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


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.


  1. 1

    Wang, S. D., Huang, K. J., Lin, Y. S. & Lei, H. Y. Sepsis-induced apoptosis of the thymocytes in mice. J. Immunol. 152 , 5014–5021 (1994).

    CAS  PubMed  Google Scholar 

  2. 2

    Ayala, A., Herndon, C., Lehman, D. & Chaudry, I. H. Differential induction of apoptosis in lymphoid tissue during sepsis: variation in onset, frequency and nature of the mediators. Blood 87, 4261–4275 (1996).

    CAS  PubMed  Google Scholar 

  3. 3

    Hotchkiss, R. S. et al. Apoptosis in lymphoid and parenchymal cells during sepsis: Findings in normal and T- and B-cell deficient mice. Crit. Care Med. 25, 1298–1307 ( 1997).

    CAS  Article  Google Scholar 

  4. 4

    Hotchkiss, R. S. et al. Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit. Care Med. 27, 1230 –1251 (1999).

    CAS  Article  Google Scholar 

  5. 5

    Thornberry, N. A. & Lazebnik, Y. Caspases: enemies within. Science 281, 1312– 1316 (1998).

    CAS  Article  Google Scholar 

  6. 6

    Nicholson, D. W. Caspase structure, proteolytic substrates, and function during apoptotic cell death. Cell Death Differ. 6, 1028– 1042 (1999).

    CAS  Article  Google Scholar 

  7. 7

    Endres, M. et al. Attenuation of delayed neuronal death after mild focal ischemia in mice by inhibition of the caspase family. J. Cere. Blood Flow Metabol. 18, 238–247 ( 1988).

    Article  Google Scholar 

  8. 8

    Fukuzuka, K. et al. Caspase-3-dependent organ apoptosis early after burn injury . Ann. Surg. 229, 851–858 (1999).

    CAS  Article  Google Scholar 

  9. 9

    Grobmeyer, S. R. et al. Peptidomimetic fluoromethylketone rescues mice from lethal endotoxic shock. Mol. Med. 5, 585– 594 (1999).

    Article  Google Scholar 

  10. 10

    Hotchkiss, R. S. et al. Prevention of lymphocyte cell death in sepsis improves survival in mice. Proc. Natl Acad, Sci. USA 96, 14541 –14546 (1999).

    CAS  Article  Google Scholar 

  11. 11

    Varfolomeev, E. E. et al. Targeted disruption of the mouse caspase 8 gene ablates cell death induction by the TNF receptors, Fas/Apo1 and DR3 and is lethal prenatally . Immunity 9, 267–276 (1998).

    CAS  Article  Google Scholar 

  12. 12

    Kuida, K. et al. Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9. Cell 94, 325– 337 (1998).

    CAS  Article  Google Scholar 

  13. 13

    Hakem, R. et al. Differential requirement for caspase 9 in apoptotic pathways in vivo. Cell 94, 339– 352 (1998).

    CAS  Article  Google Scholar 

  14. 14

    Zheng, T. S., Hunot, S., Kuida, K. & Flavell, R. A. Caspase knockouts: matters of life and death. Cell Death Differ. 6, 1043–1053 (1999).

    CAS  Article  Google Scholar 

  15. 15

    Kuida, K. et al. Decrease apoptosis in the brain and premature lethality in CPP32-deficient mice. Nature 384, 368–372 (1996).

    CAS  Article  Google Scholar 

  16. 16

    Woo, M. et al. Essential contribution of caspase 3/CPP32 to apoptosis and its associated nuclear changes. Genes Dev. 12, 806–819 (1998).

    CAS  Article  Google Scholar 

  17. 17

    Garcia-Calvo, M. et al. Inhibition of human caspases by peptide-based and macromolecular inhibitors. J. Biol. Chem. 273, 32608– 32613 (1998).

