DnaJA4敲除加重咪喹莫特诱导的小鼠银屑病样皮肤炎症

目的 探讨DnaJA4对咪喹莫特诱导小鼠银屑病样皮肤炎症的影响.方法 4组小鼠(每组8只),即应用咪喹莫特(imiquimod,IMQ)诱导银屑病样皮炎的DnaJA4敲除(knockout,KO-IMQ)组小鼠及野生型(wild-type,WT-IMQ)小鼠,涂以等量凡士林的DnaJA4敲除(knockout,KO-b...     

补体C3调控细胞凋亡抑制咪喹莫特诱导小鼠银屑病样皮肤炎症反应

目的 利用咪喹莫特(IMQ)诱导小鼠银屑病样皮炎模型,探讨补体C3在该病理过程中的作用及机制。方法 建立IMQ诱导银屑病样皮炎模型,比较C3^+/+及C3^-/-小鼠皮炎程度及病理改变;IHC检测皮损表皮细胞增殖,T细胞、中性粒细胞及巨噬细胞浸润,凋亡相关蛋白表达;TUNEL检测皮肤细胞凋亡;FCM比较小鼠皮损局部白细胞及中性粒细胞浸润及腋窝引流淋巴结IFN-γ应答。Z-VAD-FMK阻断凋亡途径,检测上述指标变化。结果 C3^-/-小鼠皮炎较C3^+/+组明显加重,表现为：角质形成细胞增生、微脓肿、棘皮症及炎症细胞浸润等显著增加(HE),角质形成细胞异常增殖(Ki67)、T细胞(CD3和CD4)、中性粒细胞(Ly-6G)及巨噬细胞(F4/80)浸润明显增加(IHC),凋亡相关蛋白(Cleaved casp3、Cyt C及BAK)表达显著上调(IHC),TUNEL阳性凋亡细胞明显增加(IF)。此外,FCM发现C3^-/-小鼠皮损局部白细胞(CD45)及中性粒细胞(Gr-1)浸润较C3     

6-羟基多巴胺阻断交感神经对咪喹莫特诱导银屑病样小鼠模型的系统性炎症的影响

 目的 探讨交感神经对咪喹莫特诱导银屑病样小鼠模型的系统性炎症的影响。 方法 将24只SPF级C57BL/6J小鼠以简单随机抽样法分为银屑病样皮炎模型组（模型组）、白念珠菌感染组、阴性对照组及银屑病样皮炎模型伴溶剂处理组（溶剂模型组）、6-羟基多巴胺（6-OHDA）处理组、溶剂对照组,每组4只。每日肉眼观察各组小鼠银屑病皮损变化情况;取小鼠背部、耳部皮损通过HE染色、q-PCR及Western blot检测白介素17A（IL-17A）炎症因子表达情况;取小鼠脾脏,通过流式细胞术检测炎症细胞、q-PCR及Western blot检测白介素6（IL-6）及白介素1β（IL-1β）观察小鼠脾脏的系统性炎症情况。结果 白念珠菌感染组小鼠背部及模型组小鼠背部均可见表皮增厚、角化不全、基底角化细胞增殖和炎症细胞浸润,且IL-17A上升,以上指标两组小鼠之间无统计学差异（均P>0.05）。相较于白念珠菌感染组,模型组还可见皮肤大量鳞屑产生及脾脏增大,脾脏炎症细胞增多,且IL-6、IL-1β水平升高（均P<0.01）。相较于溶剂模型组小鼠,6-OHDA处理组小鼠脾脏明显变小,脾脏中性粒细胞、单核细胞来源的巨噬细胞数显著降低,脾脏IL-6、IL-1β水平降低（均P<0.01）。结论 咪喹莫特诱导银屑病样小鼠模型存在系统性炎症,交感神经的激活可能参与银屑病中系统性炎症的产生。     

咪喹莫特诱导小鼠银屑病样皮损机制的研究进展

咪喹莫特作为治疗人乳头瘤病毒感染的药物,在临床应用中发现可引起银屑病样皮损并能加重银屑病患者病情,而被广泛用于银屑病发病机制及治疗靶点的研究.由咪喹莫特诱发的小鼠银屑病样模型具有操作简单、易于成模的优点.应用咪喹莫特后,小鼠体内有包括Toll样受体信号通路等多条通路被激活,其中部分为协同作用.激活的信号通路进一步诱导角质形成细胞、树突细胞、Th17、γδT细胞、中性粒细胞等产生一系列炎性因子(如白细胞介素1、23、17,干扰素α等),这些炎性因子对银屑病样皮损的形成起到重要的作用.     

