Apoptosis and caspases regulate death and inflammation in sepsis.
Although the prevailing concept has been that mortality in sepsis results from an unbridled hyper-inflammatory cytokine-mediated response, the failure of more than 30 clinical trials to treat sepsis by controlling this cytokine response requires a 'rethink' of the molecular mechanism underpinning the development of sepsis. As we discuss here, remarkable new studies indicate that most deaths from sepsis are actually the result of a substantially impaired immune response that is due to extensive death of immune effector cells. Rectification of this apoptotic-inflammatory imbalance using modulators of caspases and other components of the cell-death pathway have shown striking efficacy in stringent animal models of sepsis, indicating an entirely novel path forward for the clinical treatment of human sepsis.
Hotchkiss
Richard S
RS
Department of Anesthesiology, Washington University School of Medicine, Campus Box 8054, 660 South Euclid, St Louis, Missouri 63110, USA.
Nicholson
Donald W
DW
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D002450:Cell Communication; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000628:therapy; D011480:Protease Inhibitors / Q000627:therapeutic use; D018805:Sepsis / Q000201:enzymology* / Q000276:immunology / Q000473:pathology* / Q000628:therapy
D061945:Caspase Inhibitors; D011480:Protease Inhibitors; D020169:Caspases