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RAGE and the innate immune response in infection and inflammation
van Zoelen, M.A.D.
Publication date 2009
Link to publication
Citation for published version (APA):
van Zoelen, M. A. D. (2009). RAGE and the innate immune response in infection and inflammation.
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8
Systemic and local HMGB1
concentrations during severe
infection
Critical Care Medicine, 2007
Marieke A.D. van Zoelen1,2, Pierre-François Laterre3, Suzanne Q. van Veen4,
Jan W. van Till4, Xavier Wittebole3, Paul Bresser5, Michael W. Tanck6,
Thierry Dugernier7, Akitoshi Ishizaka8, Marja A. Boermeester4 and Tom van der Poll1,2
1Center for Infection and Immunity Amsterdam (CINIMA), 2Center for Experimental and Molecular Medicine and
Departments of 4Surgery, 5Pulmonology and 6Clinical Epidemiology, Biostatistics and Bioinformatics; Academic
Medical Center, University of Amsterdam, Amsterdam, The Netherlands
3 Department of Critical Care Medicine, St. Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium 7Department of Critical Care Medicine, Cliniques St. Pierre, Ottignies, Belgium
8Department of Medicine, Keio University, School of Medicine, Tokyo, Japan
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Abstract
Objective
High mobility group box 1 (HMGB1) has been implicated as a late mediatorin sepsis. We here sought to determine the extent of HMGB1 release in patients with sepsis stratified to the three most common infectious sources and to determine HMGB1 concentrations at the site of infection during peritonitis or pneumonia.
Design Observational studies in patients and healthy humans challenged with
lipopolysaccharide.Setting Three intensive care and one clinical research units.
Patients and Subjects
Three patient populations were studied: (i) 51 patients withsepsis due to pneumonia (29), peritonitis (12) or urinary tract infection (UTI) (10), (ii) 17 patients with peritonitis and (iii) 4 patients with community-acquired pneumonia. In addition, 8 healthy humans were studied after intravenous injection of lipopolysaccharide (4 ng/kg).
Interventions One population of healthy volunteers received lipopolysaccharide
intravenously.Measurements and Main Results Patients with severe sepsis due to pneumonia
displayed elevated circulating HMGB1 concentrations at both day 0 and 3 after inclusion. Patients with sepsis due to peritonitis had elevated HMGB1 levels at day 0, but not at day 3, whereas UTI was associated with a delayed HMGB1 response with elevated levels only at day 3. HMGB1 concentrations did not differ between survivors and non-survivors and were not correlated to either disease severity or concurrently measured cytokine levels. In line, although intravenous lipopolysaccharide injection clearly elevated plasma cytokine levels, HMGB1 remained undetectable. In patients with peritonitis, HMGB1 concentrations in abdominal fluid were >10-fold higher than in concurrently obtained plasma. In pneumonia patients, HMGB1 levels were higher in bronchoalveolar lavage fluid obtained from the site of infection than in lavage fluid from healthy controls.Conclusions In severe sepsis the kinetics of HMGB1 release may differ depending on
the primary source of infection. In patients with severe infection, HMGB1 release may predominantly occur at the site of infection.Introduction
Sepsis is the second leading cause of death in noncoronary intensive care units and the 10th leading cause of death overall (1, 2). Sepsis afflicts approximately 750,000 patients in the United States each year and - despite modern advances in the care of the critically ill - has been associated with mortality rates of 20%-50%. In sepsis, the lung is the primary source of infection (35-54%), followed by the abdomen (20-28%) and the urinary tract (8-13%) (3-5).
Sepsis is associated with the systemic activation of multiple inflammatory pathways. In earlier years much attention has been focused on the role of proinflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-1 in the pathogenesis of sepsis and the organ failure that accompanies this syndrome (6, 7). Characteristically, these cytokine mediators have a short circulating half-life and their release primarily occurs early after the exposure to an infectious challenge. In line, neutralization of endogenous TNF-α or IL-1 only confers protection against lethality during experimental sepsis (or systemic inflammatory response syndrome) when administered prophylactically or very early after the infusion of bacteria (or bacterial products). Several years ago, Wang et al. identified high mobility group box 1 (HMGB1) as a possible late mediator of sepsis (8). Unlike TNF-α and IL-1β, HMGB1 release occurred late after injection of lipopolysaccharide (LPS) into mice, starting only after 8 hours, and elevated circulating HMGB1 remained detectable up to 36 hours thereafter (8). Similarly, experimental abdominal sepsis induced by cecal ligation and puncture was associated with a late (after 18 hours) and sustained (more than 72 hours) release of HMGB1 in the circulation (9). Of importance, death of these animals paralleled the accumulation of HMGB1 in their circulation and delayed administration of neutralizing anti-HMGB1 antibodies conferred protection against lethality caused by high dose LPS administration or cecal ligation and puncture in mice (8-10) and in rats (11). Clinical observational studies have further implicated HMGB1 as a late mediator of sepsis: three investigations have reported elevated serum/plasma HMGB1 concentrations in patients with severe sepsis (8, 12, 13).
