Open AccessThe complex effects of the slow‐releasing hydrogen sulfide donor GYY 4137 in a model of acute joint inflammation and in human cartilage cells
Author(s) -
Li Ling,
Fox Bridget,
Keeble Julie,
SaltoTellez Manuel,
Winyard Paul G.,
Wood Mark E.,
Moore Philip K.,
Whiteman Matthew
Publication year - 2013
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.12016
Subject(s) - inflammation , chemistry , myeloperoxidase , in vivo , nitric oxide synthase , nitric oxide , lipopolysaccharide , in vitro , tumor necrosis factor alpha , synovial fluid , pharmacology , cyclooxygenase , arthritis , medicine , biochemistry , osteoarthritis , enzyme , biology , pathology , microbiology and biotechnology , organic chemistry , alternative medicine
The role of hydrogen sulfide ( H 2 S ) in inflammation remains unclear with both pro‐ and anti‐inflammatory actions of this gas described. We have now assessed the effect of GYY 4137 (a slow‐releasing H 2 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 GYY 4137 in a complete F reund's adjuvant ( CFA ) model of acute joint inflammation in the mouse. GYY 4137 (0.1–0.5 mM) decreased LPS ‐induced production of nitrite ( NO 2 − ), PGE 2 , 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 ‐κ B activation in vitro . Using recombinant human enzymes, GYY 4137 inhibited the activity of COX ‐2, iNOS and TNF ‐α converting enzyme ( TACE ). In the CFA ‐treated mouse, GYY 4137 (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 GYY 4137 was injected 6 hrs after CFA . GYY 4137 was also anti‐inflammatory when given 18 hrs after CFA . Thus, although GYY 4137 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.