婴幼儿皮肤微生态特点及其在特应性皮炎发病中的作用

特应性皮炎(atopic dermatitis, AD)是一种常见的慢性炎症性皮肤病, 可发生于各个年龄段, 婴幼儿尤为高发。AD病因复杂, 既往认为遗传背景、皮肤屏障功能障碍和免疫紊乱是其主要发病机制。近年来皮肤微生态在AD发病中的作用被逐渐揭示, 成人AD常伴有以金黄色葡萄球菌定植增加和菌群多样性下降为主要特征的皮肤菌群失调。婴幼儿皮肤屏障功能与免疫功能随着年龄增长发生显著变化, 其皮肤菌群特点也不同于成人, 国内对此领域关注较少, 因此本文就婴幼儿皮肤微生态的特点及其在AD发病中的作用作一综述。

     

丹参凝胶治疗对特应性皮炎小鼠模型皮肤屏障功能、表皮增生以及免疫功能的影响

摘要 目的：研究丹参凝胶治疗对特应性皮炎小鼠模型皮肤屏障功能、表皮增生以及免疫功能的影响。方法：30只C57BL/6小鼠被随机分为Control组、AD组和SG组,每组10只。AD组和SG组背部涂抹对二硝基氟苯建立特应性皮炎小鼠模型,SG小鼠在模型建立成功后涂抹丹参凝胶治疗3周,Control组和AD组涂抹凡士林作为对照。3周后,测量所有小鼠经皮水分丢失量( TEWL) 、皮肤厚度、脾脏指数、胸腺指数,血清IgE、IFN-γ和IL-4,脾脏树突状细胞、Th1和Th2细胞比例。结果：丹参凝胶治疗3周后,AD组和SG组小鼠TEWL、皮肤厚度、脾脏指数、胸腺指数,血清IgE、IFN-γ和IL-4含量,以及脾脏Th2细胞比例均显著高于对照组正常小鼠（P<0.05）,而脾脏树突状细胞、Th1细胞和Th1/Th2细胞比例均显著低于对照组正常小鼠（P<0.05）;与AD组小鼠相比,SG组小鼠TEWL、皮肤厚度、脾脏指数、胸腺指数,血清IgE、IFN-γ和IL-4含量,以及脾脏Th2细胞比例均显著降低（P<0.05）,而脾脏树突状细胞、Th1细胞和Th1/Th2细胞比例均显著升高（P<0.05）。结论：丹参凝胶具有保护特应性皮炎样小鼠皮肤屏障功能和抑制表皮增生的功能,并且可以影响特应性皮炎样小鼠脾脏树突状细胞和辅助性T细胞比例。     

溶血磷脂酸在皮肤损伤疾病中的作用及其分子机制

皮肤作为人体最大器官覆盖于全身,能阻挡有害物质的侵入,保护人体内环境稳态,参与人体代谢过程。皮肤损伤、炎症和纤维化等,都会导致皮肤屏障功能的减退,影响正常的生命活动。溶血磷脂酸(lysophosphatidic acid,LPA)是十分活跃的磷脂信号分子,参与多种生理和病理生理过程。LPA是维持体内平衡所必需的生物活性脂质介质,在皮肤中通过不同的信号通路发挥多功能磷脂信使作用。本文综述了皮肤中溶血磷脂酸受体(lysophosphatidic acid receptor,LPA1-6)及其细胞信号通路的作用及机制,综述了LPA在皮肤创面愈合、皮肤瘢痕、皮肤黑色素瘤、硬皮病、皮肤瘙痒、过敏性皮炎、皮肤屏障、皮肤疼痛,皮肤毛发生长中的作用及分子机制,有助于了解LPA在皮肤中的生理和病理生理作用。深入研究LPA的作用机制将有助于挖掘其在皮肤治疗中的作用,开发以LPA为靶点的药物。     