Notch信号通路相关配体在咪喹莫特诱导的银屑病样小鼠模型中的表达

目的：检测Notch信号通路相关配体在咪喹莫特（IMQ）诱导的银屑病样小鼠模型中的表达。方法： 6-8周雌性BALB/c小鼠随机分为IMQ模型组及空白对照组。HE染色观察皮损病理变化。RT-PCR及免疫组化分别检测IMQ模型组及空白对照组皮肤受体Notch1、Notch2、配体Jagged-1、目标基因Hes-1的mRNA和蛋白表达水平。结果：IMQ模型组小鼠皮肤出现典型银屑病样改变。IMQ模型组小鼠皮损中受体Notch 1、Notch2、配体Jagged-1、目标基因Hes-1的mRNA和蛋白表达水平高于对照组（P<0.05）。结论：Notch信号通路在咪喹莫特诱导的银屑病样小鼠模型中被激活。     

芹菜素对咪喹莫特诱导的小鼠银屑病样皮损的影响及机制

目的：观察芹菜素对咪喹莫特（IMQ）造模小鼠及对角质形成细胞（HaCaT细胞）炎症通路和细胞增殖的影响。方法：小鼠随机分为4组,连续6 d使用凡士林或IMQ涂抹背部皮肤建立对照组和银屑病模型,期间每日予芹菜素或玉米油灌胃。于第7天比较治疗后各组皮损变化;蛋白免疫印迹法（western blot）检测各组核因子κB抑制蛋白（IKB)α、磷酸化（phosphorylation,p)-IKBα、凋亡及细胞核因子-κB p65(NF-κB p65）、p-NF-κB p65、信号转导与转录激活因子（STAT)3、p-STAT3、细胞增殖抗原（Ki-67）和角蛋白（keratin,K)17蛋白变化。体外实验设对照组、模型组、5μmol/L芹菜素处理组和10μmol/L芹菜素处理组;western blot检测各组角质形成细胞p-STAT3、STAT3、p-IKB α、IKB α、p-NF-κB p65、NF-κB p65、Ki-67和K17变化。结果：芹菜素改善了IMQ诱导的银屑病样小鼠的皮损及病理改变。与造模组比较,干预组小鼠皮损中p-STAT3、p-IκB、p-NF-κB p65、Ki-67、...     

人脐带间充质干细胞对咪喹莫特诱导的银屑病样皮炎小鼠模型的治疗作用

目的 研究人脐带间充质干细胞(MSC)对咪喹莫特诱导的银屑病样皮炎小鼠模型的治疗作用及机制.方法 将18只C57BL/6小鼠按随机数字表等分为凡士林组、模型组和治疗组,每组6只.小鼠背部剃毛后,模型组和治疗组小鼠背部涂抹5％咪喹莫特乳膏62.5 mg每天1次,连续6d,凡士林组小鼠涂抹等量的凡士林软膏;治疗组小鼠在第1...     

