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患者的皮肤皮肤水平的IL-18水平明显高于健康对照组中的IL-18水平，并且与Scorad，血清IL-18的水平，IL-18，IgE，乳酸脱氢酶（LDH），胸腺和激活调控的趋化因子（TARC），血液嗜酸菌和transinophiles and Transepidermal损失（Tewl）（Tewl）。在血清IgE <1500 IU mL的AD组中，与没有金黄色葡萄球菌的角质层相比，在与金黄色葡萄球菌共同定殖的患者的角质层中观察到IL-18水平明显更高。从这些结果可以得出的结论是，表皮IL-18的产生与AD的严重程度有关，金黄色葡萄球菌的定殖似乎有助于这种IL-18产量，尤其是在IGE相对较低的AD组中，并且磁带剥离提供了一种易于且无创的方法，可以评估Elisa的EliSA生产。 2-1）瘙痒是牛皮癣的常见症状，会影响生活质量。这种症状涉及传感器的过度连接……在银屑病病变中更多的y c纤维。两个细胞外分子，神经生长因子（NGF）和Semaphorin-3a调节C纤维延伸。在这项研究中，通过免疫 - 归化学和定量的反向转录PCR来量化这两个分子在活检标本中的表达水平。与健康样品相比，银屑病样品中的Semaphorin-3a表达较低，而NGF较高。银屑病皮肤中表皮中的C纤维神经也增加了。 Semaphorin-3a mRNA表达与牛皮癣的瘙痒强度和严重程度负相关。我们建议降低Semaphorin-3a和NGF表达水平升高可能会触发C纤维的生长，从而导致瘙痒。 2-2）鼻粘膜打喷嚏和持续的瘙痒是过敏性鼻炎（AR）的令人痛苦的症状。最近的研究表明，鼻涡流中感觉神经元的过度感染是潜行和瘙痒的根本原因之一。由于先前已证明Semaphorin-3a（Sema3a）限制了感觉神经元的神经的神经，因此呈现鼻粘膜中的SEMA3A表达降低可能有助于过敏。对卵蛋白敏感AR的小鼠模型的分析表明，鼻上皮的SEMA3A表达降低，这是由于涡轮层的层中神经纤维密度增加而实现的。在救援实验中，AR模型小鼠中重组SEMA3A的鼻内给药可缓解潜行和鼻摩擦症状。此外，组织学检查还表明，在经SEMA3A处理的鼻鼻甲的层层中，神经纤维密度降低。这些结果表明，AR的鼻高敏性可能归因于SEMA3A表达的降低，而SEMA3A的鼻内给药可能提供了一种新的方法来减轻AR治疗的过敏症状。 3）CTP在体外和体内鼠皮肤上增强了人真皮成纤维细胞中的透明质酸产生。口服CTP在丙酮诱导的干燥皮肤模型小鼠中显着降低了TEWL并抑制了刮擦行为。在CTP治疗的小鼠中，皮肤内神经的生长受到了极大的抑制。定量PCR分析和免疫组织化学研究表明，CTP废除了丙酮处理诱导的NGF的增加，并降低了SEMA3A水平。从这些结果可以得出的结论是，除了减少瘙痒外，CTP的口服给药可改善皮肤干燥，并使表皮中的轴突施加因子归一化。 CTP可用于针对干燥皮肤和瘙痒的新治疗策略。较少的