Challenge to the developmental study of new biomarker and new treatment in recalcitrant allergic skin disease

难治性过敏性皮肤病新生物标志物和新疗法开发研究面临的挑战

基本信息

批准号：
21591471
负责人：
IKEZAWA Zenro
金额：
$ 3万
依托单位：
International University of Health and Welfare (2011)Yokohama City University (2009-2010)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2009
资助国家：
日本
起止时间：
2009 至 2011
项目状态：
已结题

项目摘要

1) IL-18 levels in the horny layer were significantly higher in the skin lesions of patients with AD than in healthy controls and correlated with SCORAD, levels of serum IL-18, IgE, lactate dehydrogenase(LDH), thymus and activation-regulated chemokine(TARC), blood eosinophils and transepidermal water loss(TEWL). In the AD group with serum IgE<1500 IU mL, significantly higher IL-18 levels were observed in the horny layer of patients colonized with S. aureus compared with those who were not. From these results, it may be concluded that epidermal IL-18 production is associated with the severity of AD, that staphylococcus aureus colonization seems to contribute to this IL-18 production, especially in the AD group with relatively low IgE production, and that tape stripping provides an easy and noninvasive method to assess epidermal IL-18 production by ELISA. 2-1) Pruritus is a common symptom of psoriasis, which affects quality of life. This symptom accompanies the hyperinnervation of sensor … More y C-fibres in psoriatic lesions. Two extracellular molecules, nerve growth factor(NGF) and semaphorin-3A, regulate C-fibre extension. In this study, the expression levels of these 2 molecules in biopsy specimens from psoriatic and healthy skin were quantified by immune-histochemistry and quantitative reverse-transcription PCR. Semaphorin-3A expression was lower in the psoriatic samples compared with the healthy samples, whereas NGF was higher. C-fibre innervation in the epidermis was also increased in psoriatic skin. Semaphorin-3A mRNA expression was negatively correlated with itch intensity and severity of psoriasis. We propose that decreased semaphorin-3A and increased NGF expression levels may trigger the outgrowth of C-fibres, leading to pruritus. 2-2) Sneezing and persistent itching of the nasal mucosa are distressing symptoms of allergic rhinitis(AR). Recent studies have revealed that hyperinnervation of sensory neurons in the nasal turbinate is one of the underlying causes of sneezing and itching. Since Semaphorin-3A(Sema3A) has been previously shown to restrict innervation of sensory neurons, it is presumed that reduced Sema3A expression in the nasal mucosa might contribute to the hypersensitivity. Analysis of the mouse model of ovalbumin-sensitized AR demonstrated a decreased expression of Sema3A in the nasal epithelium, which was accompanied by an increased nerve fiber density in the lamina propria of the turbinate. In rescue experiments, intranasal administration of recombinant Sema3A in the AR model mice alleviated sneezing and nasal rubbing symptoms. In addition, histological examinations also revealed that nerve fiber density was decreased in the lamina propria of the Sema3A-treated nasal turbinate. These results suggest that the nasal hypersensitivity of AR may be attributed to reduction of Sema3A expression and intranasal administration of Sema3A may provide a novel approach to alleviate the allergic symptoms for AR treatment. 3) CTP enhanced hyaluronic acid production in human dermal fibroblasts in vitro and in murine skin in vivo. Oral administration of CTP in acetone-induced dry skin model mice significantly decreased TEWL and suppressed scratching behavior. Intraepidermal nerve growth was dramatically inhibited in CTP-treated mice. Quantitative PCR analysis and immunohistochemical study revealed that CTP abolished the increased NGF and decreased Sema3A levels induced by acetone treatment. From these results, it may be concluded that oral administration of CTP improves dry skin and normalizes axon-guidance factors in the epidermis in addition to reducing pruritus. CTP may be used in a new therapeutic strategy against dry skin and pruritus. Less

1)AD患者皮损角质层IL-18水平显着高于健康对照者,且与SCORAD、血清IL-18、IgE、乳酸脱氢酶(LDH)、胸腺和活化调节水平相关趋化因子(TARC)、血嗜酸性粒细胞和经皮失水量(TEWL)在血清IgE<1500 IU·mL的AD组中显着升高。与未定植的患者相比，在金黄色葡萄球菌定植的患者的角质层中观察到 IL-18 水平，从这些结果可以得出结论，表皮 IL-18 的产生与 AD 的严重程度相关，即金黄色葡萄球菌定植。似乎有助于这种 IL-18 的产生，特别是在 IgE 产生相对较低的 AD 组中，并且胶带剥离提供了一种简单且非侵入性的方法来通过 ELISA 评估表皮 IL-18 的产生。 2-1) 瘙痒是银屑病的常见症状，影响生活质量，这种症状伴随着银屑病病变中两种细胞外分子神经生长因子 (NGF) 和 semaphorin-3A 的过度神经支配。调节 C 纤维延伸在这项研究中，这两种分子在银屑病和健康皮肤活检标本中的表达水平通过以下方法进行量化。免疫组织化学和反转录 PCR 发现，与健康样本相比，银屑病定量样本中的 Semaphorin-3A 表达较低，而表皮中的 C 纤维神经支配在银屑病皮肤中也有所增加。我们认为 semaphorin-3A 的减少和 NGF 表达水平的增加可能会引发银屑病的生长。 C 纤维，导致瘙痒。2-2) 打喷嚏和鼻粘膜持续瘙痒是过敏性鼻炎 (AR) 的令人痛苦的症状。最近的研究表明，鼻甲感觉神经元的过度神经支配是过敏性鼻炎的根本原因之一。由于 Semaphorin-3A(Sema3A) 先前已被证明可以限制感觉神经元的神经支配，因此推测鼻腔中 Sema3A 的表达减少。对卵清蛋白致敏 AR 小鼠模型的分析表明，鼻内上皮中 Sema3A 的表达减少，同时鼻甲固有层中的神经纤维密度增加。给 AR 模型小鼠注射重组 Sema3A 可以缓解打喷嚏和擦鼻症状。此外，组织学检查还发现，AR 模型小鼠的神经纤维密度降低。这些结果表明，AR 的鼻过敏可能归因于 Sema3A 表达的减少，并且鼻内施用 Sema3A 可能为缓解 AR 治疗的过敏症状提供一种新方法。在丙酮诱导的干性皮肤模型小鼠中，口服CTP可显着降低体外人真皮成纤维细胞和体内小鼠皮肤中透明质酸的产生。定量 PCR 分析和免疫组织化学研究表明，CTP 消除了丙酮治疗引起的 NGF 增加和 Sema3A 水平降低。除了减少瘙痒之外，CTP 的施用还可改善皮肤干燥并使表皮中的轴突导向因子正常化，这可用于对抗干燥的新治疗策略。皮肤瘙痒较少。