Recently, high HMGB1 concentrations were found in the pulmonary epithelial lining fluid of patients with sepsis and acute lung injury, suggesting that this mediator is present at the site of local tissue injury (13). In the present study we sought to determine the extent of systemic HMGB1 release in patients with severe sepsis stratified to the three most common primary sources of infection (lung, abdomen and urinary tract) and to examine local HMGB1 levels, at the site of the infection, in patients with peritonitis and pneumonia.
Materials and Methods
Patients and design
All studies were approved by the scientific and ethics committees of the Academic Medical Center (Amsterdam, the Netherlands), the St. Luke University Hospital and the St. Pierre’s Hospital (both in Brussels, Belgium). Written informed consent was obtained from all subjects or their relatives. The study included three patient populations: (i) 51 patients with severe sepsis, defined as a known or suspected infection plus a systemic inflammatory response syndrome and failure of at least one organ (14); these patients were admitted to the intensive care unit of either St. Luke University Hospital or St. Pierre’s Hospital at the day the diagnosis of severe sepsis was made and serum was obtained on inclusion (“day 0”) and at 3 days thereafter (“day 3”). Low-dose steroids were given to 35 patients (69%) with refractory septic shock, i.e. only to patients requiring vasopressors
for a prolonged period of a minimum of 6 hours. They were given at a dose of 50 mg every 8 hours, until vasopressors could be weaned but no longer than 7 days and then tapered within 2-3 days. 31 healthy subjects served as controls; (ii) 17 peritonitis patients admitted to the surgical ward of the Academic Medical Center; these patients were part of a previous study examining the impact of peritonitis on coagulation and fibrinolysis (15). They required emergency laparotomy because of peritonitis caused by perforation or infection of a visceral organ, by ischemia/necrosis of part of the gastrointestinal tract or by postoperative peritoneal infection. Abdominal fluid was aspirated with a syringe from an abdominal drain in cavum Douglasi. EDTA anticoagulated blood and abdominal fluid samples were taken at index laparotomy for peritonitis (t = 0) and after 1, 2 and 3 days. Blood and abdominal fluid were centrifuged at 1200 x g and 650 x g, respectively for 10 minutes at 4° C; (iii) four spontaneously breathing patients with unilateral community-aquired pneumonia; these patients were previously described in detail (16). Briefly, they fulfilled the following criteria: fever (temperature > 37.7 °C), a chest radiograph within 2 days after admission suspect for a new unilateral infiltrate, no antibiotic pretreatment and arterial partial pressure of oxygen > 7.5 kilopascals while breathing room air. Ten healthy volunteers not taking any medication served as control subjects. Broncholaveolar lavage was performed in a standardized fashion, according to the guidelines of the American Thoracic Society, by use of a flexible fiberoptic video-bronchoscope as described (16). In addition to these three patient populations, eight healthy males (22.6 ± 0.6 years) were studied after intravenous injection of lipopolysaccharide (Escherichia coli LPS, lot G,
United States Pharmacopeial Convention, Rockville, MD) at a dose of 4 ng/kg. In these subjects EDTA anticoagulated blood was obtained before and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 24 hours after challenge.
