Serum High-mobility Group Box Chromosomal Protein 1 Research Articles

Impact of perioperative high mobility group box chromosomal protein 1 expression on long-term outcomes in patients with esophageal squamous cell carcinoma.

High mobility group box chromosomal protein-1 (HMGB-1) is a potential late mediator of sepsis and a possible risk factor for postoperative pulmonary complications after esophagectomy. This study aimed to determine the relationship between HMGB-1 and clinicopathological factors and long-term prognosis after esophagectomy for esophageal cancer. We measured perioperative serum HMGB-1 levels using ELISA and HMGB-1 protein by immunohistochemistry expression in resected specimens. Postoperative serum HMGB-1 levels were significantly higher than preoperative levels. Preoperative serum HMGB-1 levels were significantly higher in patients with more intraoperative bleeding, longer intensive care unit stays, and postoperative pneumonia. Postoperative serum HMGB-1 levels were significantly higher in older patients and those with longer operation time and more intraoperative bleeding. There were significant differences in long-term outcomes according to postoperative but not preoperative serum HMGB-1 levels. Multivariate analysis demonstrated that advanced pathological stage, postoperative pulmonary complications, and higher postoperative serum HMGB-1 levels were independently associated with relapse-free survival and overall survival. Preoperative serum HMGB-1 levels were significantly higher in patients with high HMGB-1 expression than those with low HMGB-1 expression by immunohistochemistry, whereas such statistical differences were not observed in postoperative serum HMGB-1. There were no differences in relapse-free survival and overall survival according to HMGB-1 expression by immunohistochemistry. Serum HMGB-1 levels were significantly increased after esophagectomy for esophageal cancer. Elevated postoperative serum HMGB-1, which was associated not only with poor long-term but also short-term outcomes such as postoperative complications, might serve as a potential marker for prognosis in esophageal cancer.

Increased of serum high-mobility group box chromosomal protein 1 correlated with intestinal mucosal barrier injury in patients with severe acute pancreatitis

BackgroundSecondary infections are the leading cause of death in patients with severe acute pancreatitis (SAP). The gut represents the main source of pancreatic contamination and related septic complications. High-mobility group box chromosomal protein 1 (HMGB1) was recently identified to play an important role in the SAP intestinal mucosal barrier dysfunction.ObjectiveTo investigate the correlation of high-mobility group box 1 (HMGB1) with intestinal barrier injury and infections in patients with severe acute pancreatitis (SAP).MethodsThe serum levels of HMGB1, amylase, lipase, and biochemical indicators were measured in 80 patients with SAP at the time of admission. Furthermore, relationship between their serum HMGB1 levels and intestinal barrier injury, infection and other clinical factors were analyzed.ResultsThe mean value of serum HMGB1 levels was significantly higher in patients with SAP (6.02 ± 2.42 ng/mL) than that in healthy volunteers (1.87 ± 0.63 ng/mL). Serum HMGB1 levels were significantly positively correlated with the Ranson score. The HMGB1 levels were higher in patients with infection during the clinical course, the HMGB1 levels in non-survivors were higher than those in survivors, and positively correlated with DAO activity, L/M ratio, the concentration of endotoxin (R = 0.484, P <0.01).ConclusionsHMGBl level of patients with severe acute pancreatitis was significantly increased, and can be used as an important indicator to determine the intestinal barrier dysfunction and infection.

Preoperative chemoradiation therapy for esophageal cancer is a risk factor for the elevation of high mobility group box-1, leading to an increase in postoperative severe pulmonary complications

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.

Serum high mobility group box protein 1 as a clinical marker for ovarian cancer.