咪喹莫特诱导的银屑病样小鼠模型的组织学及免疫学特征初步探究

目的:研究咪喹莫特诱导的银屑病样小鼠模型的皮肤组织学及免疫学特征。方法:将20只BALB/c小鼠随机分为造模组和对照组,每组10只。所有小鼠背部剃毛后,造模组小鼠于背部皮肤及单侧耳部每日涂抹共计62.5 mg的5%咪喹莫特乳膏1次,连续7 d,空白组小鼠涂抹等量凡士林。每日记录小鼠PASI评分及耳部厚度,并于末次涂药24 h后处死,取背部皮肤进行多聚甲醛固定,行HE染色及Ki-67免疫组化分析。取脾脏称重,以流式细胞术检测脾脏中的Th细胞亚群。结果:造模组小鼠于第二天逐渐出现红斑、鳞屑、皮肤增厚及耳部肿胀,其PASI评分随造模时间延长而增加。造模组小鼠皮损出现银屑病样病理改变,其表皮厚度明显增加(t=15.12,P<0.001),且Ki-67阳性率明显上升,每个高倍镜视野下阳性细胞数目明显增加(t=10.50,P<0.001)。造模组小鼠脾脏重量和细胞计数较对照组明显增加,且Th1、Th17细胞亚群的比例及绝对计数较对照组明显上升(P值均<0.05),Th2细胞比例及计数无明显变化(P值均>0.05)。结论:咪喹莫特诱导的银屑病样小鼠模型可较好地模拟寻常型银屑病的临床、组织病理和免疫学特征,是一种有效的银屑病模型。     

外用紫草素对咪喹莫特诱导银屑病样小鼠模型的干预作用及对CEBPD表达的影响

目的:探讨外用紫草素对咪喹莫特诱导的银屑病样小鼠模型的干预作用及对CCAAT增强子结合蛋白δ（CEBPD）表达的影响。方法:将20只SPF级BALB/c雄性小鼠按照简单随机抽样法分为模型组、紫草素1组、紫草素2组及空白对照组,每组5只。模型组、紫草素1组和紫草素2组小鼠背部脱毛区均每日外涂5%咪喹莫特乳膏（IMQ）50...     

清热凉血方对咪喹莫特诱导的银屑病样小鼠模型JAKs/STATs通路表达影响的研究

目的 观察清热凉血方对咪喹莫特诱导的银屑病样小鼠模型皮损中酪氨酸激酶/信号转导因子和转录激活因子(JAKs/STATs)信号通路表达的影响.方法 BALB/c雄性小鼠48只,随机分为空白组、模型组、雷公藤多苷组及清热凉血方低、中、高浓度组,每组8只,采用外用咪喹莫特乳膏诱导产生银屑病样皮损.肉眼观察小鼠背部皮损严重程度...     

阿维A对寻常型银屑病患者血清MMP-2及TIMP-2的影响

目的：确定基质金属蛋白酶-2（MMP-2）及金属蛋白酶组织抑制剂-2（TIMP-2）在寻常型银屑病发病中的作用及阿维A对其的调节作用。方法：应用双抗体夹心酶联免疫吸附法（ELISA）检测30例寻常型银屑病患者经阿维A治疗前后外周血清中MMP-2及TIMP-2的水平。结果：寻常型银屑病患者血清中MMP-2、TIMP-2、MMP-2／TIMP-2的水平较正常人对照组显著增高（P〈0．001）。治疗后血清中MMP-2、TIMP-2、MMP-2／TIMP-2较治疗前显著下降（P〈0．01）。结论：阿维A可通过降低血清MIRP-2，升高TIMP-2水平而起到治疗作用。     

Poly(ADP-ribose) polymerase-1 depletion enhances the severity of inflammation in an imiquimod-induced model of psoriasis

Poly(ADP-ribose) polymerase-1 (PARP1) is a pro-inflammatory protein, whose pro-inflammatory properties were demonstrated in human. The pro-inflammatory properties of PARP1 were shown in Th1- and Th2-mediated inflammatory pathologies, but not Th17-mediated inflammation. Thus, we studied the role of PARP1 in the imiquimod-induced model of psoriasis. To our surprise, in imiquimod-induced psoriasis, PARP1 acted as an anti-inflammatory factor and its genetic deletion exacerbated symptoms. We showed that in the absence of PARP1, the epidermis thickened and the number of TUNEL-positive cells decreased in the epidermis. These data indicate programmed cell death is decreased in keratinocytes. Changes in involucrin expression suggest that keratinocyte differentiation is hampered. Furthermore, epidermal expression of IL6 increased in the psoriasiform lesions of PARP1 knockout mice, suggesting that the inflammatory response is also derailed in the absence of PARP1. Finally, we showed that PARP1 expression is reduced in human psoriatic lesions compared with control skin samples. In imiquimod-treated HPV-KER keratinocytes, PARP inhibition recapitulated the in vivo findings, namely keratinocyte hyperproliferation; furthermore, the mRNA expression of psoriasis-associated cytokines (IL6, IL1β, IL8, IL17 and IL23A) was also induced. The inhibition of TRPV1 abrogated the effects of the combined imiquimod + PARP inhibitor treatment.     

