Occurrence of substance P,vasoactive intestinal peptide,and calcitonin gene-related peptide in dermographism and cold urticaria

Summary Substance P (SP), calcitonin gene-related peptide (CGRP), and vasoactive intestinal peptide (VIP) were assayed in lesions and normal skin of patients with dermographism and cold urticaria utilizing suction-induced blisters. There was no difference in SP and VIP concentrations between challenged and control skin of urticaria patients. On the whole, however, the concentration of both neuropeptides, and VIP in particular, was higher in the urticaria patients than in control subjects. CGRP levels were not increased. SP and VIP in blood samples from veins draining challenged skin areas were below the detection limit. It is concluded that SP and VIP may potentiate histamine in wheal formation and thus contribute to the increased reactivity of the skin to trauma and temperature changes in patients with physical urticaria.     

Skin levels of vasoactive intestinal polypeptide in atopic dermatitis

Summary Atopic dermatitis (AD) can be exacerbated by various factors, including emotional stress, scratching and sweating. The aim of the present study was to evaluate the hypothesis that the inflammatory reaction in AD is also neurogenic. For this purpose, the levels of vasoactive intestinal polypeptide were measured radioimmunologically in whole-tissue homogenates of lesional skin of 13 patients with atopic dermatitis. Radioimmunoassay was performed using an antiserum, AH78, recognizing the carboxy-terminal fragment vasoactive intestinal polypeptide (22–28). Vasoactive intestinal polypeptide immunoreactivity was detected in relatively low amounts in control skin (0.428±0.08 pmol/g tissue), whereas a marked increase in the peptide was observed in lesional skin of patients with atopic dermatitis (5.62±1.25 pmol/g tissue). These results seem to suggest that vasoactive intestinal polypeptide could have a pathogenetic relevance in skin lesions of atopic dermatitis.This work was presented in part at the XXth Annual Meeting of the European Society for Dermatological Research, Turin, Italy, 9–12 June 1990     

降钙素基因相关肽对朗格汉斯细胞功能影响的研究进展

在慢性炎症性皮肤病的神经免疫调节过程中,神经肽对于皮肤免疫细胞的调节作用受到越来越多的重视.在精神紧张、应激和压力的作用下,皮肤局部神经纤维产生降钙素基因相关肽,调节皮肤的朗格汉斯细胞.朗格汉斯细胞是表皮中重要的专职抗原提呈细胞.近年来发现,降钙素基因相关肽不仅可以影响朗格汉斯细胞的增殖、分化,而且影响其抗原提呈功能.降钙素基因相关肽可以抑制朗格汉斯细胞核因子κB通路的活化、抑制其协同刺激分子的表达,进而影响朗格汉斯细胞介导的免疫反应.     

Study of substance P and its receptor neurokinin-1 in psoriasis and their relation to chronic stress and pruritus

Substance P and its receptor(R) neurokinin (NK)-1 may have a role in the pathogenesis of psoriasis. Stress has been reported to play a role in the onset and exacerbation of psoriasis, which might include the substance P-NK-1 receptor(R) pathway. A feature of psoriasis, that has been correlated to the severity of stress and secretion of substance P, is pruritus. The objective of this study was to investigate the expression of substance P and the NK-1R in involved and noninvolved psoriatic skin, using a biotinylated streptavidin technique. Moreover, a possible correlation between the patient′s level of chronic stress, measured by salivary cortisol samples, degree of lesional pruritus, measured by means of a visual analogue scale, and the expression of substance P- and the NK-1R, was investigated. There was a low number of substance P positive nerve fibres in noninvolved and involved skin, the major immunoreactivity for substance P being found in inflammatory cells. The number of substance P- and NK-1R positive inflammatory cells was increased in involved compared to noninvolved psoriatic skin. The substance P positive cells were mostly lymphocytes, while most of the NK-1R positive cells were mast cells. NK-1R immunoreactivity was also seen as a reticular pattern in the upper part of the epidermis of involved skin in the majority of the patients. Low cortisol ratios in the patients, being an indicator of chronic stress, were correlated to an increased number of substance P- and NK-1R positive inflammatory cells in noninvolved psoriatic skin, and higher cortisol ratios to the presence of keratinocyte NK-1R immunoreactivity in involved skin. The degree of pruritus could not be correlated to the number of substance P positive fibers nor cells. Nonneuronal substance P and its receptor NK-1 might have a role in psoriasis, also during chronic stress.     