The aim of the study was to evaluate the clinical value of serum high mobility group box chromosomal protein 1 (HMGB1) in ovarian cancer and analyze the correlation between HMGB1 and ovarian cancer clinicopathologic outcomes.A total of 105 patients with diagnosed epithelial ovarian cancer, 46 patients with ovarian benign disease and 33 healthy volunteers were enrolled from January 2011 through January 2013. Serum HMGB1 levels were analyzed by enzyme-linked immunosorbent assay.The mean value of serum HMGB1 levels in ovarian cancer patients (78.18±54.87ng/ml) was significantly higher than those in benign patients (33.98±9.97ng/ml) and healthy control (26.71±7.99ng/ml, p < 0.0001), respectively. The serum HMGB1 levels were 40.33±6.50ng/ml, 61.16±20.15ng/ml, 81.81±51.15ng/ml and 119.48±84.28ng/ml in patients with TNM stage I, II, III, and IV, respectively (p < 0.0001). There were 81 of the 105 ovarian cancer patients obtained complete remission, the serum HMGB1 levels before treatment(71.99±42.49ng/ml) were much higher than that at remission stage(42.10±15.48ng/ml) (p < 0.0001). During our investigating period, 28 ovarian cancer patients underwent recurrence, the serum HMGB1 levels were 75.54±39.50ng/ml in these recurrent ovarian cancer patients compared to 42.04±10.68ng/ml in non-recurrent ovarian cancer (p < 0.0001). None of the remission or recurrent patients came from benign ovarian tumor group.Our study suggests that HMGB1 may be a useful clinical marker for evaluating progression and predicting prognosis of ovarian carcinoma. Targeting HMGB1 production or release might have potential approaches for ovarian carcinoma treatment.

(Pro)renin receptor blocker improves survival of rats with sepsis

BackgroundThe renin-angiotensin system (RAS) affects inflammatory responses during sepsis. Nonproteolytic activation of prorenin by the (pro)renin receptor has recently been shown to stimulate the tissue RAS. In the present study, the effect of (pro)renin receptor blocker (PRRB) pretreatment on sepsis in a rat cecal ligation and puncture (CLP) model was investigated. Materials and methodsMale Sprague-Dawley rats underwent CLP and were randomly divided into two groups: PRRB-treated group and control peptide–treated group. Survival was analyzed for 7 d after CLP. The serum concentrations of cytokines and high-mobility group box chromosomal protein 1 (HMGB1) were measured at three time points (0, 3, and 6 h after CLP). Hematoxylin-eosin staining and immunohistochemical staining for nonproteolytically activated prorenin and HMGB1 were performed on the cecum to assess pathologic changes found 6 h after CLP. ResultsTreatment with PRRB improved the survival rate of the post-CLP septic rats (P = 0.023). PRRB also significantly reduced serum tumor necrosis factor-α, interleukin-1β, and HMGB1 levels 6 h after CLP. In CLP rats that were treated with control peptide, the expression of activated prorenin was elevated in peritoneal foam cells. Moreover, expression of HMGB1 was increased in peritoneal inflammatory cells. In contrast, both were markedly suppressed in CLP rats that were treated with PRRB. ConclusionsPRRB significantly improved the survival rate of rats with clinically relevant sepsis, possibly by attenuating a sepsis-induced systemic inflammatory response. We propose that overactivation of the RAS by activation of prorenin in foam cells may be a significant contributor to sepsis.

Effect of continuous veno-venous hemofiltration on the peripheral blood levels of high mobility group box chromosomal protein 1 in patients with systemic inflammatory response syndrome or sepsis

