Detection of hydrogen sulfide in plasma and knee-joint synovial fluid from rheumatoid arthritis patients: Relation to clinical and laboratory measures of inflammation

Institute of Biomedical and Clinical Science, Peninsula Medical School, University of Exeter, St. Luke's Campus, Magdalen Road, Exeter, Devon, UK.
Annals of the New York Academy of Sciences (Impact Factor: 4.38). 08/2010; 1203(1):146-50. DOI: 10.1111/j.1749-6632.2010.05556.x
Source: PubMed


Blood concentrations of hydrogen sulfide (H(2)S) are markedly elevated in several animal models of inflammation. Pharmacological inhibition of H(2)S synthesis reduces inflammation and swelling, suggesting that H(2)S is a potential inflammatory mediator. However, it is currently unknown whether H(2)S synthesis is perturbed in human inflammatory conditions or whether H(2)S is present in synovial fluid. We analyzed paired plasma and synovial fluid (SF) aspirates from rheumatoid arthritis (RA; n= 20) and osteoarthritis (OA; n= 4) patients and plasma from age matched healthy volunteers (n= 20). Median plasma H(2)S concentrations from healthy volunteers and RA and OA patients were 37.6, 36.6, and 37.6 microM, respectively. In RA patients, median synovial fluid H(2)S levels (62.4 microM) were significantly higher than paired plasma (P= 0.002) and significantly higher than in synovial fluid from OA patients (25.1 microM; P= 0.009). SF H(2)S levels correlated with clinical indices of disease activity (tender joint count, r= 0.651; P < 0.05) and markers of chronic inflammation; Europhile count (r=-0.566; P < 0.01) and total white cell count (r=-0.703; P < 0.01). Our study shows for the first time that H(2)S is present in synovial fluid and levels correlated with inflammatory and clinical indices in RA patients.

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    • "The detrimental properties are mostly associated with extracellular (circulating or endothelium-bound) MPO. Of particular relevance, where sulfide is proposed to have a protective role, for example during reperfusion injury (Elrod et al., 2007), inhibition of leukocyte adherence (Zanardo et al., 2006), in rheumatoid arthritis (Whiteman et al., 2010), neurodegeneration (Gong et al., 2011) or in atherosclerosis (Mani et al., 2013), active MPO was proposed to act as a protagonist (such as reperfusion injury, Nicholls and Hazen, 2005; leukocyte adherence, Johansson et al., 1997; Wang et al., 2006; rheumatoid arthritis, Stamp et al., 2012; neurodegeneration, Yap et al., 2007 and in atherosclerosis, Heinecke, 1997; Nicholls and Hazen, 2005). The aim of this study was to investigate the interactions of human MPO with sulfide to assess whether a direct reaction could potentially generate a link between the mediatory roles of MPO and sulfide in the above mentioned physiological events. "
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    ABSTRACT: Background and purpose: The actions of hydrogen sulfide in human physiology have been extensively studied and, although it is an essential mediator of many biological functions, the underlying molecular mechanisms of its actions are ill-defined. To elucidate the roles of sulfide in inflammation, we have investigated its interactions with human myeloperoxidase (MPO), a major contributor to inflammatory oxidative stress. Experimental approach: The interactions of sulfide and MPO were investigated using electron paramagnetic resonance, electronic circular dichroism, UV-vis and stopped-flow spectroscopies. Key results: We found favourable reactions between sulfide and the native-ferric enzyme as well as the MPO redox intermediates, ferrous MPO, compound I and compound II. Sulfide was a potent reversible inhibitor of MPO enzymic activity with an IC50 of 1 µM. In addition, the measured second-order rate constants for the reactions of sulfide with compound I [k = (1.1 ± 0.06) × 10(6) M(-1) s(-1)] and compound II [k = (2.0 ± 0.03) × 10(5) M(-1) s(-1)] suggest that sulfide is a potential substrate for MPO in vivo. Conclusion and implications: Endogenous levels of sulfide are likely to inhibit the activity of circulating and endothelium-bound MPO. The fully reversible inhibition suggests a mediatory role of sulfide on the oxidant-producing function of the enzyme. Furthermore, the efficient HOCl oxidation of sulfide to give polysulfides (recently recognized as important components of sulfide biology) together with MPO-catalysed sulfide oxidation and the lack of interaction between MPO and sulfide oxidation products, predict a modulatory role of MPO in sulfide signalling.
    Full-text · Article · May 2014 · British Journal of Pharmacology
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    • "This observation would support the well-documented role of H2S in angiogenesis3137 which occurs during the vascularization of the pouch. H2S has recently been suggested to be a biomarker of disease progression in rheumatoid arthritis38 and acute lung infection39. The present study represents the first description of H2S measurement in vivo using a non-invasive method, and suggests that this could be translated to the determination of inflammation and leukocyte activation in a clinical setting. "
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    ABSTRACT: Hydrogen sulfide is an essential gasotransmitter associated with numerous pathologies. We assert that hydrogen sulfide plays an important role in regulating macrophage function in response to subsequent inflammatory stimuli, promoting clearance of leukocyte infiltrate and reducing TNF-α levels in vivo following zymosan-challenge. We describe two distinct methods of measuring leukocyte hydrogen sulfide synthesis; methylene blue formation following zinc acetate capture and a novel fluorescent sulfidefluor probe. Comparison of these methods, using pharmacological tools, revealed they were complimentary in vitro and in vivo. We demonstrate the application of sulfidefluor probe to spectrofluorimetry, flow cytometry and whole animal imaging, to monitor the regulation of hydrogen sulfide synthesis in vivo during dynamic inflammatory processes. Both methodologies revealed that granulocyte infiltration negatively affects hydrogen sulfide synthesis. Our report offers an insight into the profile of hydrogen sulfide synthesis during inflammation and highlight opportunities raised by the development of novel fluorescent hydrogen sulfide probes.
    Full-text · Article · Jul 2012 · Scientific Reports
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    ABSTRACT: Hydrogen sulfide is rapidly gaining ground as a physiological mediator of inflammation, but there is no clear consensus as to its precise role in inflammatory signaling. This article discusses the disparate anti-inflammatory ('the good') and proinflammatory ('the bad') effects of endogenous and pharmacological H(2)S in disparate animal model and cell culture systems. We also discuss 'the ugly', such as problems of using wholly specific inhibitors of enzymatic H(2)S synthesis, and the use of pharmacological donor compounds, which release H(2)S too quickly to be physiologically representative of endogenous H(2)S synthesis. Furthermore, recently developed slow-release H(2)S donors, which offer a more physiological approach to understanding the complex role of H(2)S in acute and chronic inflammation ('the promising') are discussed.
    Preview · Article · Jan 2011 · Expert Review of Clinical Pharmacology
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