Effects of olopatadine hydrochloride, an antihistamine drug, on skin inflammation induced by repeated topical application of oxazolone in mice

BACKGROUND: Olopatadine hydrochloride (olopatadine) is one of the second-generation antihistamines, which is prescribed for allergic disorders such as rhinitis, urticaria and eczema dermatitis. OBJECTIVES: To investigate the possible anti-inflammatory effect of olopatadine on the chronic contact hypersensitivity response to repeated topical application of oxazolone in mice. METHODS: The preventive and therapeutic effects of oral olopatadine were quantified by measurements of ear swelling, cytokine protein and mRNA expression in the ear lesion, and were compared with those of topical betamethasone 17-valerate (betamethasone). RESULTS: The ear receiving repeated applications of oxazolone exhibited erythema, oedema and abrasion. Both preventive and therapeutic administration of olopatadine (10 mg kg(-1) day(-1)) significantly inhibited the ear swelling and the increased production of interleukin (IL)-4, IL-1beta, granulocyte-macrophage colony-stimulating factor (GM-CSF) and nerve growth factor. In the histopathological analysis, olopatadine ameliorated epidermal hyperplasia and infiltration of inflammatory cells. Consistent with these results, olopatadine significantly reduced the increased expression of interferon-gamma and IL-4 mRNA. Although betamethasone (0.012 mg ear(-1) day(-1)) showed similar activities to olopatadine against these responses, it caused atrophy of the ear skin. CONCLUSIONS: These results indicate that olopatadine is an antihistamine agent having inhibitory activities against chronic inflammatory dermatitis, possibly resulting from its diminishing effect on elevated cytokines.     

Severity scores, itch scores and plasma substance P levels in atopic dermatitis treated with standard topical therapy with oral olopatadine hydrochloride

Atopic dermatitis (AD) is a common chronic or chronically relapsing, severely pruritic, eczematous skin disease. Recently, substance P (SP) has been demonstrated to be one of the important neuropeptides for mediating itch–scratch and stress–scratch cycles. In this study, we examined the severity scores, itch scores and plasma SP levels in 19 patients with AD treated with standard topical therapy with or without an oral antihistamine, olopatadine hydrochloride, for 4 weeks. The standard therapy decreased SCORAD scores, itch behavioral rating scores and plasma SP levels at post-treatment in the mass, but the topical therapy with olopatadine was more effective than the topical therapy alone, suggesting a potential additive effect.     

Topical application of the immunosuppressant tacrolimus accelerates carcinogenesis in mouse skin

BACKGROUND: Tacrolimus, produced by the fungus Streptomyces tsukabaensis, is a potent macrolide immunosuppressant widely used in liver and kidney transplantation. Topical tacrolimus has recently been found to be an effective treatment for atopic dermatitis (AD). OBJECTIVES: Because of the well-known association between T-cell immunosuppression and an increased risk of carcinogenesis, we investigated the effect of topical tacrolimus on skin carcinogenesis in 117 mice. METHODS: Approximately 8 cm2 of the shaved dorsal skin of 7-week-old female CD-1 mice was treated with 7,12-dimethylbenz[alpha]anthracene (DMBA) dissolved in acetone, which is in general use as a tumour initiator, or acetone alone, on day 1 of the experiment, followed by promoting treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA) with or without tacrolimus, or acetone with or without tacrolimus, for 20 weeks. The mice were divided into six treatment groups: (1) DMBA followed by acetone; (2) DMBA followed by TPA; (3) DMBA followed by acetone + tacrolimus; (4) DMBA followed by TPA + tacrolimus; (5) acetone followed by acetone + tacrolimus; and (6) acetone followed by acetone (control). RESULTS: The induction of skin tumours was significantly greater in the TPA-treated groups than in the absence of TPA. However, after 14 weeks there was marked synergy between tacrolimus and the DMBA/TPA regimen, with 0.47 +/- 0.13 (mean +/- SD) new tumours per mouse per week in group 4 vs. 0.10 +/- 0.025 in group 2 (P < 0.01), and 0.01 +/- 0.002 in group 3. A significant reduction in the CD4/CD8 ratio was found in axillary and inguinal lymph nodes in tacrolimus-treated mice, supporting the presumption that the immunosuppressive effect of the drug was responsible for its effect in promoting tumorigenesis. The major increase in tumours caused by topical tacrolimus was of papillomas, not squamous cell carcinomas. Papillomas are uncommon in humans, and are benign. However, 8.5% of the tumours found in the experiment were squamous cell carcinomas, and a considerable synergy between topical tacrolimus and conventional carcinogens was observed, raising the spectre of some risk of skin carcinogenesis in AD patients undergoing prolonged treatment with tacrolimus. CONCLUSIONS: Caution and careful surveillance are required with regard to skin lesions in patients treated with tacrolimus for prolonged periods.     