Objective To investigate the effect of continuous veno-venous hemofiltration (CVVH) on the peripheral blood levels of high mobility group box chromosomal protein 1 (HMGB-1) in patients with systemic inflammatory response syndrome (SIRS) or sepsis.Methods Thirty patients with SIRS or sepsis in Intensive Care Unit of our hospital were scheduled for treatment of CVVH.The replacement liquid was put in by the pattern of pre-dilution of 40％ and post-dilution of 60％.The flow-rate was 3 L/h.The blood flow-rate was from 200 to 300 ml/min.5 ml blood from right radial artery was got at the time points of preCVVH,CVVH 2 h,6 h,8 h and post-CVVH 12 h and the serum was stored at the temperature of-20 ℃ after high speed centrifugation,and 2 ml filter liquor was reserved at the time point of CVVH 6 h.The concentration of serum and filter liquor HMGB-1 was measured by ELISA,but that of TNF-α and IL-6 were measured by radioimmunity.Results 30 patients adept CVVH therapy within 24 h to the hospital,and their therapy time was 2 ～ 5(2.4 ± 1.5) d.Among them,17 cases survived and 13 cases died with a fatality rate of 43.3％.Serum concentration of HMGB-1 decreased from the baseline in patients,although this decrease was not statistically significant[(11.88 ± 6.06) ng/ml,(11.97 ± 5.66) ng/ml,(11.94 ± 5.94) ng/ml,(11.73 ± 5.19) ng/ml vs (13.87 ± 4.68) ng/ml,P ＞ 0.05],Serum concentration of both TNF-αand IL-6 after therapy significantly decreased compared to the baseline in patients [TNF-α: (0.28 ± 0.15)ng/ml,(0.30 ± 0.14) ng/ml,(0.29 ± 0.19) ng/ml,(0.33 ± 0.19) ng/ml vs (0.41 ± 0.12) ng/ml,IL-6:(408.20 ±92.18)pg/ml,(250.51 ± 107.34)pg/ml,(276.00 ± 126.20) pg/ml,(315.16 ± 130.97) pg/ml vs (513.35 ± 125.95) pg/ml,P ＜ 0.05].Conclusions CVVH could decrease the concentration of HMGB-1 in peripheral blood,which would be one of the mechanisms of action for CVVH on sepsis. Key words: Systemic inflammatory response syndrome/therapy; Sepsis/therapy; High mobility group proteins/blood; Hemofiltration

High mobility group box chromosomal protein 1 in acute-on-chronic liver failure patients and mice with ConA-induced acute liver injury

High mobility group box chromosomal protein 1 (HMGB1) is an important proinflammatory molecule in many inflammatory disorders, but little is known about its role in acute-on-chronic liver failure (ACLF). Here, we investigated the relationship between the expression of HMGB1 and the disease onset and severity of ACLF patients and mice with acute liver injury/failure induced by concanavalin A (ConA). Peripheral blood mononuclear cells (PBMCs) and serum from ACLF patients were collected, and a mouse model of acute liver injury/failure was induced by ConA. HMGB1 mRNA expression in patient PBMCs or in murine livers and serum HMGB1 protein in ACLF patients and mice were assayed by RT-PCR and Western blotting, respectively. HMGB1 translocation in hepatocytes of ConA-treated mice was assessed by immunohistochemical staining. Up-regulated HMGB1 mRNA levels in PBMCs and accumulated protein in serum were both correlated with disease severity in ACLF patients. In the animal model, HMGB1 levels increased at 4h and reached its peak value at 8–12h after challenge with ConA, which suggests that HMGB1 is a relatively late proinflammatory cytokine compared with TNF-α. Translocation of HMGB1 from the nucleus to the cytoplasm in hepatocytes was correlated with the severity of liver injury in mice. While specific anti-HMGB1 antibodies and nicotine protected mice from acute liver injury/failure by reducing mortality and improving liver tissue injury, treatment with recombinant HMGB1 led to an increased mortality due to ConA challenge. Thus, the data from the present study suggest that HMGB1 plays a critical role in the systemic inflammation of ACLF and could be a potential therapeutic target in the treatment of ACLF.

