Protection of mice from endotoxic death by 2-methylthio-ATP.
The lethal effects of endotoxin, a bacterial product shed into the blood during bacteremia, are thought to be due to macrophage release of mediators such as tumor necrosis factor alpha and interleukin 1. Although much is known about the pathophysiology of endotoxemia, relatively little is known about the cellular signaling mechanisms that are involved. The data in this study suggest that extracellular adenine nucleotides can influence the development of endotoxin shock. An adenine nucleotide analog, 2-methylthio-ATP, inhibited the endotoxin-stimulated release of toxic mediators (i.e., tumor necrosis factor alpha and interleukin 1), and it protected mice from endotoxin-induced death. These studies suggest a fundamental and unusual role for adenine nucleotides on endotoxin action, and they provide a potentially new therapeutic approach for the control of the pathophysiology of Gram-negative septicemia.
Department of Medical Microbiology, University of Wisconsin Medical School, Madison 53706.
R A
RA
Proctor
L C
LC
Denlinger
P S
PS
Leventhal
S K
SK
Daugherty
J W
JW
van de Loo
T
T
Tanke
G S
GS
Firestein
P J
PJ
Bertics
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D002462:Cell Membrane / Q000201:enzymology; D003643:Death; D004731:Endotoxins / Q000037:antagonists & inhibitors / Q000633:toxicity*; D004926:Escherichia coli; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D007700:Kinetics; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000633:toxicity*; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012772:Shock, Septic / Q000503:physiopathology / Q000517:prevention & control*; D013873:Thionucleotides / Q000494:pharmacology*
D004731:Endotoxins; D008070:Lipopolysaccharides; D013873:Thionucleotides; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D020558:GTP Phosphohydrolases; C008501:2-methylthio-ATP