Prevention of lymphocyte cell death in sepsis improves survival in mice

RS Hotchkiss, KW Tinsley… - Proceedings of the …, 1999 - National Acad Sciences
RS Hotchkiss, KW Tinsley, PE Swanson, KC Chang, JP Cobb, TG Buchman, SJ Korsmeyer…
Proceedings of the National Academy of Sciences, 1999National Acad Sciences
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 …
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-α 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.
National Acad Sciences