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

Li L, Fox B, Keeble J, Salto-Tellez M, Winyard PG, Wood ME, Moore PK, Whiteman M - J. Cell. Mol. Med. (2013)

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Pharmaceutical Science Research Division, King's College London, London, England.

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Histological assessment of the effects of GYY4137 on CFA-induced knee joint inflammation. GYY4137 (50 mg/kg, i.p.) or vehicle control saline (0.5 ml/kg, i.p.) was administered to mice 6 hrs after intra-articular injection of CFA or saline and killed 24 hrs thereafter. Figure shows photomicrographs of knee joint sections (200×) and inserts show intra-articular (marked with *) and peri-articular space of knee joints (600×) representative of three separate animals. In these inserts, please note A) the absence of inflammatory cells in the intra-articular space of the non-inflamed joint; B) the presence of florid inflammation in the same space of a CFA-treated animal; and C) the reduction in inflammation achieved in the same space of the GYY4137-CFA-treated animal.
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fig08: Histological assessment of the effects of GYY4137 on CFA-induced knee joint inflammation. GYY4137 (50 mg/kg, i.p.) or vehicle control saline (0.5 ml/kg, i.p.) was administered to mice 6 hrs after intra-articular injection of CFA or saline and killed 24 hrs thereafter. Figure shows photomicrographs of knee joint sections (200×) and inserts show intra-articular (marked with *) and peri-articular space of knee joints (600×) representative of three separate animals. In these inserts, please note A) the absence of inflammatory cells in the intra-articular space of the non-inflamed joint; B) the presence of florid inflammation in the same space of a CFA-treated animal; and C) the reduction in inflammation achieved in the same space of the GYY4137-CFA-treated animal.

Mentions: GYY4137 (50 mg/kg, i.p.) or saline was administered to mice either 1 hr before or 6 or 18 hrs after intra-articular injection of CFA. In all cases, animals were killed 24 hrs after CFA injection. Saline did not cause knee joint swelling at any time-point of injection (data not shown). Pre-treatment (1 hr) of animals with GYY4137 resulted in a significant increase in CFA-induced knee joint swelling (Fig. 6A) without any change in synovial fluid MPO activity (Fig. 6B). In contrast, injection of GYY4137 18 hrs after CFA reduced knee joint swelling (Fig. 6C) and also decreased synovial fluid MPO activity (Fig. 6D). Administration of GYY4137 6 hrs after intra-articular injection of CFA did not affect knee joint diameter (Fig. 7A), but did significantly reduce synovial fluid MPO activity (Fig. 7B) and NAG (Fig. 7C), TNF-α (Fig. 7D), IL-1β (Fig. 7E), IL-6 (Fig. 7F) and IL-8 (Fig. 7G) concentrations. Intriguingly, despite the apparent inability of GYY4137 administered 6 hrs after CFA injection to affect knee joint swelling, evidence of reduced neutrophil infiltration and inflammation was also apparent upon histological examination of treated knee joints (Fig. 8).


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

Li L, Fox B, Keeble J, Salto-Tellez M, Winyard PG, Wood ME, Moore PK, Whiteman M - J. Cell. Mol. Med. (2013)

Histological assessment of the effects of GYY4137 on CFA-induced knee joint inflammation. GYY4137 (50 mg/kg, i.p.) or vehicle control saline (0.5 ml/kg, i.p.) was administered to mice 6 hrs after intra-articular injection of CFA or saline and killed 24 hrs thereafter. Figure shows photomicrographs of knee joint sections (200×) and inserts show intra-articular (marked with *) and peri-articular space of knee joints (600×) representative of three separate animals. In these inserts, please note A) the absence of inflammatory cells in the intra-articular space of the non-inflamed joint; B) the presence of florid inflammation in the same space of a CFA-treated animal; and C) the reduction in inflammation achieved in the same space of the GYY4137-CFA-treated animal.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3823018&req=5

fig08: Histological assessment of the effects of GYY4137 on CFA-induced knee joint inflammation. GYY4137 (50 mg/kg, i.p.) or vehicle control saline (0.5 ml/kg, i.p.) was administered to mice 6 hrs after intra-articular injection of CFA or saline and killed 24 hrs thereafter. Figure shows photomicrographs of knee joint sections (200×) and inserts show intra-articular (marked with *) and peri-articular space of knee joints (600×) representative of three separate animals. In these inserts, please note A) the absence of inflammatory cells in the intra-articular space of the non-inflamed joint; B) the presence of florid inflammation in the same space of a CFA-treated animal; and C) the reduction in inflammation achieved in the same space of the GYY4137-CFA-treated animal.
Mentions: GYY4137 (50 mg/kg, i.p.) or saline was administered to mice either 1 hr before or 6 or 18 hrs after intra-articular injection of CFA. In all cases, animals were killed 24 hrs after CFA injection. Saline did not cause knee joint swelling at any time-point of injection (data not shown). Pre-treatment (1 hr) of animals with GYY4137 resulted in a significant increase in CFA-induced knee joint swelling (Fig. 6A) without any change in synovial fluid MPO activity (Fig. 6B). In contrast, injection of GYY4137 18 hrs after CFA reduced knee joint swelling (Fig. 6C) and also decreased synovial fluid MPO activity (Fig. 6D). Administration of GYY4137 6 hrs after intra-articular injection of CFA did not affect knee joint diameter (Fig. 7A), but did significantly reduce synovial fluid MPO activity (Fig. 7B) and NAG (Fig. 7C), TNF-α (Fig. 7D), IL-1β (Fig. 7E), IL-6 (Fig. 7F) and IL-8 (Fig. 7G) concentrations. Intriguingly, despite the apparent inability of GYY4137 administered 6 hrs after CFA injection to affect knee joint swelling, evidence of reduced neutrophil infiltration and inflammation was also apparent upon histological examination of treated knee joints (Fig. 8).

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Pharmaceutical Science Research Division, King's College London, London, England.

Show MeSH
Related in: MedlinePlus