奥洛他定联合金蝉止痒颗粒治疗对湿疹患者皮肤损伤、皮肤屏障功能及炎症因子的影响

摘要 目的：探究金蝉止痒颗粒辅助治疗对湿疹患者皮肤损伤、皮肤屏障功能及炎症因子的影响。方法：选取2020年6月~2022年5月来我院皮肤科就诊治疗的120例慢性湿疹的患者,按照治疗方式的不同分为对照组（n=60）与观察组（n=60）,其中对照组口服奥洛他定治疗,观察组在对照治疗基础之上加服金蝉止痒颗粒。对比两组患者治疗后的临床疗效、湿疹皮肤损伤严重程度评分皮肤屏障功能和炎性因子水平的变化。记录并比较两组患者的不良反应发生情况。结果：观察组总有效率（95.00%）显著高于对照组总有效率（60.00%）,差异有统计学意义（P<0.05）。治疗后与治疗前相比,两组患者瘙痒评分、皮损面积评分及EASI评分均显著下降,且观察组各项指标优于对照组,有统计学意义（P<0.05）。两组患者TEWL指标显著降低,而WCSC和SC指标显著升高,且观察组上述指标显著优于对照组,差异均有统计学意义（P<0.05）。两组患者血清IL-2水平明显升高,而IL-4、TNF-α水平显著降低,且观察组较对照组变化更为明显,差异均有统计学意义（P<0.05）。对照组患者的不良反应发生率为5.00%,治疗组为3.33%,两组比较无统计学意义（P>0.05）。结论：奥洛他定联合金蝉止痒颗粒治疗湿疹能够减少皮肤损伤,修复湿疹患者皮肤屏障损伤,调节血清炎症因子的变化,改善湿疹患者临床症状。     

性别对皮肤屏障障碍模型小鼠表皮厚度及丝聚合蛋白表达的影响

目的探索性别对小鼠皮肤屏障功能的影响。方法用丙酮-乙醚法和胶带粘贴法复制皮肤屏障功能障碍模型、观察性别对皮肤屏障障碍模型小鼠的表皮厚度和丝聚合蛋白(FLG)表达的影响。结果与正常对照组相比,丙酮-乙醚组和胶带粘贴组小鼠表皮厚度增宽(P0.05);正常对照组雄鼠与雌鼠相比,表皮厚度无差异;而丙酮-乙醚组和胶带粘贴组雌鼠表皮厚度均较同组雄鼠增加(P0.05)。丙酮-乙醚组和胶带粘贴组与正常对照组相比,FLG蛋白表达水平降低(P0.05),同组雄鼠表达水平均低于雌鼠(P0.05)。结论皮肤机械屏障功能被破坏后,小鼠的表皮厚度变化存在性别差异,而FLG蛋白表达在正常或是皮肤屏障障碍小鼠中的性别差异均有统计学意义,提示在研究小鼠皮肤屏障障碍相关疾病的发病机制和治疗措施时应重视性别差异。     

益生菌对特应性皮炎的防治及机制研究进展

特应性皮炎(atopic dermatitis, AD)是一种以反复发作和严重瘙痒为特征、发病率最高的过敏性皮肤病。AD的致病机制涉及遗传易感性、表皮屏障功能障碍、微生物组失调、免疫反应失衡以及环境等多个因素,而现有治疗用药副作用大、疗效欠佳。目前研究已发现肠道菌群尤其是益生菌在AD中起着重要作用。益生菌能够通过抑制病原菌、增强屏障功能、改善肠道环境和平衡Th1/Th2免疫应答等机制改善AD症状。本文综述了AD患者皮肤及肠道微生态特征,基于AD发病的致病机制和影响因素,系统阐明益生菌缓解AD的机制,以期为益生菌治疗AD及相关皮肤过敏性疾病提供理论支持。     

人造皮肤

皮肤可以让我们保持体内的水分平衡,而且它也是抵抗外界细菌的一道屏障。如果没有皮肤的保护,重度烧伤者会出现严重脱水,一些危及生命的细菌趁机还会来捣乱。怎么办呢?将健康皮肤移植到受伤区域是解决这一     

2种腺病毒介导的eGFP对人成纤维细胞转染效率的研究

目的:比较2种不同腺病毒(adenovirus,AD)介导的增强型绿色荧光蛋白(enhanced green fluorescent protein,eGFP)对人皮肤成纤维细胞(Human Fibroblast,HFB)的转染效率.方法:原代分离培养人皮肤成纤维细胞并鉴定,按照感染复数MOI为10、25、50、100转染传2代的人成纤维细胞,流式细胞检测AD5-EGFP和AD5/F35-EGFP对HFB的转染效率,荧光显微镜观察转染后的荧光强度.MTT法检测AD5.EGFP和AD5/F35-EGFP对HFB的毒性.结果:两种腺病毒对HFB的转染效率随着MOI增加而增高.AD5.EGFP和AD5/F35.EGFP在MOI为10、25、50、100时转染效率分别为9.44 3.44%、31.96 11.19%、51.7 7.24%、69.99 3.26%和22.82 8.98%、55.08 2.19%、63.37 7.24%、88.63 2.58%.两种病毒在转染过程中,细胞生长正常,MTT显示各转染组与未转染组的吸光度值无统计学差异.结论:AD5/F35载体对HFB嗜性显著高于AD5.在皮肤组织的基因修饰中,AD5/F35比AD5更具优越性.     

