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

• Published in: Journal of cellular and molecular medicine 2013-03, Vol.17 (3), p.365-376
• Main Authors: Li, Ling, Fox, Bridget, Keeble, Julie, Salto‐Tellez, Manuel, Winyard, Paul G., Wood, Mark E., Moore, Philip K., Whiteman, Matthew
• Format: Article
• Language: English
• Subjects: Acute Disease; Animals; Arthritis - drug therapy; Arthritis - etiology; Arthritis - metabolism; Cartilage - drug effects; Cartilage - metabolism; Cartilage - pathology; Cells, Cultured; Chondrocytes - drug effects; Chondrocytes - metabolism; Chondrocytes - pathology; COX‐2; Cyclooxygenase 2 - metabolism; cytokines; Cytokines - metabolism; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Fibroblasts - drug effects; Fibroblasts - metabolism; Fibroblasts - pathology; Freund's adjuvant; GYY4137; Humans; hydrogen sulfide; Hydrogen Sulfide - metabolism; inflammation; Inflammation - drug therapy; Inflammation - etiology; Inflammation - metabolism; Inflammation Mediators - metabolism; Joints - drug effects; Joints - metabolism; Joints - pathology; lipopolysaccharide; Lipopolysaccharides - pharmacology; Mice; Morpholines - pharmacology; myeloperoxidase; NF-kappa B - metabolism; Nitric Oxide Synthase Type II - metabolism; Organothiophosphorus Compounds - pharmacology; Original; Synovial Membrane - drug effects; Synovial Membrane - metabolism; Synovial Membrane - pathology; synoviocyte; TNF‐alpha converting enzyme; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/jcmm.12016

The role of hydrogen sulfide (H2S) 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 H2S 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.