Measurements and assays
Data were collected prospectively from patient records, patient data management system (at the intensive care unit) and hospital information system. The following variables were collected when appropriate: date of birth, gender, APACHE-II and sepsis-related organ failure assessment (SOFA) scores, presence of septic shock, of organ dysfunction (both defined according to the consensus published in Crit Care Med 1992 (17)) and of coagulopathy, use of steroids, length of intensive care stay and of hospital stay, blood culture results, date of death and etiology of peritonitis. HMGB1 was measured by ELISA with the use of monoclonal antibodies to HMGB1 and with standardization to a curve of recombinant human HMGB1 as described previously (18, 19). Briefly, polystyrene microtiter plates were coated with monoclonal anti-calf HMGB1 antibody. Wells were incubated with bovine serum albumin, washed and the calibrator and samples were added to the wells. After washing, another anti-human HMGB1 peroxidase-conjugated monoclonal antibody (a synthetic peptide was used as immunogen) was added to each well. After another washing step, the luminescence reagent was added to the wells. The luminescence was measured using a microplate luminescence reader. Recovery, calculated from data (n = 10) at several concentrations of purified human HMGB1 added to pooled serum as the ratio of the observed concentration to the expected concentration multiplied by 100%, ranged from 92% to 111% in the HMGB1 ELISA assay (19). The detection limit was 0.3 ng/ml and the coefficient of variation < 3%. Tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-8, IL-10 and IL-12p70 were determined using a cytometric beads array (CBA) multiplex assay (BD Biosciences, San Jose, CA). Detection limit was 2.5 pg/ml for all 6 cytokines.
Statistical analysis
Data are presented as mean ± SEM, median and 25-75% interquartile ranges (IQRs) or number (percentage) when appropriate. Differences between sepsis groups and between abdominal fluid and plasma were performed with non-parametric repeated measures ANOVA or Kruskall-Wallis test. Differences between time points within groups were compared using the Wilcoxon signed-rank test. HMGB1 levels between survivors and non-survivors were compared with a Mann Whitney U test. Correlations were calculated using Spearman’s rho test. p ≤ .05 was considered statistically significant. Statistical analysis
Results
Sepsis results in elevated serum HMGB1 levels irrespective of the source
of the infection
The demographic and clinical characteristics of patients with severe sepsis are presented in Table 1. In total 51 patients were included with an overall in-hospital mortality of 45%.
Table 1. Characteristics of patients with severe sepsis, stratified to the source of infection Patients with severe sepsis Patients with sepsis due to Peritonitis Patients with sepsis due to Pneumonia Patients with sepsis due to UTI Characteristic n = 51 n = 12 (24) n = 29 (57) n = 10 (20) Age, years 68 ± 1.6 63 ± 4.0 69 ± 1.9 69 ± 3.6 Male sex 31 (61) 9 (75) 16 (55) 6 (60) APACHE-II score 27 ± 1.1 27 ± 1.9 26 ± 1.5 29 ± 2.6 SOFA-score 10 ± 0.6 10 ± 1.1 9 ± 0.9 11 ± 1.7 Shocka 35 (69) 8 (67) 21 (72) 6 (60) Respiratory failurea 32 (63) 2 (17) 25 (86) 5 (50) Renal failurea 25 (49) 4 (33) 14 (48) 7 (70) Metabolic acidosisa 20 (39) 6 (50) 8 (28) 6 (60) Thrombocytopeniaa 17 (33) 6 (50) 5 (17) 6 (60) INR 1.6 ± 0.1 2.4 ± 0.5 1.3 ± 0.1 1.8 ± 0.3 Use of steroids 25 (56) 8 (67) 13 (45) 4 (40)
ICU stay, days 10 (4-25) 15 (7-29) 10 (4-22) 8 (2-14)
Hospital stay, days 23 (12-41) 30 (13-49) 20 (12-36) 31 (14-52)
Pos. blood culture 23 (45) 6 (50) 11 (38) 6 (60)
Mortality 23 (45) 8 (67) 12 (41) 3 (30)
UTI, urinary tract infection; APACHE, acute physiology and chronic health evaluation; SOFA, sepsis-related organ failure asessment; INR,
International Normalized Ratio; ICU, intensive care unit.
Data are mean ± SEM, median (25%-75% interquartile range) or no. (%) when appropriate.
The primary source of infection was the lung in 29 patients (52%), the abdomen in 12 patients (24%) and the urinary tract in 10 patients (20%). When compared with healthy controls, sepsis patients demonstrated elevated serum HMGB1 concentrations both on admission (day 0) and at day 3 (Fig. 1A, both p < .005).
Figure 1. Serum HMGB1 levels in patients with severe sepsis. HMGB1 concentrations in serum
from patients with severe sepsis (all patients, panel A, n = 51) and subgroups of sepsis patients with different infectious sources; abdomen (peritonitis, panel B, n = 12), lungs (pneumonia, panel C, n = 29) and urinary tract (UTI, panel D, n = 10) and from healthy controls (n = 31). UTI = urinary tract infection. Data are mean ± SEM. *(**) p < .0(00)5 vs. healthy controls.