噬菌体展示肽在促进药物透过皮肤和血脑屏障中的应用

本文阐述了噬菌体展示肤在促进药物透过皮肤、血脑等生理屏障方面的研究应用及其展望.     

小细胞外囊泡在皮肤光老化等皮肤疾病中的作用及机制研究进展

小细胞外囊泡(small extracellular vesicles, sEVs)是近几年纳米医学界的新星,它有着独特的形态结构和理化性质,可以充当细胞间信息传递的介质,并作为疾病发生发展过程中的生物学标志物。现今人们越来越关注皮肤光老化问题,有关sEVs延缓和改善皮肤光老化的研究也逐渐成为热点。来源于间充质干细胞的sEVs不仅在皮肤光老化中有减轻炎症反应和减弱氧化损伤等的作用,而且对于其他皮肤疾病(例如皮肤创伤、斑块状银屑病、系统性红斑狼疮以及皮肤肿瘤等)也有着显著的作用。此外,由于sEVs的囊泡性质, sEVs正在成为一种新的药物递送系统。然而在将干细胞源性sEVs作为一种新的治疗方法时,仍需重视其安全性和毒性问题。     

Junctions and Inflammation in the Skin

Abstract

The skin forms a life-sustaining barrier between the organism and physical environment. The physical barrier of skin is mainly localized in the stratum corneum (SC); however, nucleated epidermis also contributes to the barrier through tight, gap, and adherens junctions (AJs), as well as through desmosomes and cytoskeletal elements. Many inflammatory diseases, such as atopic dermatitis (AD) and psoriasis, are associated with barrier dysfunction. It is becoming increasingly clear that the skin barrier function is not only affected by inflammatory signals but that defects in structural components of the barrier may be the initiating event for inflammatory diseases. This view is supported by findings that mutations in filaggrin, a key structural epidermal barrier protein, cause the inflammatory skin disease AD, and that a loss of AJ components, namely epidermal p120 catenin or α-catenin results in skin inflammation.     

Skin barrier homeostasis in atopic dermatitis: feedback regulation of kallikrein activity

Atopic dermatitis (AD) is a widely spread cutaneous chronic disease characterised by sensitive reactions (eg. eczema) to normally innocuous elements. Although relatively little is understood about its underlying mechanisms due to its complexity, skin barrier dysfunction has been recognised as a key factor in the development of AD. Skin barrier homeostasis requires tight control of the activity of proteases, called kallikreins (KLKs), whose activity is regulated by a complex network of protein interactions that remains poorly understood despite its pathological importance. Characteristic symptoms of AD include the outbreak of inflammation triggered by external (eg. mechanical and chemical) stimulus and the persistence and aggravation of inflammation even if the initial stimulus disappears. These characteristic symptoms, together with some experimental data, suggest the presence of positive feedback regulation for KLK activity by inflammatory signals. We developed simple mathematical models for the KLK activation system to study the effects of feedback loops and carried out bifurcation analysis to investigate the model behaviours corresponding to inflammation caused by external stimulus. The model analysis confirmed that the hypothesised core model mechanisms capture the essence of inflammation outbreak by a defective skin barrier. Our models predicted the outbreaks of inflammation at weaker stimulus and its longer persistence in AD patients compared to healthy control. We also proposed a novel quantitative indicator for inflammation level by applying principal component analysis to microarray data. The model analysis reproduced qualitative AD characteristics revealed by this indicator. Our results strongly implicate the presence and importance of feedback mechanisms in KLK activity regulation. We further proposed future experiments that may provide informative data to enhance the system-level understanding on the regulatory mechanisms of skin barrier in AD and healthy individuals.     

Keratinocytes regain momentum as instigators of cutaneous inflammation

The primary role of skin is to serve as a protective coat and epidermal keratinocytes are responsible for this barrier function. Besides providing structural support, keratinocytes can initiate inflammatory reactions, thereby enhancing healing of skin that follows barrier perturbation. In complex diseases such as psoriasis, in which both barrier function and cutaneous inflammation are dysregulated, it is unclear whether the primary pathogenic disturbance resides in keratinocytes or in immunocytes, which are commingled in psoriatic plaques. Researchers have turned to animal models of cutaneous inflammation to gain insights into the pathogenesis of psoriasis. A recent report in which the inducible epidermal deletion of Jun proteins in adult mice triggered inflammatory skin lesions and destructive arthritis has shifted momentum towards the keratinocyte as a key instigator of cutaneous inflammation. However, because this transgenic mouse model mimics only some features of psoriasis, further studies are required before the prevailing view of psoriasis as a fundamentally immunocyte-driven disease can be replaced by the notion that keratinocytes are the primary pathogenic cells in psoriasis.     

