The complex effects of the slow-releasing hydrogen sulfide donor GYY4137 in a model of acute joint inflammation and in human cartilage cells.

Abstract

The role of hydrogen sulfide (H2 S) in inflammation remains unclear with both pro- and anti-inflammatory actions of this gas described. We have now assessed the effect of GYY4137 (a slow-releasing H2 S donor) on lipopolysaccharide (LPS)-evoked release of inflammatory mediators from human synoviocytes (HFLS) and articular chondrocytes (HAC) in vitro. We have also examined the effect of GYY4137 in a complete Freund's adjuvant (CFA) model of acute joint inflammation in the mouse. GYY4137 (0.1-0.5 mM) decreased LPS-induced production of nitrite (NO2 (-) ), PGE2 , TNF-α and IL-6 from HFLS and HAC, reduced the levels and catalytic activity of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) and reduced LPS-induced NF-κB activation in vitro. Using recombinant human enzymes, GYY4137 inhibited the activity of COX-2, iNOS and TNF-α converting enzyme (TACE). In the CFA-treated mouse, GYY4137 (50 mg/kg, i.p.) injected 1 hr prior to CFA increased knee joint swelling while an anti-inflammatory effect, as demonstrated by reduced synovial fluid myeloperoxidase (MPO) and N-acetyl-β-D-glucosaminidase (NAG) activity and decreased TNF-α, IL-1β, IL-6 and IL-8 concentration, was apparent when GYY4137 was injected 6 hrs after CFA. GYY4137 was also anti-inflammatory when given 18 hrs after CFA. Thus, although GYY4137 consistently reduced the generation of pro-inflammatory mediators from human joint cells in vitro, its effect on acute joint inflammation in vivo depended on the timing of administration.

• Authors: Ling Li, Bridget Fox, Julie Keeble, Manuel Salto-Tellez, Paul G Winyard, Mark E Wood, Philip K Moore, Matthew Whiteman
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 17 Issue 3 Pg. 365-76 (Mar 2013) ISSN: 1582-4934 [Electronic] England
• PMID: 23356870 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 The Authors. Published by Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

Chemical References

• Cytokines
• GYY 4137
• Inflammation Mediators
• Lipopolysaccharides
• Morpholines
• NF-kappa B
• Organothiophosphorus Compounds
• Tumor Necrosis Factor-alpha
• Nitric Oxide Synthase Type II
• Cyclooxygenase 2
• Hydrogen Sulfide

Topics

• Acute Disease
• Animals
• Arthritis (drug therapy, etiology, metabolism)
• Cartilage (drug effects, metabolism, pathology)
• Cells, Cultured
• Chondrocytes (drug effects, metabolism, pathology)
• Cyclooxygenase 2 (metabolism)
• Cytokines (metabolism)
• Disease Models, Animal
• Enzyme-Linked Immunosorbent Assay
• Fibroblasts (drug effects, metabolism, pathology)
• Humans
• Hydrogen Sulfide (metabolism)
• Inflammation (drug therapy, etiology, metabolism)
• Inflammation Mediators (metabolism)
• Joints (drug effects, metabolism, pathology)
• Lipopolysaccharides (pharmacology)
• Mice
• Morpholines (pharmacology)
• NF-kappa B (metabolism)
• Nitric Oxide Synthase Type II (metabolism)
• Organothiophosphorus Compounds (pharmacology)
• Synovial Membrane (drug effects, metabolism, pathology)
• Tumor Necrosis Factor-alpha (metabolism)