Prevention of lymphocyte cell death in sepsis improves survival in mice.
Sepsis induces extensive lymphocyte apoptosis, a process which may be beneficial to host survival by down-regulating the inflammatory response or, alternatively, harmful by impairing host defenses. To determine the beneficial vs. adverse effects of lymphocyte apoptosis in sepsis, we blocked lymphocyte apoptosis either by N-benzyloxycarbonyl-Val-Ala-Asp(O-methyl) fluoromethyl ketone (z-VAD), a broad-spectrum caspase inhibitor, or by use of Bcl-2 Ig transgenic mice that selectively overexpress the antiapoptotic protein Bcl-2 in a lymphoid pattern. Both z-VAD and Bcl-2 prevented lymphocyte apoptosis and resulted in a marked improvement in survival. z-VAD did not decrease lymphocyte tumor necrosis factor-alpha production. Considered together, these two studies employing different methods of blocking lymphocyte apoptosis provide compelling evidence that immunodepression resulting from the loss of lymphocytes is a central pathogenic event in sepsis, and they challenge the current paradigm that regards sepsis as a disorder resulting from an uncontrolled inflammatory response. Caspase inhibitors may represent a treatment strategy in this highly lethal disorder.
Hotchkiss
R S
RS
Department of Anesthesiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA. hotch@morpheus.wustl.edu
Tinsley
K W
KW
Swanson
P E
PE
Chang
K C
KC
Cobb
J P
JP
Buchman
T G
TG
Korsmeyer
S J
SJ
Karl
I E
IE
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D008214:Lymphocytes / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000502:physiology*; D018805:Sepsis / Q000276:immunology / Q000401:mortality*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha