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Published on: May 2, 2018
Myeloperoxidase and Eosinophil Peroxidase Inhibit Endotoxin Activity and Increase Mouse Survival in a
Robert C Allen1, Mary L Henery2, John C Allen2
1Department of Pathology, Creighton University School of Medicine, Omaha, NE 68124, USA.
Abstract:
Myeloperoxidase (MPO) and eosinophil peroxidase (EPO) are cationic haloperoxidases with potent microbicidal and detoxifying activities. MPO selectively binds to and kills some Gram-positive bacteria (GPB) and all Gram-negative bacteria (GNB) tested. GNB contain endotoxin, i.e., lipopolysaccharide (LPS) comprising a toxic lipid A component. The possibility that MPO and EPO bind and inhibit the endotoxin of GNB was tested by mixing MPO or EPO with LPS or lipid A and measuring for inhibition of endotoxin activity using the chromogenic Limulus amebocyte lysate (LAL) assay. The endotoxin-inhibiting activities of MPO and EPO were also tested in vivo using an LPS 90% lethal dose (LD90) mouse model studied over a five-day period. Mixing MPO or EPO with a fixed quantity of LPS from Escherichia coli O55:B5 or with diphosphoryl lipid A from E. coli F583 inhibited LAL endotoxin activity in proportion to the natural log of the MPO or EPO concentration. MPO and EPO enzymatic activities were not required for inhibition, and MPO haloperoxidase action did not increase endotoxin inhibition. Both MPO and EPO increased mouse survival in the LPS LD90 model. In conclusion, MPO and EPO nonenzymatically inhibited in vitro endotoxin activity using the LAL assay, and MPO and high-dose EPO significantly increased mouse survival in a LPS LD90 model, and such survival was increased in a dose-dependent manner.
Insights
Myeloperoxidase (MPO) and eosinophil peroxidase (EPO) nonenzymatically inhibit bacterial endotoxin (LPS) activity. Both MPO and EPO enhance survival in lethal endotoxin mouse models, demonstrating their protective potential.
Area of Science:
- Biochemistry
- Immunology
- Microbiology
Background:
- Myeloperoxidase (MPO) and eosinophil peroxidase (EPO) are key enzymes involved in host defense.
- Gram-negative bacteria (GNB) possess lipopolysaccharide (LPS), a potent endotoxin, which can cause severe inflammatory responses.
- The interaction of MPO and EPO with LPS is not fully understood.
Purpose of the Study:
- To investigate the potential of MPO and EPO to bind and inhibit GNB endotoxin (LPS).
- To evaluate the efficacy of MPO and EPO in mitigating LPS-induced toxicity in vivo.
Main Methods:
- In vitro inhibition of LPS and lipid A activity using the Limulus amebocyte lysate (LAL) assay.
- In vivo assessment of MPO and EPO efficacy in a 90% lethal dose (LD90) LPS mouse model over five days.
Main Results:
- MPO and EPO demonstrated dose-dependent inhibition of LPS and lipid A activity in the LAL assay.
- Neither MPO nor EPO enzymatic activity was necessary for endotoxin inhibition.
- Both MPO and EPO significantly increased mouse survival in the LPS LD90 model, with a dose-dependent effect observed for high-dose EPO.
Conclusions:
- MPO and EPO possess nonenzymatic endotoxin-inhibiting capabilities.
- MPO and EPO offer significant protection against lethal endotoxemia in vivo.
- These findings highlight MPO and EPO as potential therapeutic agents against Gram-negative bacterial infections.
