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 T 15.6 ng/mL [control subjects], P < 0.0001) and at day 3 (637.2 +/- 111.2 vs. 106.2 T 15.6 ng/mL [control subjects], P G 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 G 0.005 and P G 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 T 15.6 ng/mL, control subjects, P G 0.0001 and P G 0.05, respectively]). Remarkably, patients with sepsis due to pneumonia had the highest S100A12 levels (716.9 T 167.0 and 787.5 T 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 = j0.185, P = 0.19) or Sepsis-Related Organ Failure Assessment scores (r = j0.194, P = 0.17). Intravenous lipopolysaccharide injection in healthy humans elevated systemic S100A12 levels (peak levels at 3 h of 59.6 T 22.0 vs. 12.4 T 3.6 ng/mL; t = 0 h, P G 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 T 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.