S100A12 and soluble receptor for advanced glycation end products levels during human severe sepsis.

S100A12 is highly expressed, and serum levels correlate with individual disease activity in patients with inflammatory diseases. We here sought to determine the extent of S100A12 release and its soluble high-affinity receptor for advanced glycation end products (sRAGE) in patients with severe sepsis stratified to the three most common infectious sources (lungs, abdomen, and urinary tract) and to determine S100A12 and sRAGE concentrations at the site of infection during peritonitis. Two patient populations were studied: (a) 51 patients with sepsis due to (i) peritonitis (n = 12), (ii) pneumonia (n = 29), or (iii) urinary tract infection (n = 10); and (b) 17 patients with peritonitis. In addition, eight healthy humans were studied after intravenous injection of lipopolysaccharide (4 ng/kg). Compared with healthy volunteers, patients with severe sepsis displayed increased circulating S100A12 concentrations at day 0 (591.2 ± 101.0 vs. 106.2 ± 15.6 ng/mL [control subjects], P < 0.0001) and at day 3 (637.2 ± 111.2 vs. 106.2 ± 15.6 ng/mL [control subjects], P < 0.0001). All three severe sepsis subgroups had elevated serum S100A12 concentrations at both time points (sepsis due to [i] peritonitis [393.5 ± 89.9 at day 0 and 337.9 ± 97.2 at day 3 vs. 106.2 ± 15.6 ng/mL, control subjects, P < 0.005 and P < 0.05, respectively]; [ii] pneumonia [716.9 ± 167.0 at day 0 and 787.5 ± 164.7 at day 3 vs. 106.2 ± 15.6 ng/mL, control subjects, both P < 0.0001]; and [iii] urinary tract infection [464.2 ± 115.6 at day 0 and 545.6 ± 254.9 at day 3 vs. 106.2 ± 15.6 ng/mL, control subjects, P < 0.0001 and P < 0.05, respectively]). Remarkably, patients with sepsis due to pneumonia had the highest S100A12 levels (716.9 ± 167.0 and 787.5 ± 164.7 ng/mL at days 0 and 3, respectively). S100A12 levels were not correlated to either Acute Physiology and Chronic Health Evaluation II scores (r = -0.185, P = 0.19) or Sepsis-Related Organ Failure Assessment scores (r = -0.194, P = 0.17). Intravenous lipopolysaccharide injection in healthy humans elevated systemic S100A12 levels (peak levels at 3 h of 59.6 ± 22.0 vs. 12.4 ± 3.6 ng/mL; t = 0 h, P < 0.005). In contrast to S100A12, sRAGE concentrations did not change during severe sepsis or human endotoxemia. During peritonitis, S100A12 concentrations in abdominal fluid (12945.8 ± 4142.1 ng/mL) were more than 100-fold higher than in concurrently obtained plasma (121.2 ± 80.4 ng/mL, P < 0.0005), whereas sRAGE levels in abdominal fluid (148.8 ± 36.0 pg/mL) were lower than those in plasma (648.7 ± 145.6 pg/mL, P < 0.005) and did not increase. In conclusion, in severe sepsis, S100A12 is released systemically irrespective of the primary source of infection. During abdominal sepsis, S100A12 release likely predominantly occurs at the site of infection. Concentrations of its high-affinity sRAGE do not change during infection or human endotoxemia.

Expression and role of myeloid-related protein-14 in clinical and experimental sepsis.

RATIONALE: Myeloid-related protein-8 (MRP8) and MRP14 can form heterodimers that elicit a variety of inflammatory responses. We showed that MRP8/14 is a ligand for Toll-like receptor-4, and that mice deficient in MRP8/14 are protected against endotoxic shock-induced lethality. OBJECTIVES: To determine (1) the extent of MRP8/14 release in patients with sepsis and/or peritonitis and in healthy humans exposed to LPS and (2) the contribution of MRP8/14 to the host response in murine abdominal sepsis. METHODS: MRP8/14 was measured in 51 patients with severe sepsis, 8 subjects after intravenous injection of LPS, and 17 patients with peritonitis. Host responses to sepsis were compared in mrp14 gene-deficient (and thereby MRP8/14-deficient) and wild-type mice intraperitoneally injected with Escherichia coli. MEASUREMENTS AND MAIN RESULTS: Patients with sepsis displayed elevated circulating MRP8/14 concentrations on both Days 0 and 3, and LPS injection resulted in systemic MRP8/14 release in healthy humans. In patients with peritonitis, MRP8/14 levels in abdominal fluid were more than 15-fold higher than in plasma. MRP14-deficient mice displayed improved defense against E. coli abdominal sepsis in an early phase, as indicated by diminished dissemination of the bacteria at 6 hours. In addition, MRP14-deficient mice demonstrated decreased systemic inflammation, as reflected by lower cytokine plasma concentrations, and less severe liver damage. CONCLUSIONS: Human sepsis and endotoxemia are associated with enhanced release of MRP8/14. In abdominal sepsis, MRP8/14 likely occurs primarily at the site of the infection, facilitating bacterial dissemination at an early phase and liver injury.

Systemic and local high mobility group box 1 concentrations during severe infection.

OBJECTIVE: High mobility group box 1 (HMGB1) has been implicated as a late mediator in 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 units and one clinical research unit. PATIENTS AND SUBJECTS: Three patient populations were studied: 1) 51 patients with sepsis due to pneumonia (n = 29), peritonitis (n = 12), or urinary tract infection (n = 10); 2) 17 patients with peritonitis; and 3) four patients with community-acquired pneumonia. In addition, eight healthy subjects 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 days 0 and 3 after inclusion. Patients with sepsis due to peritonitis had elevated HMGB1 levels at day 0 but not at day 3, whereas urinary tract infection was associated with a delayed HMGB1 response, with elevated levels only at day 3. HMGB1 concentrations did not differ between survivors and nonsurvivors and were not correlated to either disease severity or concurrently measured cytokine levels. In line with these observations, although intravenous lipopolysaccharide injection clearly elevated plasma cytokine levels, HMGB1 remained undetectable. In patients with peritonitis, HMGB1 concentrations in abdominal fluid were more than ten-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.