Suppressive effect of 1,4-anhydro-4-seleno-D-talitol (SeTal) on atopic dermatitis-like skin lesions in mice through regulation of inflammatory mediators

BackgroundAtopic dermatitis (AD) is a multifactorial chronic inflammatory disease that affects ∼20 % of children and 3% of adults globally and is generally treated by the topical application of steroidal drugs that have undesirable side-effects. The development of alternative therapies is therefore an important objective. The present study investigated the effects of topical treatment with a novel water-soluble selenium-containing carbohydrate derivative (4-anhydro-4-seleno-D-tatitol, SeTal) on the symptoms and inflammatory parameters in an AD mouse model.MethodsMice were sensitized by applying 2,4-dinitrochlorobenzene (DNCB) to their dorsal skin on days 1–3, then further challenged on their ears and dorsal skin on days 14, 17, 20, 23, 26, and 29. SeTal (1 and 2%) or hydrocortisone (1%) was applied topically to the backs of the mice from days 14–29, and skin severity scores and scratching behavior determined on day 30. The mice were euthanized, and their ears and dorsal skin removed to quantify inflammatory parameters, edema, myeloperoxidase (MPO) activity, and AD-associated cytokines (tumor necrosis factor alpha (TNF-α), interleukins (IL)-18, and IL-33).ResultsDNCB treatment induced skin lesions and increased the scratching behavior, ear edema, MPO activity (ear and dorsal skin), and cytokine levels in dorsal skin. Topical application of SeTal improved inflammatory markers (cytokine levels and MPO activity), cutaneous severity scores, and scratching behavior.ConclusionThe efficacy of SeTal was satisfactory in the analyzed parameters, showing similar or better results than hydrocortisone. SeTal appears to be therapeutically advantageous for the treatment and control of AD.     

Thematic review series: skin lipids. Peroxisome proliferator-activated receptors and liver X receptors in epidermal biology

The epidermis is a very active site of lipid metabolism, and all peroxisome proliferator-activated receptor (PPAR) and liver X receptor (LXR) isoforms are expressed in the epidermis. Activation of PPARalpha, -beta/delta, or -gamma or LXRs stimulates keratinocyte differentiation. Additionally, activation of these receptors also improves permeability barrier homeostasis by a number of mechanisms, including stimulating epidermal lipid synthesis, increasing lamellar body formation and secretion, and increasing the activity of enzymes required for the extracellular processing of lipids in the stratum corneum, leading to the formation of lamellar membranes that mediate permeability barrier function. The stimulation of keratinocyte differentiation and permeability barrier formation also occurs during fetal development, resulting in accelerated epidermal development. PPAR and LXR activation regulates keratinocyte proliferation and apoptosis, and studies have shown that these receptors play a role in cutaneous carcinogenesis. Lastly, PPAR and LXR activation is anti-inflammatory, reducing inflammation in animal models of allergic and irritant contact dermatitis. Because of their broad profile of beneficial effects on skin homeostasis, PPAR and LXR have great potential to serve as drug targets for common skin diseases such as psoriasis, atopic dermatitis, and skin cancer.     

The cell-mediated immune reaction in the cutaneous lesion of Chromoblastomycosis and their correlation with different clinical forms of the disease

Chromoblastomycosis is a fungal infection caused by dematiaceous fungi inducing skin lesions of difficult treatment and of frequent recurrence. The objective of the present investigation was to characterize cell-mediated tissue reactions in the skin in cases of Chromoblastomycosis using histopathology and immunocytochemistry methods and to correlate them with different clinical forms of Chromoblastomycosis. Biopsies from 19 patients were stained with HE and Giemsa, and serial sections were immunohistochemically stained using CD45RO, CD20, CD4, CD8, CD68, CD1a, CD34, IL4, IL10, TNF- and IFN- antibodies. A quantitative and semi quantitative analysis of the cell subsets and cytokines in the inflammatory infiltrates was performed by counting ten high-power fields (400×). The cutaneous lesion presented as verrucous plaque (n = 15) or erythematous atrophic plaque (n = 4). We observed two types of tissue reaction: A) a granulomatous reaction with a suppurative granuloma with several fungi cells in the cutaneous lesion presenting as verrucous plaque; B) a granulomatous reaction with a tuberculoid granuloma with few fungi cells in the cutaneous lesion presenting as atrophic plaque. The data obtained suggest that patients with lesion presented as verrucous plaque have a type Th2 immunological response, while patients with lesion presented as erythematous atrophic plaque have a type Th1 response.This revised version was published online in October 2005 with corrections to the Cover Date.     

