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Published on: April 11, 2012
Prevention of experimental septic shock by pretreatment of mice with muramyl peptides
E Meshcheryakova1, S Guryanova, E Makarov
1Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow. eam@mail.ibch.ru
Abstract:
Muramyl peptides, immunostimulators with macrophage as a main target cell, are used for protecting mice from LPS-lethality (the experimental model of septic shock). Different protocols of pretreatment mice by muramyl peptides lead to opposite results. LPS and glycopeptides act synergistically in the induction of lethal shock, when mice receive peptides 1 day prior to lethal dose of LPS. However, extension of the period between the peptide and LPS injections to 6 days cancels the effect of synergism. Moreover, a 14-day interval between the same injections leads to protection of 70-90% animals from the toxic effect of LPS. Lipophilic analogs require 10-100 lower concentrations to protect the animals than the parent highly hydrophilic glycopeptides. Production of TNF, IL-1 and phagocytosis by macrophages was studied within the periods corresponding to "synergism" and LPS-resistance. High level of macrophage activity was observed during the "synergism" period. Low TNF production and reduced macrophage phagocyte activity corresponded to LPS-resistant state. These results partly explain the LPS-unresponsiveness in mice after their pretreatment by muramyl peptides.
Insights
Muramyl peptides can either worsen or protect against septic shock in mice, depending on administration timing. Timing influences macrophage activity, explaining these opposite effects and potential therapeutic strategies.
Area of Science:
- Immunology
- Pharmacology
Background:
- Muramyl peptides are immunostimulators targeting macrophages.
- They are investigated for protection against lipopolysaccharide (LPS)-induced lethality, a model for septic shock.
Purpose of the Study:
- To investigate the dual effects of muramyl peptide pretreatment on LPS lethality in mice.
- To correlate these effects with macrophage activity and cytokine production.
Main Methods:
- Mice were pretreated with muramyl peptides at varying intervals (1, 6, 14 days) before lethal LPS challenge.
- Macrophage activity, including phagocytosis, TNF, and IL-1 production, was assessed during synergistic and resistant phases.
Main Results:
- Early (1-day) pretreatment synergized with LPS, increasing lethality.
- Delayed (6- and 14-day) pretreatment conferred significant protection (70-90%) against LPS.
- Lipophilic analogs were more potent than hydrophilic glycopeptides.
- High macrophage activity correlated with synergism; low activity and reduced TNF/IL-1 production correlated with LPS resistance.
Conclusions:
- The timing of muramyl peptide administration critically determines its effect on LPS-induced shock.
- Macrophage activation state, reflected in cytokine production and phagocytosis, underlies the observed synergistic and protective effects.
- These findings offer insights into modulating immune responses for septic shock treatment.
