Prevention of lymphocyte cell death in sepsis improves survival in mice

R. S. Hotchkiss*, K. W. Tinsley, P. E. Swanson, K. C. Chang, J. P. Cobb, T. G. Buchman, S. J. Korsmeyer, I. E. Karl

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

415 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)14541-14546
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume96
Issue number25
DOIs
StatePublished - 7 Dec 1999
Externally publishedYes

Keywords

  • Apoptosis
  • Endotoxin
  • Mortality
  • Programmed cell death
  • Shock

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