Inflammatory cytokine‐mediated induction of serine racemase in atopic dermatitis

Serine racemase (SR) is an enzyme that catalyses the synthesis of d ‐serine, an endogenous coagonist for N‐methyl‐D‐aspartate (NMDA)‐type glutamate receptor in the central nervous system. Our previous study demonstrated that SR was expressed in the epidermis of wild‐type (WT) mice but not in SR knockout (KO) mice. In addition, SR immune‐reactivity was only found in the granular and cornified layers of the epidermis in WT mice. These findings suggested that SR is involved in the differentiation of epidermal keratinocytes and the formation of the skin barrier. However, its role in skin barrier dysfunction such as atopic dermatitis (AD) remains elusive. AD is a chronic inflammatory disease of skin, and the clinical presentation of AD has been reported to be occasionally associated with psychological factors. Therefore, this study examined the content of d ‐serine in stratum corneum in AD patients and healthy controls using a tape‐stripping method. Skin samples were collected from the cheek and upper arm skin of AD patient's lesion and healthy individuals. The d ‐serine content was significantly increased in the involved skin of AD in comparison with healthy individuals. An immunohistochemical analysis also revealed an increased SR expression in the epidermis of AD patients. Furthermore, the SR expression in cultured human keratinocytes was significantly increased by the stimulation with tumour necrosis factor ‐α or macrophage migration inhibitory factor. Taken together, these findings suggest that d ‐serine expressed particularly strongly in AD lesional skin and that the SR expression in the keratinocytes is linked to inflammatory cytokines.     

A novel organogermanium protected atopic dermatitis induced by oxazolone

Atopic dermatitis (AD) is a chronic inflammatory disease of the skin that is often associated with other atopic diseases, such as asthma and allergic rhinitis. Although topical steroids have widely been prescribed for patients with AD, skin abnormalities are frequently observed after prolonged steroid treatment. In this study, a novel water-soluble organogermanium compound (Ge-Vit) was prepared because organogermanium is a known INF-γ inducer. The Ge-Vit treatment decreased the basal TEWL and IgE production and attenuated the disruption of the skin barrier function in a murine model of chronic contact dermatitis. The histological examination further supported the anti-AD activities. These results suggested that Ge-Vit can be a useful drug candidate for treating atopic dermatitis.     

Hyperoxygenation Attenuated a Murine Model of Atopic Dermatitis through Raising Skin Level of ROS

Atopic dermatitis (AD) is a chronic inflammatory skin disease resulting from excessive stimulation of immune cells. Traditionally, reactive oxygen species (ROS) have been implicated in the progression of inflammatory diseases, but several opposing observations suggest the protective role of ROS in inflammatory disease. Recently, we demonstrated ROS prevented imiquimod-induced psoriatic dermatitis through enhancing regulatory T cell function. Thus, we hypothesized AD might also be attenuated in elevated levels of ROS through tissue hyperoxygenation, such as by hyperbaric oxygen therapy (HBOT) or applying an oxygen-carrying chemical, perfluorodecalin (PFD). Elevated levels of ROS in the skin have been demonstrated directly by staining with dihydroethidum as well as indirectly by immunohistochemistry (IHC) for indoleamine 2,3-dioxygenase (IDO). A murine model of AD was developed by repeated application of a chemical irritant (1% 2,4-dinitrochlorobenzene) and house dust mite (Dermatophagoide farinae) extract on one ear of BALB/c mice. The results showed treatment with HBOT or PFD significantly attenuated AD, comparably with 0.1% prednicarbate without any signs of side effects, such as telangiectasia. The expressions of interleukin-17A and interferon-γ were also decreased in the AD lesions by treatment with HBOT or PFD. Enhanced expression of IDO and reduced level of hypoxia-inducible factor-1α, in association with increased frequency of FoxP3⁺ regulatory T cells in the AD lesions, might be involved in the underlying mechanism of oxygen therapy. Taken together, it was suggested that tissue hyperoxygenation, by HBOT or treatment with PFD, might attenuate AD through enhancing skin ROS level.