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

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-1−/− 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.

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Figure 1: Effect of caspase inhibitors on survival.
Figure 2: Effect of caspase inhibitors on lymphocyte apoptosis after sepsis induction.
Figure 3: Hematoxylin and eosin staining of thymi from caspase-3−/− and B6 mice.
Figure 4: Lymphocytes are required for caspase inhibitor–improved survival of mice.

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Acknowledgements

We thank M. Laregina, Assistant Director, Diagnostic Services, Division of Comparative Medicine and the Barnes Jewish Hospital Microbiology Laboratory, Washington University School of Medicine for their help with the bacteriological studies. Supported by Merck Frosst (NIH GM44118 and GM 55194) and the Alan A. and Edith L. Wolff Foundation.

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Correspondence to R. S. Hotchkiss.

Supplementary information

Web Figure 1.

Caspase inhibition by M-920 does not decrease TNF-a or IL1b. Mice underwent CLP and were treated with M-920 (20 mg/kg body weight) or diluent 90 min after surgery. A second dose of M-920 or diluent was administered at 12 h after surgery and mice were killed a 20 h after CLP. Plasma samples were obtained at various time points and the two groups of mice and TNF-a or IL1b determined by ELISA. There was a progressive increase in TNF-a or IL1b that was not affected by M-920 treatment.

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Hotchkiss, R., Chang, K., Swanson, P. et al. Caspase inhibitors improve survival in sepsis: a critical role of the lymphocyte. Nat Immunol 1, 496–501 (2000). https://doi.org/10.1038/82741

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