Impairment of skin barrier function in NC/Nga Tnd mice as a possible model for atopic dermatitis

BACKGROUND: The pathogenesis and aetiology of atopic dermatitis (AD) remain unclear. Establishment of suitable animal models should aid elucidation of the pathogenesis and development of therapy. OBJECTIVES: We focused on biophysical and biochemical parameters in the skin of NC/Nga Tnd mice to evaluate similarities to and differences from AD. METHODS: Biophysical (transepidermal water loss and skin surface conductance) and biochemical parameters (ceramide contents and activity of ceramide-metabolizing enzymes) were measured in NC/Nga Tnd mice in which spontaneous dermatitis appeared under ambient laboratory conditions (ALC). RESULTS: Biophysical parameters suggested impairment of water retention properties and barrier function. The amount of ceramide in NC/Nga Tnd mice under ALC decreased significantly. These dermatological features resembled those of AD, as did the clinical signs and histological changes. CONCLUSIONS: The results described here and previous immunological studies on AD suggest that the NC/Nga Tnd mouse may be a suitable model for certain aspects of AD.     

皮肤屏障功能与特应性皮炎

目前认为特应性皮炎发病机制不清,可能具有遗传缺陷的个体,在环境等因素的作用下皮肤的蛋白、脂质等的代谢出现异常,进而出现皮肤屏障结构的异常,导致天然保湿因子、抗菌肽减少、经皮失水率增加和pH值的升高等病理生理改变。本文将对皮肤屏障结构异常与特应性皮炎的关系进行综述。     

Comparison of skin barrier function and sensory nerve electric current perception threshold between IgE-high extrinsic and IgE-normal intrinsic types of atopic dermatitis

Background  Two types of atopic dermatitis (AD) have been proposed, with different pathophysiological mechanisms underlying this seemingly heterogeneous disorder. The extrinsic type shows high IgE levels presumably as a consequence of skin barrier damage and feasible allergen permeation, whereas the intrinsic type exhibits normal IgE levels and is not mediated by allergen-specific IgE.
Objectives  To investigate the relationship between pruritus perception threshold and skin barrier function of patients with AD in a comparison between the extrinsic and intrinsic types.
Methods  Enrolled in this study were 32 patients with extrinsic AD, 17 with intrinsic AD and 24 healthy individuals. The barrier function of the stratum corneum was assessed by skin surface hydration and transepidermal water loss (TEWL), and pruritus perception was evaluated by the electric current perception threshold (CPT) of sensory nerves upon neuroselective transcutaneous electric stimulation.
Results  Skin surface hydration was significantly lower and TEWL was significantly higher in extrinsic AD than intrinsic AD or normal controls. Although there was no statistically significant difference in CPT among extrinsic AD, intrinsic AD and normal controls, CPT was significantly correlated with skin surface hydration and inversely with TEWL in intrinsic AD and normal controls, but not extrinsic AD. Finally, CPT was correlated with the visual analogue scale of itch in the nonlesional skin of patients with extrinsic but not intrinsic AD.
Conclusions  Patients with extrinsic AD have an impaired barrier, which increases the pre-existing pruritus but rather decreases sensitivity to external stimuli. In contrast, patients with intrinsic AD retain a normal barrier function and sensory reactivity to external pruritic stimuli.     

Dietary sphingolipids improve skin barrier functions via the upregulation of ceramide synthases in the epidermis

Sphingolipids are ubiquitous in eukaryotic organisms and are significant components in foods. It has been reported that treatment with sphingolipids prevents colon cancer, improves skin barrier function and suppresses inflammatory responses. However, the mechanisms for those effects of dietary sphingolipids are not well understood. In this study, to investigate the effects of dietary glucosylceramide (GluCer) and sphingomyelin (SM) on skin function, we characterized the recovery of skin barrier function and the change in sphingolipid metabolism‐related enzymes in the epidermis using a special Mg‐deficient diet–induced atopic dermatitis‐like skin and tape‐stripping damaged skin murine models. Our results show that dietary GluCer and SM accelerate the recoveries of damaged skin barrier functions. Correspondingly, dietary sphingolipids significantly upregulated the expression of ceramide synthases 3 and 4 in the epidermis of the atopic dermatitis‐like skin model (P < 0.05). In the case of cultured cells, the expression of ceramide synthases 2‐4 in normal human foreskin keratinocytes was significantly upregulated by treatment with 0.001–0.1 μm sphingoid bases (sphinganine, sphingosine and trans‐4,cis‐8‐sphingadienine) (P < 0.05). These results suggest that the effects of dietary sphingolipids might be due to the activation of ceramide synthesis in the skin, rather than the direct reutilization of dietary sphingolipids. Our findings provide a novel insight into the mechanisms of the skin barrier improving effect and a more comprehensive understanding of dietary sphingolipids.     

