Ulinastatin, a human trypsin inhibitor, inhibits endotoxin-induced thromboxane B-2 production in human monocytes

Objectives: Ulinastatin has an inhibitory effect on certain cytokines produced from lipopolysaccharide (endotoxin)-stimulated human monocytes, However, the effects of ulinastatin on arachidonic acid metabolism in monocytes have not been determined, This study examined the effects of ulinastatin on the arachidonic acid metabolite, thromboxane B-2, in response to endotoxin-, phorbol 12-myristate 13-acetate-, or arachidonic acid-stimulated human peripheral blood monocytes. Design: Controlled, human laboratory investigation of monocyte function in vitro. Setting: Research facility of a health science university, Subjects: Five normal volunteers. Interventions: Mononuclear cells were separated from blood using Histopaque(R). Monocytes were stimulated with endotoxin (0.1 to 10 mu g/mL) or other stimulatory agents, which were added simultaneously with or without: ulinastatin (25 to 1000 U/mL), None of the compounds in this study altered the cell viability or adherent cellular protein content, Ulinastatin alone did not affect basal thromboxane B-2. Measurements and Main Results: Endotoxin induced dose-dependent increases in thromboxane B-2 production by the monocytes, Ulinastatin (100 U/mL) maximally decreased endotoxin (1.0 mu g/mL)-stimulated thromboxane B-2 production, which was not further suppressed with higher ulinastatin concentrations. Increases in thromboxane B-2, stimulated by phorbol myristic acid (10 nM) or arachidonic acid (16 mu M), were also suppressed by ulinastatin al 100 to 1000 U/mL. Conclusions: These results indicate that ulinastatin may nonspecifically but moderately down-regulate stimulated arachidonic acid metabolism in human monocytes, Therefore, the present results warrant further clinical studies to examine the beneficial effects of ulinastatin in the treatment of patients with sepsis syndrome.