serum HMGB-1 levels on POD3 or POD5 and the heart rates on POD3 or POD5. Furthermore, there was a negative correlation between the serum HMGB-1 levels and PaO2/FiO2 ratio on POD3. Conclusions: Serum HMGB-1 levels increase after major gastrointestinal surgery, and the serum peak HMGB-1 levels correlate with the duration of SIRS and postoperative pulmonary dysfunction. [Copyright &y& Elsevier]

Pathogenic infections and tissue injuries trigger the assembly of inflammasomes, cytosolic protein complexes that activate caspase-1, leading to cleavage of pro-IL-1β and pro-IL-18 and to pyroptosis, a proinflammatory cell death program. Although microbial recognition by Toll-like receptors (TLRs) is known to induce the synthesis of the major caspase-1 substrate pro-IL-1β, the role of TLRs has been considered limited to up-regulation of the inflammasome components. During infection with a virulent microbe, TLRs and nucleotide-binding oligomerization domain-like receptors (NLRs) are likely activated simultaneously. To examine the requirements and outcomes of combined activation, we stimulated TLRs and a specific NLR, nucleotide binding and oligomerization, leucine-rich repeat, pyrin domain-containing 3 (NLRP3), simultaneously and discovered that such activation triggers rapid caspase-1 cleavage, leading to secretion of presynthesized inflammatory molecules and pyroptosis. This acute caspase-1 activation is independent of new protein synthesis and depends on the TLR-signaling molecule IL-1 receptor-associated kinase (IRAK-1) and its kinase activity. Importantly, Listeria monocytogenes induces NLRP3-dependent rapid caspase-1 activation and pyroptosis, both of which are compromised in IRAK-1-deficient macrophages. Our results reveal that simultaneous sensing of microbial ligands and virulence factors by TLRs and NLRP3, respectively, leads to a rapid TLR- and IRAK-1-dependent assembly of the NLRP3 inflammasome complex, and that such activation is important for release of alarmins, pyroptosis, and early IFN-γ production by memory CD8 T cells, all of which could be critical for early host defense.