Pharmacologic 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 beta) 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 chlorpromazine significantly improved survival. Chlorpromazine and pentoxifylline 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 Klebsiella pneumoniae-infected mice despite significantly lower circulating TNF-alpha concentrations in chlorpromazine- or pentoxifylline-treated animals. The three compounds decreased circulating TNF-alpha in Candida albicans-infected mice, but survival was not influenced. In neutropenic mice, chlorpromazine had no influence on candida in organs, but in normal mice, Candida counts in kidneys were higher in chlorpromazine-treated mice. Thus, inhibition of TNF-alpha production was of no benefit in K. pneumoniae infection and worsened outcome in C. albicans infection.
Department of Internal Medicine, University Hospital Nijmegen, Netherlands.
M G
MG
Netea
W L
WL
Blok
B J
BJ
Kullberg
M
M
Bemelmans
M T
MT
Vogels
W A
WA
Buurman
J W
JW
van der Meer
D000818:Animals; D002177:Candidiasis / Q000188:drug therapy; D002746:Chlorpromazine / Q000627:therapeutic use*; D005260:Female; D007375:Interleukin-1 / Q000097:blood; D007668:Kidney / Q000382:microbiology; D007710:Klebsiella Infections / Q000188:drug therapy; D007711:Klebsiella pneumoniae / Q000472:pathogenicity; D051379:Mice; D009503:Neutropenia / Q000378:metabolism; D010431:Pentoxifylline / Q000627:therapeutic use*; D018124:Receptors, Tumor Necrosis Factor / Q000032:analysis; D012772:Shock, Septic / Q000188:drug therapy* / Q000401:mortality; D013792:Thalidomide / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000037:antagonists & inhibitors*
D007375:Interleukin-1; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D013792:Thalidomide; D010431:Pentoxifylline; D002746:Chlorpromazine