复方泽漆冲剂对血热型寻常型银屑病患者血清中MMP-2、MMP-9和IL-18的影响

目的观察复方泽漆冲剂对血热型寻常型银屑病(PV)患者血清中MMP-2、MMP-9和IL-18的变化,探讨复方泽漆冲剂对血热型PV患者血清MMP-2、MMP-9和L-18浓度的影响;方法经纳入的血热型患者分治疗组(28例)采用复方泽漆冲剂,对照组(28例)采用自拟方,4周后采用ELISA法对56例PV患者治疗前后血清中MMP-2、MMP-9和IL-18水平进行检测;结果治疗组及对照组患者血清MMP-2、MMP-9和IL-18治疗后浓度均显著低于治疗前水平P0.05;结论复方泽漆冲剂能降低血热型PV患者血清中MMP-2、MMP-9和IL-18的水平,观察MMP-2、MMP-9和IL-18浓度变化对PV的治疗和指导用药有重要的临床价值。     

树突状细胞在银屑病中的研究进展

银屑病是一种免疫系统异常激活的慢性炎症性皮肤病,其确切发病机制尚不完全清楚,但近年来,免疫应答失调在银屑病病理生理中的作用日益受到重视.树突状细胞作为先天免疫细胞,通过调节炎症相关因子和信号通路,启动和调节T细胞的免疫反应,在银屑病的发病过程中发挥重要作用.本文旨在总结近期树突状细胞在银屑病发病过程中的研究进展,以探讨...     

阿维A治疗斑块状银屑病临床疗效观察

目的:观察阿维A治疗中、重度斑块状银屑病的疗效.方法:将中、重度斑块状银屑病患者随机分成两组,分别给予阿维A和海棠合剂治疗,疗程均为8周,以银屑病面积和严重度指数(PASI)和皮肤病生活质量指数(DLQI)作为观察指标,比较两种药物的疗效.结果:治疗后,两组患者的PASI评分和DLQI评分与治疗前比较均显著下降(P＜0.01),但PASI改善率和DLQI改善率两组间比较差异无统计学意义,PASI50和PASI75有效率亦无统计学意义(P＞0.05).结论:阿维A治疗中、重度斑块状银屑病有效.     

银屑病对生殖功能和妊娠的影响

目前已有多篇文献报道银屑病可能会影响生殖功能,降低男性和女性的生育力,使得妊娠结局不佳,妊娠期脓疱型银屑病对母婴危害大等。本文综述了银屑病对生殖功能和妊娠影响的研究进展。     

Elevation of serum epidermal growth factor and interleukin 1 receptor antagonist in active psoriasis vulgaris

Background Psoriatic plaques present a complex expression profile, including high levels of cytokines, chemokines and growth factors. Circulating cytokines have been suggested to reflect the activation status of the inflammatory process. Objectives To analyse 20 cytokines, chemokines and growth factors in 14 patients with psoriasis vulgaris at the start and during the course of ultraviolet B treatment. Methods A multiplex cytokine assay was used. Results We identified increased serum levels of epidermal growth factor (EGF) (mean 323 vs. 36·6 pg mL^?1, P =0·0001), interleukin (IL)‐1 receptor antagonist (mean 39·1 vs. 14·6 pg mL^?1, P =0·02) and tumour necrosis factor‐α (mean 7·5 vs. 4·5 pg mL^?1, P =0·04) at baseline in patients with psoriasis compared with matched controls. None of these cytokines was correlated to the severity of the disease (Psoriasis Area and Severity Index) or decreased with phototherapy, suggesting that sources other than lesional skin contribute to the production of these cytokines. Using cluster analysis, we observed coordinate upregulation of EGF, IL‐6, macrophage inflammatory protein‐1β and vascular endothelial growth factor. Conclusions The sustained high expression of inflammatory circulating cytokines is a potential mechanism linking psoriasis with its extracutaneous comorbidities.     

