PROTECTION OF MICE FROM ENDOTOXIC DEATH BY 2-METHYLTHIO-ATP

The lethal effects of endotoxin, a bacterial product shed into the blo od during bacteremia, are thought to be due to macrophage release of m ediators such as tumor necrosis factor alpha and interleukin 1. Althou gh much is known about the pathophysiology of endotoxemia, relatively little is known about the cellular signaling mechanisms that are invol ved. The data in this study suggest that extracellular adenine nucleot ides can influence the development of endotoxin shock. An adenine nucl eotide analog, 2-methylthio-ATP, inhibited the endotoxin-stimulated re lease of toxic mediators (i.e., tumor necrosis factor alpha and interl eukin 1), and it protected mice from endotoxin-induced death. These st udies suggest a fundamental and unusual role for adenine nucleotides o n endotoxin action, and they provide a potentially new therapeutic app roach for the control of the pathophysiology of Gram-negative septicem ia.