The role of HMGB1 in ischemia-reperfusion injury in the rat small intestine

DOI of original article: 10.1016/j.jss.2012.0 * Corresponding author. Uniformed Services MD 20814, USA. Tel.: þ1 301 295 2552; fax: þ E-mail address: hassan_tetteh@hks09.ha 0022-4804/$ e see front matter a 2013 Elsev doi:10.1016/j.jss.2012.04.004 Kojima et al. highlight the High Mobility Group Box Chromosomal Protein 1 (HMGB1) and its potential role in response to ischemia-reperfusion injury in the small intestine [1]. Their results suggest that HMGB1 is an importantmediator in the rat model of ischemia-reperfusion injury, and that therapeutic agents may be developed for targeted therapy in ischemiarelated injury to the small intestine. Several studies have previously explored the impact and role ofHMGB1 inacute lung injuryand ischemia-reperfusion injuryof the kidney, heart, brain, and liver [2e5]. This current studyby the authors appears to be the first report that investigates HMGB1 in the intestinal rat model of ischemia-reperfusion injury, and it offers three unique perspectives that may create opportunity for further investigation and innovation in the treatment of ischemia-reperfusion injury. First, the study demonstrated that increased serum HMGB1 concentration and its localization in damaged intestinal tissue were identified after reperfusion injury. Second, the study suggests that there is strong expression of HMGB1 in the damaged cells of terminal protein of the villi of small intestine. Finally, the administration of anti-HMGB1 antibody appears to ameliorate local disturbances and improve survival in the study subjects over controls. The authors’

High-dose immunoglobulin preparations improve survival in a CLP-induced rat model of sepsis

The efficacy of intravenous immunoglobulin G in the treatment of patients with severe sepsis or septic shock is still being debated. We investigated the impact of high-dose immunoglobulin administration on the survival rate and serum high-mobility group box chromosomal protein 1 (HMGB1) level in a rat model of sepsis created by cecal ligation and puncture (CLP). Rats received either CLP-induced sepsis or had additional immunoglobulin treatment in 1,500 or 300 mg/kg. After induction of sepsis and respective treatment conditions, pulmonary and renal tissues were examined histologically for pathological changes at postoperative hour (POH) 4, and serum cytokine and HMGB1 levels were measured at POH 4, 8, 20, and 44. Using other rats, we also observed the survival rate after CLP for 7 days. Treatment with immunoglobulin significantly improved survival rate at postoperative day 7 (73% in the high-dose group vs. 33% in the control group; p = 0.037). The serum lactate dehydrogenase, endotoxin, creatinine, and blood urea nitrogen levels were significantly lower in the high-dose group than in the other groups. The serum HMGB1 level had increased at 4 h postoperatively in the control group (10.2 ± 3.3 ng/mL) and low-dose group (10.3 ± 4.0 ng/mL), but it was significantly reduced in the high-dose group (4.2 ± 0.8 ng/mL) compared with the control group (p = 0.03). Our results suggest that high-dose immunoglobulin therapy may improve the serum endotoxin and HMGB1 levels and overall survival rate in sepsis by inhibiting the inflammation.

NEUTROPHIL ELASTASE INHIBITOR IMPROVES SURVIVAL OF RATS WITH CLINICALLY RELEVANT SEPSIS

Sivelestat sodium hydrate is a selective inhibitor of neutrophil elastase, which is effective in acute lung injury associated with systemic inflammatory response syndrome. However, the effectiveness of sivelestat in sepsis has not been fully examined. In the present study, the effect of sivelestat on severe sepsis in a rat cecal ligation and puncture (CLP) model was investigated. Adult male Sprague-Dawley rats underwent CLP and were randomly divided into two groups: sivelestat-treated group and saline-treated controls. The serum concentrations of several inflammatory mediators were measured. Hematoxylin-eosin staining, and immunohistochemical staining for high-mobility group box chromosomal protein 1 (HMGB1), IL-8, and CD68 were performed on the lungs to assess pathological changes found 12 h after the CLP procedure. Treatment with sivelestat significantly improved the survival rate of the post-CLP septic animals (P = 0.030). Sivelestat also induced a significant reduction in serum IL-1beta (P = 0.038) and IL-10 (P = 0.008) levels in these CLP rats. Serum HMGB1 levels had no significant difference between the sivelestat-treated and the control group. The lungs from sivelestat-treated rats exhibited less severe pathological changes and decreased the numbers of HMGB1, IL-8, and CD68-positive cells (P < 0.001). Sivelestat significantly improved survival rate of rats with clinically relevant sepsis, possibly by attenuating sepsis-induced systemic inflammatory response and lung injury. This may explain the implicated health benefits of sivelestat in reducing morbidity and mortality from sepsis.