降钙素基因相关肽在银屑病发病机制中的研究进展

银屑病发病机理目前尚不完全清楚,研究人员在对皮损的组织病理研究中发现,银屑病的组织病理表现及皮肤内神经纤维的过度增生均与皮损内高水平的神经介质相关,基于相关研究确立了银屑病神经源性炎症发病机制的概念［１］……     

Cutaneous vascular response to calcitonin gene-related peptide in psoriasis and normal subjects

To determine whether cutaneous blood vessels in subjects with psoriasis possess a generalized inherently abnormal response to neuropeptides, the effect of three doses of intradermally injected calcitonin gene-related peptide (CGRP) on skin blood flow in normal subjects (n= 10), and on clinically normal skin (greater than 5 cm from psoriatic lesions) in subjects with psoriasis (n= 9) was measured using a laser Doppler technique. Calcitonin gene-related peptide caused a dose-dependent increase in local blood flow in both psoriatic and normal subjects, which was not statistically different between the two groups. This study has shown that the cutaneous vasculature at sites distant from lesions of psoriasis (> 5 cm) is not inherently different from normal skin in its response to CGRP.     

Substance P and calcitonin gene-related peptide modulate leukocyte infiltration to mouse skin during allergic contact dermatitis

The effects of the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) on leukocyte infiltration during allergic contact dermatitis (ACD) in mice were studied. Concomitant topical application of SP or CGRP with the allergen oxazolone resulted in enhanced leukocyte recruitment at the sites of challenge. Immunohistochemical studies revealed that the numbers of T-helper (L3T4+) and cytotoxic (Lyt-2) lymphocytes and infiltrating macrophages (BM8+) were increased. In addition, ICAM-1 and MHC class II molecule expression by these cells was enhanced after neuropeptide application. Analysis by confocal laser scanning microscopy revealed an increase in the immunoreactivity for SP and CGRP in nerve fibres during the course of ACD. Flow cytometry studies showed that SP and CGRP did not upregulate expression of the adhesion molecules ICAM-1 and VCAM-1 by murine endothelial cell lines in vitro. This suggests that increased infiltration of leukocytes during ACD is not a consequence of direct neuropeptide-promoted upregulation of endothelial adhesion molecules in vivo. In conclusion, our observations provide evidence for a modulatory role of neuropeptides in the pathogenesis of ACD.     

神经肽CGRP对银屑病单核细胞趋化功能的调节

为探讨神经肽对银屑病免疫细胞的调节，及其在银屑病神经免疫发病机制中的作用，本研究利用体外细胞培养技术分离培养单核细胞，分别加入外源性神经肽降钙素基因相关肽（calcitonin gene-related peptide,CGRP)及其受体拮抗剂CGRP8－37。用ELISA检测培养单核细胞上清液中趋化因子的含量；利用微型趋化小室，观察CGRP对单核细胞趋化活性的调节。结果CGRP诱导银屑病活化的单核细胞分泌趋化因子巨噬细胞炎性蛋白－1α(macrophage inflammatory protein-1α，MIP-1α）和单核细胞趋化性蛋白－1α（monocyte chemotactic protein-1α,MCP-1α)增加，受体拮抗剂CGRP8－37则抑制这种诱导作用，同时CGRP促进单核细胞对淋巴细胞和中性粒细胞的趋化活性，用CGRP8－37后则趋化活性减弱。提示银屑病皮损内神经肽CGRP可以通过受体诱导单核巨噬细胞分泌MIP－1α和MCP－1α趋化因子，使淋巴细胞和中性料细胞在局部皮损区定向迁移与聚集，促进局部炎性细胞的浸润。     

血管活性肠肽在寻常性银屑病皮损表皮中的免疫组化检测

目的　检测血管活性肠肽(VIP)在寻常性银屑病皮损表皮中的水平,探讨其与银屑病发病的关系。方法　应用免疫组化法检测了VIP在24例寻常性银屑病皮损表皮中的分布。以18例正常表皮为正常对照。结果　寻常性银屑病皮损表皮中VIP的阳性检测结果明显高于对照组(P<0. 05)。结论　VIP阳性的检测结果增高可能与银屑病的发病有关。     

Acute effects of substance P and calcitonin gene-related peptide in human skin--a microdialysis study