Improvement in skin barrier function in patients with atopic dermatitis after treatment with a moisturizing cream (Canoderm)

Patients with atopic skin show a defective barrier function both in rough and in clinically normal skin, with an increasing risk of developing contact dermatitis. Moisturizing creams are often used in the treatment of dry skin. The purpose of this study was to investigate the influence of treatment with a urea-containing moisturizer on the barrier properties of atopic skin. Fifteen patients with atopic dermatitis treated one of their forearms twice daily for 20 days with a moisturizing cream. Skin capacitance and transepidermal water loss (TEWL) were measured at the start of the study and after 10 and 20 days. On day 21 the skin was exposed to sodium lauryl sulphate (SLS) and on day 22 the irritant reaction was measured non-invasively. Skin capacitance was significantly increased by the treatment, indicating increased skin hydration. The water barrier function, as reflected by TEWL values, tended to improve (P = 0.07), and the skin susceptibility to SLS was significantly reduced, as measured by TEWL and superficial skin blood flow (P < 0.05). Thus, it seems that certain moisturizers could improve skin barrier function in atopics and reduce skin susceptibility to irritants. The mechanism and the clinical relevance need further investigation.     

Murine filaggrin-2 is involved in epithelial barrier function and down-regulated in metabolically induced skin barrier dysfunction

The S100 fused-type proteins (SFTPs) are thought to be involved in the barrier formation and function of the skin. Mutations in the profilaggrin gene, one of the best investigated members of this family, are known to be the major risk factors for ichthyosis vulgaris and atopic dermatitis. Recently, we identified human filaggrin-2 as a new member of the SFTP family. To achieve further insight into its function, here the murine filaggrin-2 was analysed as a possible orthologue. The 5' and 3' ends of the mouse filaggrin-2 cDNA of the BALB/c strain were sequenced and confirmed an organization typical for SFTPs. Murine filaggrin-2 showed an expression pattern mainly in keratinizing epithelia in the upper cell layers on both mRNA and protein levels. The expression in cultured mouse keratinocytes was increased upon elevated Ca(2+) levels. Immunoblotting experiments indicated an intraepidermal processing of the 250-kDa full-length protein. In metabolically (essential fatty acid-deficient diet) induced skin barrier dysfunction, filaggrin-2 expression was significantly reduced, whereas filaggrin expression was up-regulated. In contrast, mechanical barrier disruption with acetone treatment did not affect filaggrin-2 mRNA expression. These results suggest that filaggrin-2 may contribute to epidermal barrier function and its regulation differs, at least in parts, from that of filaggrin.     

Rapid effects of olopatadine hydrochloride on the histamine-induced skin responses

Olopatadine hydrochloride is one of the second-generation nonsedating antihistamines that are used for treating allergic disorders such as urticaria, rhinitis, and atopic dermatitis. We examined the inhibitory effects of this drug on the flare and wheal responses induced by histamine iontophoresis at 30, 60, and 90 min after oral administration in a double-blind, cross-over, and placebo-controlled study. Olopatadine hydrochloride significantly inhibited the histamine-induced flare and wheal responses as early as 60 min after oral administration when compared with placebo. Significant inihibitory effects of olopatadine hydrochloride on the itch responses were seen at 90 min after administration. Thus, olopatadine hydrochloride exhibited a very rapid and potent antihistamine effect on the histamine-induced skin responses.     

