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Peptidomimetic Fluoromethylketone Rescues Mice from Lethal Endotoxic Shock

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Abstract

Background

Septic shock is a leading cause of mortality in intensive care units. No new interventions in the last 20 years have made a substantial impact on the outcome of patients with septic shock. Identification of inhibitable pathways that mediate death in shock is an important goal.

Materials and Methods

Two novel caspase inhibitors, (2-indolyl)-carbonyl-Ala-Asp-fluoromethylketone (IDN 1529) and (1-methyl-3-methyl-2-indolyl)-carbonyl-Val-Asp-fluoromethylketone (IDN 1965), were studied in a murine model of endotoxic shock.

Results

IDN 1529 prolonged survival when given before or up to 3 hr after high-dose LPS (p < 0.01) and increased by 2.2-fold the number of animals surviving longterm after a lower dose of LPS (p < 0.01). Despite its similar chemical structure, IDN 1965 lacked these protective effects. Both compounds inhibited caspases 1, 2, 3, 6, 8, and 9, and both afforded comparable reduction in Fas- and LPS-induced caspase 3-like activity and apoptosis. Paradoxically, administration of IDN 1529 but not IDN 1965 led to an increase in the LPS-induced elevation of serum cytokines related directly (IL-1β, IL-18) or indirectly (IL-1α, IL-1Ra) to the action of caspase 1.

Conclusions

A process that appears to be distinct from both apoptosis and the release of inflammatory cytokines is a late-acting requirement for lethality in endotoxic shock. Inhibition of this process can rescue mice even when therapy is initiated after LPS has made the mice severely ill.

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Acknowledgments

We thank Karen Valentino, Anu Srinivasan, and Michael Shiloh for their assistance. This work was supported in part by NIH grant GM53921 to C.F.N.; a Trauma and Injury Biology Research Fellowship to S.R.G. via NIH training grant GM08466; NIH grant AR40135 to W.P.A.; and post-doctoral fellowships from Swiss National Science Foundation and la Foundation Suisse de Bourse de Medecine et Biologie to C.G.

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Authors and Affiliations

  1. Department of Surgery, Weill Medical College of Cornell University, New York, New York, USA

    Stephen R. Grobmyer

  2. Idun Pharmaceuticals, Inc., La Jolla, California, USA

    Robert C. Armstrong & Lawrence C. Fritz

  3. Department of Medicine, Weill Medical College of Cornell University, Box 57, 1300 York Ave., New York, New York, 10021, USA

    Susan C. Nicholson &  Carl F. Nathan

  4. Department of Medicine-Division of Rheumatology, University of Colorado Health Sciences Center, Denver, Colorado, USA

    Cem Gabay & William P. Arend

  5. Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York, USA

    Strite H. Potter, Maxine Melchior &  Carl F. Nathan

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  1. Stephen R. Grobmyer
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Correspondence to Carl F. Nathan.

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Communicated by C. Nathan.

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Grobmyer, S.R., Armstrong, R.C., Nicholson, S.C. et al. Peptidomimetic Fluoromethylketone Rescues Mice from Lethal Endotoxic Shock. Mol Med 5, 585–594 (1999). https://doi.org/10.1007/BF03402071

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