PHARMACOLOGICAL INHIBITORS OF TUMOR-NECROSIS-FACTOR PRODUCTION EXERT DIFFERENTIAL-EFFECTS IN LETHAL ENDOTOXEMIA AND IN INFECTION WITH LIVE MICROORGANISMS IN MICE

Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 b eta) are principal mediators of septic shock; inhibition of TNF-alpha production may ameliorate outcome in severe infections. Pentoxifylline , chlorpromazine, and thalidomide inhibit TNF-alpha production. Their effects were tested in lethal endotoxemia in sensitized mice. Only chl orpromazine significantly improved survival. Chlorpromazine and pentox ifylline significantly reduced postendotoxin circulating TNF-alpha, by 89% and 76%, respectively. Chlorpromazine also significantly reduced IL-1 beta and soluble TNF receptor-P75. No drug improved survival in K lebsiella pneumoniae-infected mice despite significantly lower circula ting TNF-alpha concentrations in chlorpromazine- or pentoxifylline-tre ated animals. The three compounds decreased circulating TNF-alpha in C andida albicans-infected mice, but survival was not influenced. In neu tropenic mice, chlorpromazine had no influence on candidae in organs, but in normal mice, Candida counts in kidneys were higher in chlorprom azine-treated mice. Thus, inhibition of TNF-alpha production was of no benefit in K. pneumoniae infection and worsened outcome in C. albican s infection.