| 研究実績の概要 |
We found that the concentration of hydrogen sulfide (H2S) in atopic dermatitis (AD) patients was significantly higher compared to healthy control. In mammals, the endogenous production of H2S has been attributed to three enzymes: cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfur-transferase (MPST). We found that the CBS, CSE, and MPST were mainly expressed in human KCs, and all of them were increased in the lesional skin of AD patients compared with that in controls.
The epidermal hyperinnervation observed in AD lesional skin is considered a cause of peripheral itch sensitization. It is regulated by axon-guidance molecules, e.g. the balance of nerve elongation factors (NEF), such as nerve growth factor (NGF) and artemin (ARTN), and nerve repulsion factor (NRF), such as semaphorin 3A (Sema3A), produced by keratinocytes (KCs).
We investigated whether H2S have a correlation with either NEF or NRF by using mRNA microarray data from public databases (GSE36842, 5667, and 32924). Correlation analysis suggested that CBS and CSE were positively correlated with NGF, and CSE with ARTN, at least in two microarray data, but not with Sema3A. Next, we examined the NGF, ARTN, and Sema3A expression levels in normal human epidermal keratinocytes (NHEKs) stimulated with sodium hydrosulfide (NaHS), a H2S donor, either by quantitative real-time RT-PCR or ELISA. mRNA and protein data showed that incubation of NHEKs with NaHS significantly increased of either NGF and ARTN, and decreased of Sema3A productions after NaHS stimulation compare to vehicle.
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| 現在までの達成度 (区分) |
現在までの達成度 (区分)
2: おおむね順調に進展している
理由
Despite the numerous reports that H2S is involved in various pathological diseases and/or itch, however, there have been no reports of its involvement in the expression of axon-guidance molecules in human KCs. In this study, we found that H2S-producing enzymes were expressed in human skin (mainly KCs), and were increased in human AD skin lesion. Notably, the H2S donor stimulation upregulated NGF and ARTN, and downregulated Sema3A levels in the cultured NHEKs, which is considered to be a cause of peripheral itch sensitization in AD skin lesion.
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| 今後の研究の推進方策 |
We would like to investigate further the role of gasotransmitter in mouse atopic dermatitis (AD)-model of house dust mite (HDM) in Nc/Nga mice. Previously we found that HDM AD-mouse model of Nc/Nga mice induced the expression of H2S-producing enzymes in mouse skin with AD condition. Next we will investigate whether the application of H2S-producing enzymes inhibitors can modulate the AD condition of the mouse. We will measured the clinical conditions, skin barrier function, H2S-producing enzymes expression in the skin, itch-related cytokines/chemokines, and other Th2-related conditions of the mouse with or without the inhibitors. We believe that these data will emphasize the role of gasotransmitter, e.g. H2S, in the setting of itch and AD.
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