CHLORPROMAZINE DOWN-REGULATES TUMOR-NECROSIS-FACTOR-ALPHA AND ATTENUATES EXPERIMENTAL MULTIPLE ORGAN DYSFUNCTION SYNDROME IN MICE

Objectives: Chlorpromazine is a known modulator of tumor necrosis fact or (TNF)-alpha production, TNF-alpha is thought to be a key mediator i n the development of the multiple organ dysfunction syndrome (MODS), W e investigated the effect of chlorpromazine on the development of zymo san-induced MODS in mice and on plasma TNF-alpha concentrations and pr oduction capacity of TNF-alpha by peritoneal cells. Design: prospectiv e, controlled laboratory study on zymosan induced generalized inflamma tion in mice. Setting: Animal research laboratory. Subjects: C57BL/6 m ice received daily doses (4 mg/kg body weight) of chlorpromazine, begi nning 2 days before or 5 days after zymosan administration. In additio nal groups, the daily chlorpromazine dose of 4 mg/kg started 5 days af ter zymosan was increased 2 days later to 8 or 16 mg/kg/day. Measureme nts and Main Results: The animals were monitored for survival, conditi on, body weight, and body temperature. Twelve days after zymosan was a dministered, all surviving animals were killed to obtain plasma, organ s, and peritoneal cells. Plasma concentrations of TNF-alpha and lipopo lysaccharide-stimulated production of TNF-alpha by peritoneal cells we re measured. Organ weights were recorded as an indicator for organ dam age. Although survival was not improved when the animals were treated with chlorpromazine, the chlorpromazine-treated survivors showed impro ved body weight and temperature when compared with the animals receivi ng zymosan only. Also, the organ weights and lung damage improved sign ificantly in the treated group, Chlorpromazine was most effective when started before zymosan administration, When administered afterward, c linical improvement declined with the dose. In all cases, circulating TNF-alpha and production of TNF-alpha by peritoneal macrophages were l owered toward control values. Conclusion: Chlorpromazine mitigates the development of zymosan-induced MODS, possibly by reducing macrophage TNF-alpha production.