Upon activation nociceptors release neuropeptides in the skin provoking vasodilation and plasma protein extravasation in rodents, but only vasodilation in humans. Pivotal peptides in the induction of neurogenic inflammation comprise calcitonin gene-related peptide and substance P, the latter being suggested to act partly via degranulation of mast cells. In this study substance P and calcitonin gene-related peptide-induced vasodilation, protein extravasation, histamine release, and sensory effects were investigated simultaneously in human skin by dermal microdialysis. The vasodilatory prostaglandin E(2) and the mast cell activator codeine served as positive controls. Substance P and calcitonin gene-related peptide applied intradermally via large cut-off plasmapheresis capillaries induced dose-dependent local vasodilation, but only SP provoked protein extravasation in concentrations greater than 10(-9) M. Substance P-induced (10(-8)-10(-6) M) protein extravasation was not accompanied by histamine release and was unaffected by cetirizine (histamine H1 blocker, 200 microg per ml). Only the highest concentration of substance P (10(-5) M) induced significant histamine release. Neither neuropeptide caused any axon reflex erythema or any itch or pain sensation, whereas mast cell degranulation by codeine dose dependently provoked itch, flare, protein extravasation, and histamine release. In human skin calcitonin gene-related peptide and substance P induce vasodilation by a mechanism not involving histamine. No evidence for neuropeptide-induced activation of nociceptors was obtained. Our results suggest that endogenous calcitonin gene-related peptide and substance P have no acute sensory function in human skin. The lack of neurogenic protein extravasation in humans can most probably be attributed to low local concentrations of this neuropeptide still sufficient to exert trophic and immunomodulatory effects (10(-11) M), but too low to induce protein extravasation (10(-8) M) or even mast cell degranulation (10(-5) M). J Invest Dermatol 115:1015-1020 2000     

银屑病患者皮损内及血中神经肽(SP、SS)的研究

应用放射免疫分析法（ＲＩＡ）对４０例寻常性银屑病病人血及皮损中的Ｐ物质（ＳＰ）、生长抑素（ＳＳ）进行了测定，发现进行期和静止期银屑病病人皮损中ＳＰ增高，与正常人相比差异有显著性意义。ＳＰ血浆中含量、ＳＳ血及皮损中含量均与正常人无显著差别。结果提示：ＳＰ可能通过局部作用参与银屑病的病理过程，ＳＳ可能对银屑病的病理改变无影响。这也提示有必要开发安全、可靠的ＳＰ拮抗剂来治疗银屑病。     

银屑病伴瘙痒的临床特点、发病机制及治疗研究进展

【摘要】 以往认为银屑病属于非瘙痒性皮肤病,近年来,人们逐渐认识到瘙痒是加重银屑病患者疾病负担的因素之一。本文主要阐述瘙痒在银屑病中的临床特点,关注神经源性炎症中神经肽异常表达和神经末梢异常分布在瘙痒发病机制中作用,介绍治疗银屑病对瘙痒症状缓解的影响。     

银屑病患者的心理压力、神经内分泌系统与肥大细胞研究现状

银屑病中有相当比例的患者因心理压力而使病情恶化,但其机制尚不明确.心理压力能激活下丘脑-垂体-肾上腺轴和皮肤感觉神经,导致内分泌激素和神经介质释放.多种激素和神经介质能活化肥大细胞产生和释放一系列的炎症介质和细胞因子.银屑病患者中,一些激素、神经肽、感觉神经纤维和肥大细胞在表达水平和数量上增高.心理压力影响银屑病病情的机制之一可能与应激介质通过肥大细胞的作用有关.     

降钙素基因相关肽在银屑病斑块型皮损的分泌与表达

为了解精神心理刺激诱发加重银屑病的原因,探讨神经肽在银屑病发病机理中的作用,研究了降钙素基因相关肽（ＣＧＲＰ）在银悄病皮损中的分泌与表达,并确定ＣＧＲＰ作用的靶细胞,应用特异性放射免疫反相法分析,测定３２例建党型银屑病慢性斑块型皮损组织提取液中ＣＧＲＰ的含量,用抗生物素蛋白－生物素－过氧化物酶复合法和兔抗人ＣＧＲＰ抗体进行免疫组化染色,观察ＣＧＲＰ分泌表达的部位和作用的靶细胞。结果建党型银屑病慢性     

Binding and in vitro modulation of human epidermal Langerhans cell functions by substance P

Substance P (SP) is distributed in both the central and peripheral nervous system. It has various effects on immunocompetent cells, such as macrophages and lymphocytes. The aim of our study was to search for the presence of SP receptors (SP-R) on human cutaneous Langerhans cells (LC), and to determine the effects of SP on LC immunological functions in a model of mixed epidermal cell-lymphocyte reaction (MELR). Radioligand binding studies showed that LC-enriched epidermal cell suspensions reversibly bound SP, and that the specific binding increased with the percentage of LC. Functional assays showed that SP had no effect when added at concentrations from 10 ^–6 M to 10 ^–12 M to the MELR. The addition of SP at concentrations of 10 ^–4 M and 10 ^–5 M was able to inhibit the allogeneic T-cell response (98.3 ± 1.8% and 92.8 ± 8.9% inhibition, respectively) without modifying the cell viability. This inhibition was through an effect of SP on both T-cell and LC function. We conclude that SP has receptors on LC and may inhibit antigen presentation. Received: 22 July 1996     

