Secretory leukocyte protease inhibitor, an inhibitor of neutrophil activation, is elevated in serum in human sepsis and experimental endotoxemia

Objectives: To document changes in serum secretory leukocyte protease inhibitor (SLPI) in human sepsis and in experimental endotoxemia in vivo. To compare changes in serum SLPI in human sepsis with changes in interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-alpha. To determine whether or not changes in SLPI correlate with the severity of multiple organ dysfunction syndrome as measured by the maximal multiple organ dysfunction score. Finally, because neutrophils have been implicated in tissue injury associated with organ dysfunction, to determine whether recombinant human SLPI blocks activation of isolated human neutrophils. Design. Case-control study and ex-vivo cellular assay. Setting: Surgical intensive care unit and clinical research center of university hospitals; laboratory of a medical school. Interventions: None. Measurements and Main Results: There was a significant dose-dependent elevation (50.2 +/- 4.0 ng/mL, p = .01) in plasma SLPI 12 hrs after administration of lipopolysaccharide to seven healthy adults (36.4 +/- 2.3 ng/mL). Further, serum concentrations of SLPI (132 +/- 15 ng/mL) were elevated in septic surgical patients compared with healthy controls (43 +/- 2 ng/mL, p < .01) and nonseptic surgical controls (69 +/- 10 ng/mL, p = .01). Serum SLPI concentrations correlated (r(2) = .71, p < .01) better with organ dysfunction as measured by maximal multiple organ dysfunction score than did serum IL-6 (r(2) = .49, p < .01), IL-10 (r(2) = .05, p = .22), or TNF-alpha (r(2) = .02, p = .44). We found that recombinant human SLPI in vitro inhibits TNF-alpha-induced hydrogen peroxide production by human neutrophils (ID50 = 1-2 mu g/mL). Conclusions: Serum SLPI is elevated in human sepsis and experimental endotoxemia. Maximal concentrations of serum SLPI correlate significantly with maximal multiple organ dysfunction scores in patients with sepsis. Secretory leukocyte protease inhibitor may function to limit ongoing neutrophil-mediated tissue injury associated with organ dysfunction.