Peptidomimetic fluoromethylketone rescues mice from lethal endotoxic shock.

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-1beta, IL-18) or indirectly (IL-1alpha, 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.

• Authors: S R Grobmyer, R C Armstrong, S C Nicholson, C Gabay, W P Arend, S H Potter, M Melchior, L C Fritz, C F Nathan
• Journal: Molecular medicine (Cambridge, Mass.) (Mol Med) Vol. 5 Issue 9 Pg. 585-94 (Sep 1999) ISSN: 1076-1551 [Print] England
• PMID: 10551900 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibodies, Monoclonal
• Caspase Inhibitors
• Cysteine Proteinase Inhibitors
• Cytokines
• IDN 1529
• Indoles
• Interleukin-1
• Lipopolysaccharides
• N-((1,3-dimethylindole-2-carbonyl)-valinyl)-3-amino-4-oxo-5-fluoropentanoic acid
• Oligopeptides
• Recombinant Proteins
• fas Receptor
• Casp3 protein, mouse
• Caspase 3
• Caspases
• Caspase 1

Topics

• Animals
• Antibodies, Monoclonal (pharmacology)
• Apoptosis (drug effects)
• Caspase 1 (drug effects, genetics, metabolism)
• Caspase 3
• Caspase Inhibitors
• Caspases (metabolism)
• Cysteine Proteinase Inhibitors (pharmacology)
• Cytokines (blood, drug effects)
• Female
• Indoles (pharmacology)
• Interleukin-1 (metabolism)
• Lipopolysaccharides
• Liver (drug effects, pathology)
• Macrophages (drug effects, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Oligopeptides (pharmacology)
• Recombinant Proteins (drug effects, genetics, metabolism)
• Shock, Septic (drug therapy, mortality)
• Survival Rate
• fas Receptor (immunology)