Spherical Sulfated Cellulose Adsorbs High-Mobility-Group Box Chromosomal Protein 1 In Vitro and In Vivo

High-mobility-group box chromosomal protein 1 (HMGB1) has recently been identified as a late mediator of various kinds of acute and chronic inflammation. A method for efficiently removing HMGB1 from systemic circulation could be a promising therapy for HMGB1-mediated inflammatory diseases. It is well known that the cationic portion of HMGB1 binds to heparin, which has abundant sulfates in its structure. In this study, we determined whether spherical sulfated cellulose (SC) efficiently adsorbed HMGB1, as well as other inflammatory mediators, in vitro. Then, we investigated the efficacy of hemoperfusion with the SC (SC group) or cellulose beads (control group) at adsorbing endogenous mediators, including HMGB1, in vivo. We have demonstrated that the SC adsorbed significantly larger amounts of HMGB1, interleukin (IL)-4, and IL-8 when compared with cellulose beads, in vitro. Hemoperfusion with the SC for 30 minute, starting 2 hour after an abdominal opening and closure operation, significantly reduced serum HMGB1 levels (p = 0.004) and consistently increased serum IL-10 levels, in vivo. These data suggest the potential benefits of hemoperfusion using the SC in treating HMGB1-mediated inflammatory diseases.

Clinical Value of Serum HMGB1 Levels in Early Detection of Recurrent Squamous Cell Carcinoma of Uterine Cervix: Comparison with Serum SCCA, CYFRA21-1, and CEA Levels

To evaluate the clinical value of serum high mobility group box chromosomal protein 1 (HMGB1) levels in making the early diagnosis of recurrent cervical squamous cell carcinomas (CSCC) and compare it with the value of serum squamous cell carcinoma antigen (SCCA), cytokeratin fragment (CYFRA) 21-1, and carcinoembryonic antigen (CEA) levels. Immunohistochemical staining of tissue from 64 patients with recurrent CSCCs, 72 patients with non-recurrent carcinoma, and 28 healthy participants was performed to determine the expression of HMGB1 protein. The serum levels of the 4 markers in 112 patients with recurrent CSCC, 174 patients with non-recurrent disease, and 128 healthy participants were measured by enzyme-linked immunosorbent assay. The receiver operating characteristic (ROC) curves were constructed and the area under the curve (AUC) was calculated. Higher immunostaining score was found in recurrent CSCC tissue sections than in non-recurrent CSCC sections. Serum HMGB1 levels in patients with recurrent CSCC were significantly higher than in patients with non-recurrent disease and healthy controls. The AUC of HMGB1, SCCA, CYFRA21-1, and CEA was 0.816, 0.768, 0.703, and 0.625, respectively. HMGB1 had the best specificity and positive likelihood ratio (78.0% and 3.25, respectively), whereas SCCA had the best sensitivity and negative likelihood ratio (76.3% and 0.34, respectively). Parallel combined measurements increased the diagnostic sensitivity and serial combination increased the specificity. High serum HMGB1 levels were inversely correlated with disease-free survival (P=0.009, Pearson chi(2) test) and overall survival (P=0.018). HMGB1 was overexpressed in recurrent CSCCs. Serum HMGB1 level could be a useful and specific marker for evaluating the disease recurrence and predicting prognosis in patients with CSCC. Serial combined measurements of serum HMGB1, SCCA, and CYFRA21-1 increased the diagnostic specificity, and parallel combined testing increased the diagnostic sensitivity.