Ta ble 2. C yt ok in e le ve ls of pa tie nt s wi th se ve re se psi s Pa tie nt s wi th se ve re se psi s (a ll) Pa tie nt s wi th se psi s d ue t o P eri to ni ti s Pa tie nt s wi th se psi s d ue t o Pn eu m onia Pa tie nt s wi th se psi s d ue t o U TI n = 51 n = 12 n = 29 n = 10 Da y 0 Da y 3 Da y 0 Da y 3 Da y 0 Da y 3 Da y 0 Da y 3 pg/ ml IL-6 1514 ± 382 *** 1032 ± 274 ***, ## 701 ± 274 *** 1096 ± 733 *** 1423 ± 495 *** 1083 ± 661 ***, # 2050 ± 1255 *** 2075 ± 1982 ** IL -8 1198 ± 367 *** 574 ± 292 ***, ## 447 ± 212 *** 213 ± 96 ** 1111 ± 528 *** 774 ± 526 *, # 1237 ± 849 *** 866 ± 793 * IL -10 145 ± 52 *** 61 ± 27 ***, ## 94 ± 55 *** 29 ± 17 ***, # 132 ± 75 *** 46 ± 29 *** 146 ± 105 *** 196 ± 182 *** A ll c yt ok ines w er e mea su re d i n se ru m a t t he d ay of i ncl usio n ( da y 0) a nd 3 d ays t he re aft er ( da y 3). D at a a re mea n ± S EM. U T I, u rin ar y t ract i nfe ct io n. C yt ok ine le vels i n hea lth y c on tr ols w er e lo w o r b elo w det ect io n l im it. * p < .05, ** p < .01, *** p < .005 v s. hea lth y c on tr ols # p < .05, ## p < .01 v s. d ay 0
Of the subgroups of sepsis patients with different infectious sources, peritonitis and pneumonia patients displayed elevated serum HMGB1 concentrations at day 0 and day 3, although in the peritonitis subgroup the difference with healthy controls at day 3 did not reach statistical significance (p = .106) possibly related to a large interindividual variation.
Patients with sepsis due to urinary tract infection did not have elevated serum HMGB1 levels at day 0, whereas at day 3 circulating HMGB1 concentrations tended to be higher than in healthy controls (p = .054). There was no apparent correlation between serum
HMGB1 levels and the severity of disease: serum HMGB1 did not correlate with either APACHE II scores (r = -0.254, p = .080) or SOFA scores (r = -0.225, p = .120). In addition,
serum HMGB1 concentrations did not differ between survivors and non-survivors (7.2 ± 3.9 ng/ml and 3.0 ± 1.0 ng/ml, respectively, p = .710). HMGB1 serum levels on day 3 did
not differ between patients who used low-dose steroids and patients who did not (data not shown). To investigate whether serum HMGB1 levels are correlated to circulating cytokine levels in patients with severe sepsis, we measured the serum concentrations of TNF-α, IL-1β, IL-6, IL-8, IL-10 and IL-12p70 at day 0 and 3 (Table 2). TNF-α, IL-1β and IL-12p70 levels were very low or undetectable in patients and not significantly different from healthy controls (data not shown). Serum IL-6, IL-8 and IL-10 concentrations were elevated in sepsis patients at both day 0 and day 3, irrespective of the primary source of infection. However, the levels of none of these cytokines demonstrated a correlation with concurrently measured HMGB1 concentrations (data not shown). To further examine a possible relationship between systemic cytokine release and the appearance of HMGB1 in the circulation, we measured cytokine and HMGB1 levels in eight healthy humans intravenously injected with LPS. Whereas LPS induced profound increases in circulating TNF-α, IL-6, IL-8 and IL-10 concentrations (Fig. 2), HMGB1 remained undetectable up to 24 hours after LPS injection (data not shown). Together, these data suggest that sepsis results in a sustained elevation of serum HMGB1 levels irrespective of the source of the infection and that this response is not related to the severity of disease or systemic activation of the cytokine network.
