LPS challenge in D-galactosamine-sensitized mice accounts for caspase-dependent fulminant hepatitis, not for septic shock

Experimental models of sepsis using endotoxin challenges, including studies with sensitized animals with D-galactosamine, have largely contributed to the basic rationale for innovative clinical trials in human septic shock, w hich have, to date, failed. The ability of these models to reproduce human disease has been highly discussed. We report here that the widely used D-ga lactosamine/LPS model does not account for septic shock. Treatment with YVA D-CMK, a potent tetrapeptide inhibitor of caspases of the interleukin (IL)- 1 beta converting enzyme (ICE) family, protects from LPS-induced liver apop tosis and mortality in D-galactosamine-sensitized mice when administered ei ther before or up to 2 h after the lethal challenge. This curative effect i s related to complete inhibition of caspase-3 activity in the liver, Howeve r, YVAD-CMK does not affect LPS-induced release of IL-1 beta and does not p rotect from a lethal dose of LPS in unsensitized mice. These experiments de monstrate the difference between these two widely recognized experimental m odels of sepsis. LPS toxicity in D-galactosamine-treated mice, leading to b locked gene transcription, results from tumor necrosis factor (TNF)-alpha-i nduced caspase-3-dependent liver injury; not from the systemic inflammatory response. These results provide evidence that inhibitors of the ICE caspas e family can prevent or even overcome the ongoing hepatic injury induced by TNF-alpha during sepsis, ischemia-reperfusion, or severe hepatitis.