Ulinastatin, a human trypsin inhibitor, inhibits endotoxin-induced thromboxane B2 production in human monocytes.
OBJECTIVE
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 B2, in response to endotoxin-, phorbol 12-myristate 13-acetate-, or arachidonic acid-stimulated human peripheral blood monocytes.


METHODS
Controlled, human laboratory investigation of monocyte function in vitro.


METHODS
Research facility of a health science university.


METHODS
Five normal volunteers.


METHODS
Mononuclear cells were separated from blood using Histopaque. Monocytes were stimulated with endotoxin (0.1 to 10 micrograms/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 of adherent cellular protein content. Ulinastatin alone did not affect basal thromboxane B2.


RESULTS
Endotoxin induced dose-dependent increases in thromboxane B2 production by the monocytes. Ulinastatin (100 U/mL) maximally decreased endotoxin (1.0 microgram/mL)-stimulated thromboxane B2 production, which was not further suppressed with higher ulinastatin concentrations. Increases in thromboxane B2, stimulated by phorbol myristic acid (10 nM) or arachidonic acid (16 microM), were also suppressed by ulinastatin at 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.
Aibiki
M
M
Department of Anesthesiology, Kagawa Medical University, Japan.
Cook
J A
JA
D016718:Arachidonic Acid / Q000378:metabolism; D004306:Dose-Response Relationship, Immunologic; D004353:Drug Evaluation, Preclinical; D006023:Glycoproteins / Q000494:pharmacology*; D006801:Humans; D008070:Lipopolysaccharides; D008213:Lymphocyte Activation; D009000:Monocytes / Q000187:drug effects*; D018746:Systemic Inflammatory Response Syndrome / Q000188:drug therapy / Q000276:immunology; D013755:Tetradecanoylphorbol Acetate; D013929:Thromboxane B2 / Q000378:metabolism*; D014361:Trypsin Inhibitors / Q000494:pharmacology*
D006023:Glycoproteins; D008070:Lipopolysaccharides; D014361:Trypsin Inhibitors; D016718:Arachidonic Acid; D013929:Thromboxane B2; D013755:Tetradecanoylphorbol Acetate; C028665:urinastatin