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Caspase inhibition causes hyperacute tumor necrosis factor-induced shock via oxidative stress and phospholipase A2
Anje Cauwels1, Ben Janssen, Anouk Waeytens
1Molecular 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
Abstract:
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.
Insights
Caspase inhibition worsens tumor necrosis factor (TNF) toxicity in sepsis models, indicating that blocking apoptosis is not a viable therapeutic strategy. Survival from TNF shock relies on caspase-dependent processes that protect against oxidative stress.
Area of Science:
- Molecular Biology
- Immunology
- Pathophysiology
Background:
- Dysregulated apoptosis is implicated in various diseases, including sepsis.
- Tumor necrosis factor (TNF-alpha) is a key cytokine in sepsis, exhibiting both pro-apoptotic and pro-inflammatory effects.
- Caspase inhibition has been proposed as a therapeutic strategy to block apoptosis in pathological conditions.
Purpose of the Study:
- To investigate the therapeutic potential of caspase inhibition in mitigating TNF-induced toxicity in vivo.
- To determine the role of caspase-dependent and independent pathways in TNF-induced shock.
Main Methods:
- Administration of a general caspase inhibitor (zVAD-fmk) to mice subjected to TNF challenge.
- Assessment of TNF-induced toxicity, including hemodynamic collapse, organ failure, and survival.
- Evaluation of oxidative stress and mitochondrial damage markers.
Main Results:
- General caspase inhibition significantly exacerbated TNF toxicity, leading to hyperacute hemodynamic collapse, kidney failure, and death.
- Caspase inhibition enhanced oxidative stress and mitochondrial damage in response to TNF.
- Survival from TNF toxicity was found to depend on caspase-dependent processes.
Conclusions:
- Blocking apoptosis via caspase inhibition is not therapeutically beneficial and can worsen TNF-induced toxicity.
- Caspase-independent, reactive oxygen species (ROS)-mediated pathways are crucial in lethal TNF-induced shock.
- Caspase-dependent mechanisms appear to provide a protective feedback loop against excessive ROS formation and phospholipase A2 activation during TNF toxicity.