Cefepime may be an effective alternative to Imipenem. Failure to achieve SBP response at 48 hours is the strongest predictor of treatment failure. Disclosures: The following people have nothing to disclose: Ankur Jindal, Shiv K. Sarin “
“The sensitization

of hepatocytes to cell death from tumor necrosis factor α (TNFα) underlies many forms of hepatic injury, including that from toxins. Critical for hepatocyte resistance to TNFα toxicity is activation of nuclear factor κB (NF-κB) signaling, which prevents TNFα-induced death by the up-regulation of protective proteins. To further define the mechanisms of hepatocyte sensitization to TNFα killing, immunoblot analysis comparing livers from mice treated GS-1101 purchase R788 chemical structure with lipopolysaccharide (LPS) alone or LPS together with the hepatotoxin galactosamine (GalN) was performed to identify TNFα-induced protective proteins blocked by GalN. Levels of CCAAT/enhancer-binding protein β (C/EBPβ) were increased after LPS treatment but not GalN/LPS treatment. In a nontransformed rat hepatocyte cell line, TNFα-induced increases in

C/EBPβ protein levels were dependent on NF-κB–mediated inhibition of proteasomal degradation. Pharmacological inhibition of c-Jun N-terminal kinase (JNK) did not affect C/EBPβ degradation, indicating that the process was JNK-independent. C/EBPβ functioned to prevent cell death as adenoviral C/EBPβ overexpression blocked TNFα-induced apoptosis in cells sensitized to TNFα toxicity by NF-κB inhibition. C/EBPβ inhibited TNFα-induced caspase Telomerase 8 activation and downstream mitochondrial cytochrome c release and caspase 3 and caspase 7 activation. Studies in primary hepatocytes from c/ebpβ−/− mice confirmed that loss of C/EBPβ increased death from TNFα. c/ebpβ−/− mice were also sensitized to liver injury from a nontoxic

dose of LPS or TNFα. The absence of jnk2 failed to reverse the GalN-induced block in C/EBPβ induction by LPS, again demonstrating that C/EBPβ degradation was JNK-independent. Conclusion: C/EBPβ is up-regulated by TNFα and mediates hepatocyte resistance to TNFα toxicity by inhibiting caspase-dependent apoptosis. In the absence of NF-κB signaling, proteasomal degradation of C/EBPβ is increased by a JNK-independent mechanism and promotes death from TNFα. (HEPATOLOGY 2010;.) Tumor necrosis factor α (TNFα) is a critical mediator of multiple forms of liver injury, including that resulting from toxins,1, 2 ischemia/reperfusion,3, 4 viral hepatitis,5, 6 and cholestasis.7, 8 Central to TNFα’s role as a hepatotoxic factor is its ability under certain pathophysiological conditions to induce apoptotic cell death. TNFα binding to the type 1 TNFα receptor recruits a series of intracellular proteins that ultimately activate initiator caspase 8.