Caspase inhibition causes hyperacute tumor necrosis factor-induced shock via oxidative stress and phospholipase A2.
Dysregulated apoptotic cell death contributes to many pathological conditions, including sepsis, prompting the suggestion that caspase inhibition to block apoptosis could have useful therapeutic applications. Because the cytokine tumor necrosis factor (TNF, also known as TNF-alpha) is both pro-apoptotic and pro-inflammatory and is involved in septic shock, we tested whether caspase inhibition would alleviate TNF-induced toxicity in vivo. General caspase inhibition by the protease inhibitor zVAD-fmk exacerbated TNF toxicity by enhancing oxidative stress and mitochondrial damage, resulting in hyperacute hemodynamic collapse, kidney failure and death. Thus, survival of TNF toxicity depends on caspase-dependent processes. Our results demonstrated the pathophysiological relevance of caspase-independent, ROS-mediated pathways in response to lethal TNF-induced shock in mice. In addition, survival of TNF toxicity seemed to require a caspase-dependent protective feedback on excessive reactive oxygen species (ROS) formation and phospholipase A2 activation.
Cauwels
Anje
A
Molecular Pathophysiology and Experimental Therapy Unit, Department for Molecular Biomedical Research, Ghent University and Flanders Interuniversity Institute for Biotechnology, Ghent, Belgium. anje.cauwels@dmb.rug.ac.be
Janssen
Ben
B
Waeytens
Anouk
A
Cuvelier
Claude
C
Brouckaert
Peter
P
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D016824:Antigens, Human Platelet / Q000502:physiology; D017209:Apoptosis / Q000502:physiology; D061945:Caspase Inhibitors; D002403:Cathepsins / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D005260:Female; D008099:Liver / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009102:Multiple Organ Failure / Q000378:metabolism; D018384:Oxidative Stress; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2; D017382:Reactive Oxygen Species / Q000378:metabolism; D012769:Shock / Q000209:etiology* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D000590:Amino Acid Chloromethyl Ketones; D016824:Antigens, Human Platelet; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C083451:human platelet antigen 1b; D010741:Phospholipases A; D054467:Phospholipases A2; D002403:Cathepsins