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Local thymic caspase-9 inhibition improves survival during polymicrobial sepsis in mice

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Abstract

Caspase-9 is believed to play an essential role in sepsis-induced lymphocyte apoptosis. The aim of this study was therefore to evaluate its contribution within the caspase-dependent apoptosis pathway in a murine model of polymicrobial sepsis. Local injections of Z-LEHD-fmk, a specific caspase-9 inhibitor, into thymi of septic mice led to the complete inhibition of caspase-9, decreased apoptosis of resident tissue cells, and, in addition, reduced further downstream caspase-3 activity. In contrast to its systemic administration, only local injections improved the overall survival of septic mice. However, local injections of a pancaspase inhibitor (Z-VAD-fmk) did not improve survival, although caspase-3 activity was reduced to a similar degree as by the administration of Z-LEHD-fmk. These results indicate that local apoptosis of lymphatic tissue in polymicrobial sepsis is processed dependent of caspase-9 and suggests alternative caspase-dependent beneficial effects, which may determine a positive outcome.

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Abbreviations

Apaf-1:

Apoptosis protease activating factor 1

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Acknowledgement

Supported in part by grants R37 GM-40586 and P30 HL-59412 awarded by the National Institutes of Health, USPHS.

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Correspondence to Andreas Oberholzer.

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Oberholzer, C., Tschoeke, S.K., Moldawer, L.L. et al. Local thymic caspase-9 inhibition improves survival during polymicrobial sepsis in mice. J Mol Med 84, 389–395 (2006). https://doi.org/10.1007/s00109-005-0017-1

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  • DOI: https://doi.org/10.1007/s00109-005-0017-1

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