Transcriptomic and lipidomic profiling of eicosanoid/docosanoid signalling in affected and non‐affected skin of human atopic dermatitis patients

Lipoxygenases (LOX) and cyclooxygenase (COX) are the main enzymes for PUFA metabolism to highly bio‐active prostaglandins, leukotrienes, thromboxanes, lipoxins, resolvins and protectins. LOX and COX pathways are important for the regulation of pro‐inflammatory or pro‐resolving metabolite synthesis and metabolism for various inflammatory diseases such as atopic dermatitis (AD). In this study, we determined PUFAs and PUFA metabolites in serum as well as affected and non‐affected skin samples from AD patients and the dermal expression of various enzymes, binding proteins and receptors involved in these LOX and COX pathways. Decreased EPA and DHA levels in serum and reduced EPA level in affected and non‐affected skin were found; in addition, n3/n6‐PUFA ratios were lower in affected and non‐affected skin and serum. Mono‐hydroxylated PUFA metabolites of AA, EPA, DHA and the sum of AA, EPA and DHA metabolites were increased in affected and non‐affected skin. COX1 and ALOX12B expression, COX and 12/15‐LOX metabolites as well as various lipids, which are known to induce itch (12‐HETE, LTB4, TXB2, PGE2 and PGF2) and the ratio of pro‐inflammatory vs pro‐resolving lipid mediators in non‐affected and affected skin as well as in the serum of AD patients were increased, while n3/n6‐PUFAs and metabolite ratios were lower in non‐affected and affected AD skin. Expression of COX1 and COX‐metabolites was even higher in non‐affected AD skin. To conclude, 12/15‐LOX and COX pathways were mainly upregulated, while n3/n6‐PUFA and metabolite ratios were lower in AD patients skin. All these parameters are a hallmark of a pro‐inflammatory and non‐resolving environment in affected and partly in non‐affected skin of AD patients.     

Dietary deficiencies of unsaturated fatty acids and starch cause atopic dermatitis‐like pruritus in hairless mice

Hairless mice fed with a special diet (named HR‐AD) show atopic dermatitis (AD)‐like pruritic skin inflammation that is almost completely resolved with the supplementation of an unsaturated fatty acid (UFA), the linoleic acid (LA). This suggests that the dietary deficiency of LA is the key cause of this dermatitis. However, because there is no appropriate control diet for HR‐AD, the involvement of other dietary ingredients cannot be ruled out. Furthermore, it has not yet been tested whether only UFA deficiency can cause such AD‐like pruritus. In this study, using semi‐purified custom diets, we attempted to reproduce this syndrome. Four‐week‐old hairless mice were maintained on a widely used standard diet American Institute of Nutrition‐76A (AIN‐76A), its modifications, or HR‐AD. Several modifications of fat and carbohydrate components revealed that dietary deficiency of both UFAs and cornstarch was required to induce severe skin barrier dysfunction as typically occurred in HR‐AD‐fed mice. An UFA‐ and cornstarch‐deficient diet caused severe AD‐like pruritus comparable to HR‐AD, despite weak Th2 immune responses and absence of immunoglobulin E production. On the other hand, a diet lacking UFAs but containing cornstarch significantly alleviated the development of pruritic dermatitis. Furthermore, the supplementation of wheat starch similarly improved skin barrier function. In conclusion, this study showed that a lack of certain starches might also be the cause of diet‐induced AD. Our findings could help to reproduce the diet‐induced AD itch model and also provide evidence that certain starches can have protective and ameliorative effects on AD‐like pruritus.     

Oral administration of β‐carotene or lycopene prevents atopic dermatitis‐like dermatitis in HR‐1 mice

Atopic dermatitis (AD) is a chronic relapsing eczematous skin disease. Certain populations of patients are resistant to standard therapies with topical steroids and/or calcineurin inhibitors, and require systemic medication, such as immunosuppressants. Recently, several reports have shed light on the anti‐allergic effects of carotenoids. Therefore, we investigated the effect of p.o. administration of β‐carotene or lycopene on AD‐like symptoms of HR‐1 hairless mice fed with a low zinc/magnesium diet. Mice were divided into four groups: (i) fed with a standard diet (Co group); (ii) low zinc/magnesium diet (HR group); (iii) low zinc/magnesium and β‐carotene diet (HR‐C group); and (iv) low zinc/magnesium and lycopene diet (HR‐L group). They were then fed these diets for 8 weeks. Severities of dermatitis were assessed by their appearance, and histopathological and hematological observations. Mice in the HR group developed AD‐like dermatitis both clinically and histologically. HR‐C and HR‐L group mice also developed xerosis and wrinkle‐like skin changes, but they were milder than those of HR group mice. Histological analysis revealed that epidermis thickening and inflammatory cell infiltration in the skin of the HR‐C and HR‐L groups were both statistically less than those of the HR group. The concentration of thymus and activation regulated chemokine in the skin of the HR‐L group and the concentration of CCL27 in the skin of the HR‐C group were significantly lower than those of the HR group, respectively. In conclusion, p.o. administration of β‐carotene or lycopene prevents AD‐like symptoms in association with a suppression of T‐helper 2 chemokines in a murine model. Ingestion of carotenoids may be beneficial for patients with AD.     