特应性皮炎患者血浆中P物质的测定及其临床意义

目的 探讨特应性皮炎患者血清中P物质水平及其临床意义.方法 用放射免疫法测定35例特应性皮炎患者血浆中P物质浓度,观察P物质与疾病严重程度积分及嗜酸粒细胞数的关系.结果 特应性皮炎患者血浆中P物质浓度明显高于正常人对照P<0.01),且疾病的EASI评分和Rajka严重度积分与P物质浓度呈显著正相关,r分别为0.95和0.86,P均<0.01.特应性皮炎患者外周血嗜酸粒细胞数明显高于正常人对照(P<0.01),并且与疾病的严重度呈正相关(与EASI评分r=0.42,P=0.011,与Rajka严重度积分r=0.42,P=0.013):特应性皮炎患者血浆中P物质浓度与外周血嗜酸粒细胞数呈正相关(r=0.43,P=0.009).结论 P物质对判断特应性皮炎活动性可能有一定价值;P物质可能与嗜酸粒细胞共同参与特应性皮炎发病.     

EGF－R PCNA及P53基因在银屑病皮损中的表达

用ＥＧＦ－Ｒ、ＰＣＮＡ及Ｐ５３抗体和ＬＢＳＡ方法观察了４３例寻常性银屑病患者表皮及１２例正常皮肤。结果发现ＥＧＦ－Ｒ及ＰＣＮＡ表达明显增强，除基底层细胞外，棘层及颗粒层也有明显表达，个别病例角质层仍有少量表达。提示银屑病患者皮损处细胞增殖及分化调控紊乱。还发现银屑病患者皮损及皮损周未受累皮肤中无Ｐ５３的表达。     

EGF－R PCNA及P53基因在银屑病皮损中的表达

用ＥＧＦ－Ｒ、ＰＣＮＡ及Ｐ５３抗体和ＬＢＳＡ方法观察了４３例寻常性银屑病患者表皮及１２例正常皮肤。结果发现ＥＧＦ－Ｒ及ＰＣＮＡ表达明显增强，除基底层细胞外，棘层及颗粒层也有明显表达，个别病例角质层仍有少量表达。提示银屑病患者皮损处细胞增殖及分化调控紊乱。还发现银屑病患者皮损及皮损周未受累皮肤中无Ｐ５３的表达。     

The effects of substance P and vasoactive intestinal peptide on interleukin-6 synthesis in cultured human keratinocytes

Interleukin-6 (IL-6) is a cytokine implicated as a key mediator of immune and inflammatory responses in psoriasis. Recent studies have shown that neuropeptides, substance P (SP) and vasoactive intestinal peptide (VIP), can modulate a production of IL-6 from cells, such as monocytes and astrocytes, participating in an immune reaction. The aim of this study was to assess the role of the neuropeptides on cytokine production of keratinocytes in physiologic or pathologic conditions. Cultured human keratinocytes derived from normal foreskin and psoriatic lesions were treated with various concentrations of SP or VIP, in the presence or absence of fetal bovine serum. The secretion of IL-6 by the treated keratinocytes was analyzed by enzyme-linked immunosorbent assay. Although neither SP nor VIP, by itself, was able to induce IL-6 synthesis in cultured human keratinocytes, we have found that SP, not VIP, significantly reduced 5% fetal bovine serum-induced IL-6 production in time- and dose-dependent fashion. This down-regulatory effect of SP was reversed by spantide, a SP antagonist. Lesional psoriatic keratinocytes showed a similar, but weaker, response when compared with normal keratinocytes. These data suggested that SP might modulate IL-6 synthesis of keratinocytes in either physiologic or pathologic conditions such as psoriasis.     

Neural and vascular regulatory factors of the skin

Background Neural and vascular factors regulate many aspects of dermal function, including blood flow, inflammation, tissue repair and eccrine secretion. Abnormalities of neurovascular regulation may contribute to dermatological manifestations of a wide range of diseases including psoriasis, nodular prurigo and leprosy, diabetes mellitus and Raynaud's disease. Aims In this review we discuss evidence for roles played by neural and vascular regulatory factors in skin, with particular reference to the regulatory peptides substance P, calcitonin gene-related peptide. vasoactive intestinal polypeptide, neuropeptide Y and endothelin and to the important endothelial cell product nitric oxide. Conclusions An understanding of the anatomical basis of neurovascular regulation and the changes which occur during disease may lead to novel diagnostic and prognostic tests for dermatological conditions, while an understanding of specific receptors mediating the actions of regulatory peptides will lead to the development of specific antagonists as a novel approach in clinical dermatology.