High Mobility Group Box Chromosomal Protein 1 in Patients with Renal Diseases

Background/Aim: The high mobility group box chromosomal protein 1 (HMGB1), a nuclear DNA-binding protein, has recently been recognized as a new proinflammatory cytokine. The purpose of this study was to examine the significance of HMGB1 in patients with renal diseases. Methods: HMGB1 concentrations in sera were measured by enzyme-linked immunosorbent assay, and antibodies against HMGB1 were examined by Western blotting in patients who underwent renal biopsies and in healthy controls. Immunohistochemistry for HMGB1 was also performed. Results: Serum HMGB1 was more likely to be positive in patients who underwent renal biopsies as compared with the controls. Patients with anti-neutrophil cytoplasmic antibody-related glomerulonephritis (ANCA-GN) and those with Henoch-Schönlein purpura nephritis showed a significantly higher tendency to be HMGB1 positive. The presence of anti-HMGB1 antibody was not associated with the presence of serum HMGB1. Immunohistochemistry revealed that HMGB1 was expressed in mononuclear cells in the interstitium or in the glomeruli of some patients with ANCA-GN or IgA nephropathy (IgAN). Subanalysis demonstrated that among patients with IgAN, those who had crescent formation showed a higher tendency to be HMGB1 positive than those who did not. Conclusions: HMGB1 was expressed in the sera of patients with renal diseases who underwent renal biopsies, especially among those who had vasculitis including ANCA-GN, Henoch-Schönlein purpura nephritis, and IgAN with glomerular crescents.

Significant Increase of Serum High-Mobility Group Box Chromosomal Protein 1 Levels in Patients With Severe Acute Pancreatitis

Multiple organ failure because of systemic inflammatory response in the early phase and sepsis in the late phase is the main contributor to high mortality in severe acute pancreatitis (SAP). High-mobility group box chromosomal protein 1 (HMGB1) was recently identified as a potent proinflammatory mediator and increases in various pathological conditions such as sepsis. The aim of this study was to investigate contributions of HMGB1 in SAP. We measured serum HMGB1 concentrations by an enzyme-linked immunosorbent assay in 45 patients with SAP at the time of admission. Furthermore, relationship between their serum HMGB1 levels and clinical factors was analyzed. The mean value of serum HMGB1 levels was significantly higher in patients with SAP (5.4 +/- 1.3 ng/mL) than that in healthy volunteers (1.7 +/- 0.3 ng/mL). Serum HMGB1 levels were significantly positively correlated with the Japanese severity score and Glasgow score. Serum HMGB1 levels were significantly positively correlated with lactate dehydrogenase, C-reactive protein, and total bilirubin. The HMGB1 levels were higher in patients with organ dysfunction and infection during the clinical course. The HMGB1 levels in nonsurvivors were higher than those in survivors. Serum HMGB1 levels gradually declined after the admission. Serum HMGB1 levels were significantly increased in patients with SAP and were correlated with disease severity. These results suggest that HMGB1 may act as a key mediator for inflammation and organ failure in SAP.

Anti‐High‐Mobility Group Box Chromosomal Protein 1 Antibodies Improve Survival of Rats with Sepsis

High-mobility group box chromosomal protein 1 (HMGB1) has recently been shown to be an important late mediator of endotoxin shock, intraabdominal sepsis, and acute lung injury, and a promising therapeutic target of severe sepsis. We sought to investigate the effect of antibodies to HMGB1 on severe sepsis in a rat cecal ligation and puncture (CLP) model. Adult male Sprague-Dawley rats underwent CLP and then were randomly divided into two groups: treatment with anti-HMGB1 polyclonal antibodies, and non-immune IgG-treated controls. The serum HMGB1 concentrations were measured at ten time points (preoperatively, and postoperatively at 4, 8, 20, 32, and 48 h and at 3, 4, 5, and 6 days). Hematoxylin-eosin staining, elastica-Masson staining, and immunohistochemical staining for HMGB1 were performed on the cecum and the lung to assess pathological changes 24 h after the CLP procedure. Treatment with anti-HMGB1 antibodies significantly increased survival [55% (anti-HMGB1) vs. 9% (controls); P< 0.01]. The serum HMGB1 concentrations at postoperative hours 20 and 32 of the anti-HMGB1 antibody-treated animals were significantly lower than those of the controls (P < 0.05). Treatment with anti-HMGB1 antibodies markedly diminished the pathological changes and the number of HMGB1-positive cells in the cecum and the lung. The present study demonstrates that anti-HMGB1 antibodies are effective in the treatment of severe sepsis in a rat model, thereby supporting the relevance of HMGB1 eradication therapy for severe sepsis.