Peritonitis and pneumonia are associated with local HMGB1 release
Next we wished to investigate whether HMGB1 release occurs at the site of infection. For this we measured HMGB1 in abdominal fluid of patients with peritonitis (n = 17) and in bronchoalveolar lavage fluid of patients with pneumonia (n = 4). The demographic and clinical characteristics of peritonitis patients are presented in Table 3. Patients with pneumonia were described previously (16).None of these patients needed to be intubated and none died. Remarkably, both infections were accompanied by high local HMGB1 concentrations. In patients with peritonitis, HMGB1 concentrations in abdominal fluid were more than 10-fold higher than in concurrently obtained plasma and these local levels remained elevated throughout the 3-day sampling period (Fig. 3A). In patientsFigure 2. LPS induced cytokine release in healthy humans. Plasma cytokine concentrations in
healthy volunteers (n = 8) intravenously challenged with LPS (4 ng/kg, t = 0 hrs). Data are mean ± SEM of TNF-α (A), IL-6 (B), IL-8 (C) and IL-10 (D).
with pneumonia, HMGB1 concentrations were higher in bronchoalveolar lavage fluid harvested from the infected lung than in lavage fluid obtained from healthy controls (Fig. 3B, p < .005). Local HMGB1 levels did not correlate with local cytokine levels (data not
shown).
Discussion
HMGB1 has been widely studied as a nuclear protein that binds DNA, stabilizes nucleosomes and facilitates gene transcription (20). The re-discovery of HMGB1 as an extracellular protein with cytokine-like activity and its pivotal role as a late mediator of experimental sepsis have prompted clinical studies to characterize the release of HMGB1 in patients with sepsis. We here demonstrate that the levels of HMGB1 are elevated in the circulation of patients with sepsis of various origins. Of these, patients with urinary
Table 3. Characteristics of patients with peritonitis Patients with Peritonitis Characteristic n = 17 Age, years 61 ± 4.0 Male sex 9 (53) APACHE-II score 14 ± 0.8 SOFA score 7 ± 1.4
ICU stay, days 5 (1-20)
Hospital stay, days 30 (17-53)
28-day Mortality 0 (0) Etiology of peritonitis Perforation 8 (47) Anastomotic leakage 7 (41) Abscess 1 (6) Other 1 (6)
APACHE, acute physiology anc chronic health evaluation; SOFA, sepsis-related organ failure asessment; ICU, intensive care unit. Data are mean ± SEM, median (25%-75% interquartile range) or no. (%).
tract infection seemed to have a delayed appearance of HMGB1 in the circulation when compared with patients with pneumonia or peritonitis. Importantly, patients with peritonitis demonstrated strongly elevated HMGB1 concentrations in abdominal fluid, whereas patients with pneumonia displayed elevated levels in BALF obtained from the infected site. These data show for the first time that in patients with severe infection, HMGB1 release occurs at the primary site of infection.
HMGB1 is a 215 amino acid protein that is highly conserved among species. HMGB1 can be secreted by a variety of cell types including monocytes, macrophages, endothelial cells, enterocytes, pituicytes, dendritic cells and natural killer cells (20). HMGB1 can enhance the production of proinflammatory cytokines by monocytes, activate endothelial cells and cause epithelial-cell barrier leak in the gut (21-23). In animal models of sepsis, the kinetics of HMGB1 release in vivo is delayed and more sustained when compared with
the secretion of proinflammatory cytokines like TNF-α, IL-1β and IL-6 (9, 10). In line, various interventions that inhibit HMGB1 activity or production, such as anti-HMGB1 antibodies - the A-box segment of HMGB1 –, ethyl pyruvate and nicotine reduced sepsis
Figure 3. Local HMGB1 concentrations during infection. HMGB1 concentrations in abdominal
fluid and plasma from patients with peritonitis (A, n = 17) and in bronchoalveolar lavage fluid from patients with pneumonia (B, n = 4). 10 healthy controls served as controls for the patients with pneumonia. Data are mean ± SEM. ** p < .005 vs. healthy controls, *** p < .001 abdominal fluid vs. plasma.
and/or LPS lethality even if treatment was postponed for many hours up to one day (9-11, 24, 25). Notably, recent investigations have implicated apoptosis of immune cells as a crucial event in the pathogenesis of sepsis, playing a major role in immunosuppression and lethality (26). Interestingly, prevention of lymphocyte apoptosis improved survival after cecal ligation and puncture (27), whereas anti-HMGB1 treatment reduced lethality in the same model without influencing apoptosis (10), indicating that HMGB1 production is downstream of apoptosis in the final common pathway to organ damage in severe sepsis. Together these data strongly suggest that the release of HMGB1 is a relatively late event in sepsis that significantly contributes to an adverse outcome.