Impaired skin barrier and atopic diathesis in perioral dermatitis

Background: Perioral dermatitis (PD) is a common dermatological disease whose aetiology and pathogenesis remain speculative. We investigated skin barrier function and various markers of the atopic diathesis to elucidate their impact on the development of perioral dermatitis. Patients and methods: Forty patients (24 to 69 years of age) with PD were evaluated. Transepidermal water loss was measured in three regions of the face (lateral chin, perinasal cheek and side of the nose) and the patients were assessed for clinical criteria for atopy. Prick tests were performed, and specific IgE against a mixture of aeroallergens (CAP SX1) was measured. The control group consisted of 62 individuals (20 to 68 years of age) without a history of PD or active disease. Results: Transepidermal water loss was significantly increased (P < 0.001) on all regions of the face in the patient over the control group. Significantly (P < 0.001) higher values were also found for the patient group regarding history (52.5 % vs. 17.7 %) and clinical signs of atopic diathesis (≥ 4 features: 72.5 % vs. 0 %), prick test reactivity (≥ 2 reactive prick tests: 60 % vs. 12.9 %), and specific IgE against aeroallergens (CAP SX1 classes ≥ 2: 60.0 % vs. 17.7 %). Conclusions: Our findings emphasize the relevance of impaired skin barrier function as a pathogenic factor in the causation of perioral dermatitis. The susceptibility of atopic skin to irritants increases as soon as the skin becomes eczematous. Therefore, we propose that atopic diathesis serves as an intensifier, supporting development and continued presence of perioral dermatitis after nonspecific irritant mechanisms have induced impaired skin barrier function.     

神经酰胺在人皮肤中的主要功能

皮肤中神经酰胺主要位于表皮,是表皮中的主要脂质,具有保湿、信号转导、免疫调节等功能。其含量的变化可能导致皮肤屏障功能受损,甚至一些皮肤疾病的发生,如特应性皮炎、银屑病等。本文对皮肤中神经酰胺的主要作用进行综述。     

Epithelial barrier function and atopic diathesis in rosacea and perioral dermatitis

BACKGROUND: Rosacea and perioral dermatitis (PD) are common dermatoses, the aetiology and pathogenesis of which remain speculative. Objectives To investigate skin barrier function and features of atopy in both diseases. METHODS: We studied 75 patients with rosacea and 75 with PD. Transepidermal water loss (TEWL) was measured in three regions of the face (lateral chin, perinasal cheek, side of the nose) and the patients were assessed for atopy by clinical criteria, prick tests and specific IgE against a mixture of aeroallergens (CAP SX1). The control group consisted of 125 individuals with no history of rosacea, PD or active atopic disease. RESULTS: In patients with PD, TEWL was significantly increased (P < 0.001) at all measurement points in comparison with the rosacea and control groups. Significantly (P < 0.001) higher values were also found regarding history and clinical signs of an atopic diathesis, prick test reactivity and specific IgE against aeroallergens. CONCLUSIONS: PD is characterized by a skin barrier disorder of facial skin. It differs from rosacea in that it involves a significantly increased TEWL and features of an atopic diathesis. However, it remains disputed as to whether PD is an individual skin disease or a subtype of rosacea in atopic patients.     

Atopic dermatitis-like pruritic skin inflammation caused by feeding a special diet to HR-1 hairless mice

Dry skin/barrier dysfunction is considered to be one of the characteristic features of atopic dermatitis (AD). When HR-1 hairless mice are fed a special diet, HR-AD, dry red skin is induced. We examined whether HR-AD-fed mouse could be used as a model for AD by showing itch-associated scratching behaviour and by analysing the immunological change. HR-1 mice were fed HR-AD from 4 weeks old. HR-AD-fed mice showed severe dry skin symptoms accompanied by a decrease in dermal water content and an increase in transepidermal water loss and prolonged scratching bout duration on day 14 or 28. These symptoms became gradually worse until day 56. Marked epidermal hyperplasia and slight increase in CD4+ cells in the skin were observed from day 28. In contrast, increases in circulating T cells and serum immunoglobulin E were seen from day 41. Other skin-infiltrating inflammatory cells, such as eosinophils and mast cells, were increased on day 56 but not on day 28. Though daily oral treatment with dexamethasone reduced the increased numbers of these cells, it did not affect the dry skin symptoms or the prolonged scratching episodes. In contrast, the development of dry skin was inhibited by feeding with 10% normal diet-containing HR-AD. The skin barrier dysfunction in HR-AD-fed mice is closely associated with the development of AD-like pruritus. Changes in the immunological parameters observed may be the consequence of skin barrier dysfunction. Our findings suggest that HR-AD-fed mouse could be used as a dry skin-based experimental model for AD.     

Olopatadine,a non‐sedating H1 antihistamine,decreases the nocturnal scratching without affecting sleep quality in atopic dermatitis

We have demonstrated for the first time that a second‐generation antihistamine ameliorates nocturnal scratching behavior in atopic dermatitis patients using a modified wristwatch‐type acoustic scratching counting system that we have recently developed. We also analyzed the sleep quality by simultaneous recording of electroencephalogram, and found that sleep quality was unaffected.     

