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 (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.

GYY4137, a Slow-Releasing Hydrogen Sulfide Donor, Ameliorates Renal Damage Associated with Chronic Obstructive Uropathy

“…Unlike NaHS, GYY4137 results in a sustained elevation of plasma H 2 S levels upon intraperitoneal (IP) and intravenous (IV) administration 11 . GYY4137 also possesses significant anti-inflammatory, anti-oxidant and anti-apoptotic characteristics, as demonstrated by our lab and others, which makes it an ideal potential therapy against renal injury [12][13][14][15] .…”

GYY4137, a Novel Water-Soluble, H2S-Releasing Molecule

“…Thus, GYY4137 pretreatment reduces the secretion of proinflammatory mediators like interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), NO, and prostaglandin E 2 (PGE 2 ) (Whiteman et al, 2010) in mouse macrophages stimulated with LPS as well as in IL-8-stimulated airway smooth muscle cells (Perry et al, 2011). In human synoviocytes and articular chondrocytes, GYY4137 decreased LPS-evoked production of nitrite (NO 2 À ), PGE 2 , TNF-α, and IL-6 (Li, Fox, et al, 2013). Similarly, in human chondrocytes isolated from osteoarthritis tissues, GYY4137 reduces NO, PGE 2 , IL-6, and MMP-13 synthesis from cells stimulated with IL-1β (Fox et al, 2012).…”

Estudo dos efeitos do composto GYY-4137, um doador de sulfeto de hidrogênio (H₂S), na sinovite aguda induzida por carragenina na articulação temporomandibular de ratos.

“…Tem efeito pró-nociceptivo quando administrado por via intratecal (Maeda et al, 2009), intraplantar (Kawabata et al, 2007 ou intracolônica Por outro lado, as propriedades anti-inflamatórias do H 2 S têm sido observadas em diversos modelos experimentais, tais como o de edema de pata induzido por CGN (Zanardo et al, 2006), artrite (Ekundi-Valentim et al, 2010;Li et al, 2013), lesão pulmonar (Esechie et al, 2008), asma (Benetti et al, 2013) e em modelo de dor viceral induzida por distensão coloretal (Distrutti et al, 2010).…”

“…Neste sentido, a introdução recente de doadores de H 2 S de liberação lenta (p. ex. GYY-4137) vem promovendo resultados mais consistentes e promissores quanto às ações antiinflamatórias desse gasotransmissor (Li et al, 2013;Whiteman et al, 2011;Whiteman, Winyard, 2011). Enquanto a liberação de H 2 S a partir do NaHS é espontânea e rápida, a liberação de H 2 S pelo composto GYY-4137 ocorre de forma lenta (e assim durante longos períodos de tempo), possivelmente mimetizando a cinética de produção endógena do H 2 S (Whiteman et al, 2010 (Cunha et al, 2008;Donatti et al, 2014;Zanardo et al, 2006).…”

“…Nesse contexto, pode ocorrer a progressão da doença e a utilização de métodos terapêuticos invasivos e não reversíveis, aumentando o risco de cronificação da inflamação (Liu, Steinkeler, 2013 (Li et al, 2013), inflamação articular induzida por CFA (Li et al, 2013), cultura de macrófagos RAW264.7 tratados com LPS (Whiteman et al, 2011) e em modelo de miocardite causada por infecção por vírus Coxsackie tipo B3 em cardiomiócitos de ratos (Wu et al, 2015).…”