Our findings of elevated serum concentrations of HMBG1 in patients with severe sepsis of various origins confirm and extend previous studies. In their original paper describing HMGB1 as a secreted product mediating LPS lethality, Wang et al. reported elevated serum HMGB1 levels in 25 critically ill patients with severe sepsis; measurements were performed only on admission and patients who died had higher HMGB1 concentrations than those who survived (8). Another more recent study examined the kinetics of HMGB1 release in 64 patients with sepsis (12). In line with our current investigation, circulating HMGB1 concentrations remained elevated in most patients for several days after admission; moreover, consistent with our data no correlation was found between HMGB1 levels and severity of disease (12). A third study reported elevated circulating HMGB1 levels in patients with disseminated intravascular coagulation with varying underlying conditions (28). We here show that patients with sepsis resulting from either pneumonia or peritonitis have elevated serum HMGB1 concentrations on admission and three days later, although in abdominal sepsis patients HMGB1 was not statistically significantly increased anymore, possibly due to a large interindividual variation. In patients with sepsis resulting from the urinary tract, serum HMGB1 was not elevated on admission; in these patients HMGB1 was increased at day 3. Considering that HMGB1 concentrations were similar in survivors and non-survivors and that they were not correlated with APACHE-II or SOFA scores, these differences can not be readily explained by differences in severity of disease. Additional research is warranted to further explore the potential differences in the kinetics of HMGB1 release in patients with sepsis depending on the primary source of the infection. The absence of a correlation between serum HMGB1 and concurrently measured cytokine concentrations suggest that these host responses are not linked. To further investigate this issue we measured the levels of these cytokines and HMGB1 at multiple time points after intravenous injection of LPS into healthy humans. In accordance with the absence of a correlation between circulation levels of cytokines and HMGB1 in sepsis patients, a bolus intravenous injection of LPS did not induce detectable plasma levels of HMGB1 although this challenge elicited profound rises in the levels of TNF-α, IL-6, IL-8 and IL-10.
We here measured immunoreactive HMGB1 which may differ from biologically active HMGB1. It is still unknown whether the currently used HMGB1 assays used by our and other laboratories detect biologically active HMGB1 (29). It has been suggested that the biological activities of HMGB1 could vary depending on its post-translational modifications (30); HMGB1 released passively from necrotic cells is molecularly different from the HMGB1 actively secreted by e.g. inflammatory cells because the latter event
requires acetylation (31). The observed elevated systemic and local HMGB1 levels in patients from our studies could be due to this passive as well as active release of HMGB1. Just like currently used (and published) HMGB1 detection methods by other laboratories, our HMGB1 ELISA does not distinguish between these (and possible other) different
forms of HMGB1. Further experiments are needed to 1) investigate the biological activity of (different forms of ) HMGB1 and 2) develop HMGB1 ELISA assays which distinguish between these (possibly also functionally) different forms of HMGB1.
To the best of our knowledge local HMGB1 levels at sites of infection have not been reported in patients before. We here report for the first time that both patients with peritonitis and patients with pneumonia displayed elevated levels in fluid obtained from the abdomen and bronchoalveolar space, respectively. In patients with peritonitis, local HMGB1 levels were approximately 10-fold higher than in concurrently obtained plasma. Local release of HMGB1 in the bronchoalveolar compartment has been implicated in the pathogenesis of acute lung injury, i.e. patients and animals with acute lung injury had
elevated pulmonary HMGB1 concentrations and inhibition of HMGB1 attenuated lung inflammation and damage (13, 32-34). It remains to be established to what extent local HMGB1 release contributes to circulating HMGB1 in sepsis and to what extent it contributes to damage at the site of infection and distant organs.
Conclusions
The role of HMGB1 as a late mediator of sepsis has been established by a number of studies in experimental animals. We here expand previous studies on HMGB1 levels in patients with sepsis (8, 12, 13), showing that HMGB1 release occurs in sepsis irrespective of the primary source of infection, although in urinary tract infection HMGB1 secretion into the circulation may be delayed when compared to pneumonia and peritonitis. In patients were severe infection HMGB1 release may predominantly occur at the site of infection.
Acknowledgements
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