The effect of methotrexate on the expression of cell adhesion molecules and activation molecule CD69 in psoriasis

BACKGROUND: The mechanism of the action of methotrexate (MTX) in the treatment of psoriasis has not been completely elucidated. OBJECTIVE: To assess the effect of MTX on the expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin, activation molecule CD69 and T-cell phenotype in skin specimens from patients with psoriasis. METHODS: We performed an immunohistochemical analysis of the expression of T-cell phenotype and cell adhesion/activation molecules in skin biopsies from patients with psoriasis treated with a fixed dose of MTX (12.5 mg/week). To determine data on the epidermal/dermal T-cell infiltration we carried out a manual quantification. RESULTS: Skin samples prior to therapy showed a moderate to severe inflammatory infiltrate, mainly due to T lymphocytes with a helper/inducer (CD4) phenotype. Most of these cells also expressed ICAM-1 and VCAM-1. Blood vessels showed expression of E-selectin and VCAM-1, and keratinocytes were positive for ICAM-1 staining. The cell infiltrate was reduced after therapy, as well as the expression of cell adhesion molecules. However, we also noted the persistence of the T lymphocyte phenotype CD8(+), expressing the CD69 activation molecule, after the MTX treatment. CONCLUSIONS: MTX downregulates the expression of some adhesion molecules, a phenomenon that may contribute to its anti-inflammatory therapeutic effect in psoriasis. The infiltrating T cells post-treatment have an activated cytotoxic phenotype, which may suggest a pathogenic role in the continuation and/or recurrence of psoriasis.     

Role of neutrophils in induction of acute inflammation in T-cell-mediated immune dermatosis, psoriasis: a neutrophil-associated inflammation-boosting loop

A growing body of evidence has indicated that T-cell-mediated immunity plays an important role in triggering and maintenance of psoriatic lesions. In this review we present our own experimental results as well as those from the literature related to the pathomechanism of the development of inflammatory changes in psoriatic lesions. First of all it is important to acknowledge the fact that psoriatic lesions are not uniform as assumed by many authors but that they are actually rather heterogeneous both clinically and histologically even within the same plaques. Lymphokines produced by activated T cells in psoriatic lesions have a strong influence on the proliferation of the epidermis, whose stimulated kertinocytes released several cytokines, which in turn enhance the activation state of T cells. Thus, they form a vicious cycle, a T-cell-mediated inflammation-sustaining loop. Although the interaction between T-cell-mediated immunity and epidermal keratinocytes may well explain the maintenance of background "chronic" inflammatory changes diffusely observed throughout psoriatic lesions, it is not enough to explain the island-like, "acute" inflammatory changes observed within and at the border of the plaque lesions. Characteristic neutrophil accumulation under the stratum corneum can be observed in the highly inflamed and therapeutically recalcitrant areas of psoriatic lesions. They are chemotactically attracted and activated there by synergistic action of chemokines, IL-8 and Gro-a released by the stimulated keratinocytes, and particularly C5a/C5a des arg produced via the alternative complement pathway activation possibly on the surface of corneocytes. In this review, we emphasize that the accumulation of neurophils is not simply a passive event. We think that those stimulated neutrophils are able to influence not only the growth and differentiation of epidermal keratinocytes but also the activation-state of T cells by aberrant expression of HLA-DR on their surfaces as well as by their effects. These T cells in turn influence the transepidermal neutrophil migration through the effect of their lymphokines on the keratinocyte production of pro-inflammatory mediators including C3. Therefore, we propose a neutrophil-associated inflammation-boosting loop that may well explain the localized "acute" inflammatory changes scattered over the "chronic" psoriatic plaques as well as in the acutely inflamed lesions of pustular psoriasis.