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Phenylmethimazole inhibits production of proinflammatory mediators and is protective in an experimental model of endotoxic shock*
- Source :
- Critical care medicine. 40(3)
- Publication Year :
- 2011
-
Abstract
- Background One form of sepsis, or endotoxic shock, is a hyperactivated systemic response caused by excessive expression of proinflammatory mediators, which results from Gram-negative bacterial lipopolysaccharide-stimulated Toll-like receptor-4 signaling. This lipopolysaccharide signaling is known to consist of a MyD88-dependent nuclear factor-κB-mediated pathway that results in production of proinflammatory mediators (tumor necrosis factor-α, interleukin-6, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, inducible nitric oxide synthase, cyclooxygenase-2) and a MyD88-independent interferon regulatory factor-mediated pathway that regulates production of Type 1 interferon-inducible proteins (interferon γ-induced protein-10, monocyte chemotactic protein-1). In prior studies, phenylmethimazole markedly decreased virally induced Toll-like receptor-3 expression and signaling and significantly suppressed murine colitis in an experimental model wherein lipopolysaccharide is known to play an important role. Objective In this study, we probed the hypothesis that phenylmethimazole inhibits lipopolysaccharide-mediated Toll-like receptor-4 signaling and is efficacious in attenuating inflammatory changes and improving survival in an in vivo murine model of endotoxic shock. Design Experimental animal model. Setting University laboratory. Subjects Male C57BL/6J mice weighing 18-22 g. Interventions Phenylmethimazole (1 mg/kg) was administered intraperitoneally to mice before a lethal lipopolysaccharide challenge (25 mg/kg). RAW264.7 mouse macrophage cells were pretreated with phenylmethimazole followed by lipopolysaccharide stimulation. Measurements and main results : Macroscopic observations revealed that phenylmethimazole was significantly protective in controlling clinical manifestations of endotoxic shock and death under conditions wherein flunixin of meglumine and prednisolone were marginally effective. A combination of enzyme-linked immunosorbent assay, Northern blot, reverse transcriptase-polymerase chain reaction, immunohistochemistry, and Western blot analyses showed that phenylmethimazole attenuated lipopolysaccharide-induced increases in production of proinflammatory cytokines (tumor necrosis factor-α, interleukin-6, interferon-γ), endothelial cell adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1), inducible nitric oxide synthase and cyclooxygenase-2, interferon regulatory factor-1, interferon-inducible proteins (interferon γ-induced protein-10, monocyte chemotactic protein-1), and signal transducer and activator of transcription-1 phosphorylation in multiple tissues in mice. Consistent with these observations, electrophoretic mobility shift assay demonstrated that phenylmethimazole inhibited in vitro lipopolysaccharide-induced nuclear factor-κB and interferon regulatory factor-1 activation in RAW 264.7 mouse macrophages. Conclusions Collectively, these results provide direct evidence that phenylmethimazole diminishes lipopolysaccharide-induced MyD88-dependent as well as MyD88-independent signaling pathways and is protective in an experimental model of endotoxic shock.
- Subjects :
- Male
Lipopolysaccharide
Pharmacology
Critical Care and Intensive Care Medicine
Proinflammatory cytokine
chemistry.chemical_compound
Mice
Interferon
Medicine
Animals
Cell adhesion
Inflammation
Methimazole
biology
business.industry
Monocyte
Thiones
Shock, Septic
Nitric oxide synthase
Mice, Inbred C57BL
Disease Models, Animal
medicine.anatomical_structure
chemistry
biology.protein
Cytokines
Tumor necrosis factor alpha
Signal transduction
business
medicine.drug
Subjects
Details
- ISSN :
- 15300293
- Volume :
- 40
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Critical care medicine
- Accession number :
- edsair.doi.dedup.....010e9a93eefa8d53bc8a007291039d8c