    CAS  Article  Google Scholar 

  18. 18

    Baker, C. C., Chaudry, I. H., Gains, H. O. & Baue, A. E. Evaluation of factors affecting mortality rate after sepsis in a murine cecal ligation and puncture mode. Surgery 94, 331–335 (1983).

    CAS  PubMed  Google Scholar 

  19. 19

    Remick, D. G., Newcomb, D. E., Bolgos, G. L. & Call, D. R. Comparison of the mortality and inflammatory response of two models of sepsis: lipopolysaccharide versus cecal ligation and puncture. Shock 13, 110–116 ( 2000).

    CAS  Article  Google Scholar 

  20. 20

    Hotchkiss, R. S. et al. Overexpression of Bcl-2 in transgenic mice decreases apoptosis and improves survival in sepsis. J. Immunol. 162, 4148–4156 (1999).

    CAS  PubMed  Google Scholar 

  21. 21

    Hotchkiss, R. S. et al. Evaluation of the role of cellular hypoxia in sepsis by the hypoxic marker [18F]fluoromisonidazole. Am. J. Physiol. 30, 965–972 (1991).

    Google Scholar 

  22. 22

    Janicke, R. U., Sprengart, M. L., Wati, M. R. & Porter, A. G. Caspase-3 is required for DNA fragmentation and morphological changes associated with apoptosis. J. Biol. Chem. 273, 9357 –9360 (1998).

    CAS  Article  Google Scholar 

  23. 23

    Medzhitov, R., Janeway, C. Innate immunity. N. Engl. J. Med. 343, 338–344 ( 2000).

    CAS  Article  Google Scholar 

  24. 24

    Abbas, A. K., Lichtman, A. H. & Pober, J. S. in Cellular and Molecular Immunology 4th edn, 4 (W. B. Saunders Co., Philadelphia, 2000).

    Google Scholar 

  25. 25

    Janeway, C. A., Travers, P., Walport, M. & Capra, J. D. in Immunobiology: The immune system in health and disease 4th edn, 219 (Current Biology Publications, London, 1999).

    Google Scholar 

  26. 26

    Braun, J. S. et al. Neuroprotection by a caspase inhibitor in acute bacterial meningitis. Nature Med. 5, 298– 302. (1999).

    CAS  Article  Google Scholar 

  27. 27

    Oberholzer, A., Oberholzer, C. & Moldawer, L. L. Cytokine signaling- regulation of the immune system in normal and critically ill states. Crit. Care Med. 28, S3 (2000).

    Article  Google Scholar 

  28. 28

    Yagupsky, P. & Notte, F. S. Quantitative aspects of septicemia . Clin. Microbiol. Rev. 3, 269– 279 (1990)

    CAS  Article  Google Scholar 

  29. 29

    Bell, L. M., Alpert, G., Campos, J. M. & Plotkin, S. A. Routine quantitative blood cultures in children with Haemophilus influenzae or Streptococcus pneumoniae bacteremia. Pediatrics 76, 901–904 ( 1985).

    CAS  PubMed  Google Scholar 

  30. 30

    Goronzy, J., Weyand, C., Quan, J., Fathman, C. G. & O'Hanley, P. Enhanced cell-mediated protection against fatal Escherichia coli septicemia induced by treatment with recombinant IL-2 . J. Immunol. 142, 1134– 1138 (1989).

    CAS  PubMed  Google Scholar 

  31. 31

    Docke, W. E. et al. Monocyte deactivation in septic patients: restoration by IFN-γ treatment. Nature Med. 3, 678– 681 (1997).

    CAS  Article  Google Scholar 

  32. 32

    Garcia-Calvo et al. Inhibition of human caspases by peptide-based and macromolecular inhibitors . J. Biol. Chem. 273, 32608– 32613 (1998).

    CAS  Article  Google Scholar 

  33. 33

    Garcia-Calvo, M. et al. Purification and catalytic properties of human caspase family members. Cell Death Differ 6, 362– 369 (1999).

    CAS  Article  Google Scholar 

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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).

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