Serum concentrations of high-mobility group box chromosomal protein 1 before and after exposure to the surgical stress of thoracic esophagectomy: a predictor of clinical course after surgery?

High-mobility group box chromosomal protein 1 (HMGB-1) has recently been shown as an important late mediator of endotoxin shock, intra-abdominal sepsis, and acute lung injury. However, its role in the systemic inflammatory response syndrome after major surgical stress, which may lead to multiple organ dysfunction syndrome, has not been thoroughly investigated. We hypothesized that serum HMGB-1 participates in the pathogenesis of postoperative organ system dysfunction after exposure to major surgical stress. A prospective clinical study was performed to consecutive patients (n = 24) with carcinoma of the thoracic esophagus who underwent transthoracic esophagectomy with three field lymph node resection between 1998 and 2003 at Keio University Hospital, Japan. Serum HMGB-1 concentrations were measured by enzyme-linked immunosorbent assay. Preoperative serum HMGB-1 levels correlated with postoperative duration of SIRS, mechanical ventilation, and intensive care unit stay. Three of the 24 patients had serious postoperative complications: sepsis in two, and acute lung injury in one. Serum HMGB-1 levels in patients without complications increased within the first 24 h postoperatively, remained high during postoperative days 2-3, and then decreased gradually by postoperative day 7. In patients with serious complications, serum HMGB-1 was significantly higher than that found in patients without postoperative complications at every time point except postoperative day 2. Preoperative serum HMGB-1 concentration seems to be an important predictor of the postoperative clinical course. Transthoracic esophagectomy induces an increase in HMGB-1 in serum even in patients without complications. Postoperative serum HMGB-1 concentrations were higher in patients who developed complications, and may be a predictive marker for complications in this setting.

HMGB1 is a potent trigger of arthritis.

Rheumatoid arthritis is a chronic inflammatory disease characterized by synovial inflammation and structural damage of joints. Although the cause of rheumatoid arthritis (RA) remains unknown, the excessive production of proinflammatory cytokines such as tumour necrosis factor (TNF) and interleukin-1 (IL-1) by intra-articular macrophages occupies a critical pathogenic role in the development and progression of the disease. High mobility group box chromosomal protein 1 (HMGB1) is a recently identified mediator of interest in human and experimental arthritides. HMGB1 can either be actively secreted from macrophages or passively released from necrotic cells of all kinds. Activated macrophages and unprogrammed cell death caused by ischaemia or activated complement are all prominent features of chronic arthritis, contributing to the persistent synovial inflammation. HMGB1 is cytoplasmically and extracellularly overexpressed in inflammatory synovial tissue in human RA as well as experimental collagen-induced arthritis. Elevated levels of HMGB1 are also present in synovial fluid samples from RA patients. Synovial tissue from rats with experimental arthritis exhibits aberrant deposition of HMGB1 preceding the onset of clinical signs of arthritis, and the expression becomes prominent after the onset of clinical disease. The synovial levels of HMGB1 are comparable with those of TNF and IL-1beta at the peak of manifest disease. HMGB1-targeted intervention with either neutralizing antibodies or the antagonistic A box domain of HMGB1 ameliorates collagen-induced arthritis both in mice and rats, and inhibits the local overexpression of IL-1beta in the joints. It is thus conceivable that therapeutic HMGB1 blockade may contribute to future treatment of human chronic arthritis.