Effects of a ceramide‐containing water‐in‐oil ointment on skin barrier function and allergen penetration in an IL‐31 treated 3D model of the disrupted skin barrier

Atopic dermatitis (AD) is a chronically relapsing, pruritic inflammation of the skin with dryness and disturbed skin barrier function. Recently, we established that IL‐31 treatment of human 3D skin models resulted in a disrupted skin barrier phenotype resembling AD. In this model, we found that IL‐31 interferes with the differentiation of keratinocytes and inhibits the expression of terminal differentiation markers. In the present study, we investigated the effects of a ceramide‐containing water‐in‐oil skin care ointment on the physical skin barrier structure and function in disrupted skin barrier models, generated either by using primary normal human epidermal keratinocytes (NHEK) or HaCaT cells. We observed that the physical skin barrier of the models recovered after daily topical treatment with the ceramide‐containing ointment. Topical application of the ointment prevented downregulation of filaggrin and disorganization of other differentiation markers, such as keratin 10 and β4‐integrin, as demonstrated by immunohistological analysis. The expression of Ki67 was also upregulated in response to the ointment. Furthermore, functional studies revealed that local application of the ointment diminished the increased uptake of fluorescently labelled recombinant allergens of timothy grass (phl p1) in our model. In conclusion, our data revealed that topical application of a ceramide‐containing skin care ointment reduced IL‐31 induced impairments of the physical skin barrier and skin barrier function in an in vitro model of the disrupted skin barrier. This standardized model can be utilized in the future to monitor ex vivo effects of various topical therapies on skin morphology, physiology, and gene expression.     

Superiority of a vitamin B12‐barrier cream compared with standard glycerol‐petrolatum‐based emollient cream in the treatment of atopic dermatitis: A randomized,left‐to‐right comparative trial

Atopic dermatitis (AD) is a result of complex genetic, epigenetic, environmental, and immunological interactions with an overlapping epidermal barrier defect. The study evaluates the efficacy and tolerability of topical Vitamin B12‐barrier cream (MB12) compared with standard glycerol‐petrolatum‐based emollient cream (GPC) used three times a day for mild AD. The study was conducted as a on one hemi‐body randomized, controlled, single‐blind, intra‐patient left‐to‐right comparative trial by patients with clinical diagnosis of mild AD measured with total SCORAD index over 4 months. MB12 was compared on one hemi‐body treated (GPC). The comparisons of score values were performed primarily by using non‐parametric procedures: Mann–Whitney‐U test (for independent samples) and Wilcoxon test (for dependent samples). All 22 patients were randomized (left or right side treated with MB12 or GPC). At week 12 a reduction from baseline in SCORAD index was assessed in both body sites with 77.6% SCORAD index reduction in the MB12 treated body sites versus 33.5% in the GPC treated body sites. These results suggest that MB12 could represent a new option in the treatment of mild AD.     

Distinct barrier integrity phenotypes in filaggrin-related atopic eczema following sequential tape stripping and lipid profiling

Background Filaggrin gene (FLG) loss‐of‐function mutations have been shown to represent the strongest so far known genetic risk factor for atopic dermatitis (AD). Whereas the barrier characteristics in FLG mutation carriers under baseline conditions have been investigated, there are only limited data on the permeability barrier function in filaggrin‐AD under compromised conditions. Aim We investigated: (i) stratum corneum (SC) integrity/cohesion; (ii) barrier recovery after controlled mechanical and irritant‐induced barrier abrogation; and (iii) the lipid composition of the non‐lesional and lesional skin of AD patients harbouring the European R501X, 2282del4, 3702delG, R2447X or S3247X FLG variants. Methods Thirty‐seven AD patients (14 FLG mutation carriers and 23 non‐carriers) and 20 healthy controls participated in the study. Stratum corneum integrity/cohesion was assessed by measurement of transepidermal water loss (TEWL) and amount of removed protein following sequential tape stripping. Barrier recovery was monitored by repeated measurements of TEWL and erythema up to 96 h after barrier abrogation. Samples for lipid analysis were obtained from non‐lesional and lesional skin using the cyanoacrylate method. Results Tape stripping revealed distinct genotype‐related impairment of the SC integrity/cohesion. No differences in the rate of barrier recovery among the groups were found. The SC lipid analysis revealed significant differences regarding the percentage amount of cholesterol, ceramide/cholesterol ratio and triglycerides in the uninvolved skin as well as the amounts of free fatty acids, CER[EOH] and triglycerides in the skin lesions of the AD FLG mutation carriers. Conclusions Our results provide evidence for discernible FLG‐related barrier integrity phenotypes in atopic eczema.