Caspase inhibitors improve survival in sepsis: A critical role of the lymphocyte

R. S. Hotchkiss, K. C. Chang, P. E. Swanson, K. W. Tinsley, J. J. Hui, P. Klender, S. Xanthoudakis, S. Roy, C. Black, E. Grimm, R. Aspiotis, Y. Han, D. W. Nicholson, I. E. Karl

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444 Scopus citations

Abstract

Sepsis induces lymphocyte apoptosis and prevention of lymphocyte death may improve the chances of surviving this disorder. We compared the efficacy of a selective caspase-3 inhibitor to a polycaspase inhibitor and to caspase-3-/- mice. Both inhibitors prevented lymphocyte apoptosis and improved survival. Caspase-3-/- mice shared a decreased, but not total, block of apoptosis. The polycaspase inhibitor caused a very substantial decrease in bacteremia. Caspase inhibitors did not benefit RAG-I-/- mice, which had a >tenfold increase in bacteremia compared to controls. Adoptive transfer of T cells that overexpressed the anti-apoptotic protein Bcl-2 increased survival. T cells stimulated with anti-CD3 and anti-CD28 produced increased interleukin 2 and interferon γ by 6 h. Thus, caspase inhibitors enhance immunity by preventing lymphocyte apoptosis and lymphocytes act rapidly, within 24 h, to control infection.

Original languageEnglish
Pages (from-to)496-501
Number of pages6
JournalNature immunology
Volume1
Issue number6
DOIs
StatePublished - Dec 2000

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    Hotchkiss, R. S., Chang, K. C., Swanson, P. E., Tinsley, K. W., Hui, J. J., Klender, P., Xanthoudakis, S., Roy, S., Black, C., Grimm, E., Aspiotis, R., Han, Y., Nicholson, D. W., & Karl, I. E. (2000). Caspase inhibitors improve survival in sepsis: A critical role of the lymphocyte. Nature immunology, 1(6), 496-501. https://doi.org/10.1038/82741