Interleukin‐4 and interleukin‐13 evoke scratching behaviour in mice

Persistent and relapsing itch commonly manifests in inflammatory skin disorders such as atopic dermatitis (AD). AD pathogenesis is driven by interleukin‐4 (IL‐4) and interleukin‐13 (IL‐13). Dupilumab, a monoclonal antibody blocking the action of IL‐4 and IL‐13 effectively reduces the symptoms of AD and itch. Little is known whether IL‐4 and IL‐13 directly contribute to itch transduction. A recently published study (Oetjen et al, Cell, 2017, 171, 217) found IL‐4 and IL‐13 to directly activate itch‐sensory neurons in vitro. Surprisingly, they found no significant increase in scratching after intradermally injecting high doses (2.5 ug/ml) of IL‐4 and IL‐13 into mice. Similar experiments in our lab, however, suggested that both IL‐4 and IL‐13 contribute to acute itch in vivo. We intradermally injected lower doses (1 ug/ml) of IL‐4 and IL‐13 into mice and found a significant increase of scratching bouts compared to vehicle. Interestingly, the combined treatment of IL‐4 and IL‐13 produced additive increase of scratching and acute pruritus at an earlier time point compared to each cytokine administered alone. In summary, our study shows a rapid and significant increase of scratching after intradermal injection of IL‐4, IL‐13 or combined IL‐4/ IL‐13 compared to vehicle in mice 5‐10 minutes after injection. Our data suggest that IL‐4 and IL‐13 alone and combined directly act as potent acute pruritogens on sensory nerves. This finding expands our understanding of cytokines as pruritogens, how targeted anticytokine medications act in AD, and about neuroimmune communication in the skin.     

Cynomolgus monkey model of interleukin‐31‐induced scratching depicts blockade of human interleukin‐31 receptor A by a humanized monoclonal antibody

Scratching is an important factor exacerbating skin lesions through the so‐called itch‐scratch cycle in atopic dermatitis (AD). In mice, interleukin (IL)‐31 and its receptor IL‐31 receptor A (IL‐31RA) are known to play a critical role in pruritus and the pathogenesis of AD; however, study of their precise roles in primates is hindered by the low sequence homologies between primates and mice and the lack of direct evidence of itch sensation by IL‐31 in primates. We showed that administration of cynomolgus IL‐31 induces transient scratching behaviour in cynomolgus monkeys and by that were able to establish a monkey model of scratching. We then showed that a single subcutaneous injection of 1 mg/kg nemolizumab, a humanized anti‐human IL‐31RA monoclonal antibody that also neutralizes cynomolgus IL‐31 signalling and shows a good pharmacokinetic profile in cynomolgus monkeys, suppressed the IL‐31‐induced scratching for about 2 months. These results suggest that the IL‐31 axis and IL‐31RA axis play as critical a role in the induction of scratching in primates as in mice and that the blockade of IL‐31 signalling by an anti‐human IL‐31RA antibody is a promising therapeutic approach for treatment of AD. Nemolizumab is currently under investigation in clinical trials.     

Vital role of the itch-scratch response in development of spontaneous dermatitis in NC/Nga mice

BACKGROUND: The itch sensation and the resultant response, scratching, are important symptoms of atopic dermatitis (AD) and have a significant impact on the quality of life of affected patients. However, the influence of the itch-scratch response on the pathology of AD has not been precisely elucidated. OBJECTIVES: To investigate the role of scratching behaviour in the development of spontaneous dermatitis using conventionally raised NC/Nga mice (Conv-NC mice), which are known to be an animal model for human AD. METHODS: Capsaicin-sensitive sensory nerves of the mice were ablated by neonatal capsaicin treatment (Cap-NC mice), and the development of spontaneous dermatitis in the Cap-NC mice was compared chronologically with that in Conv-NC mice. RESULTS: Scratching behaviour was almost completely prevented in Cap-NC mice raised for 84 days under conventional conditions, and the development of dermatitis and elevation of the serum IgE level were significantly suppressed. Histological analysis revealed that the numbers of infiltrating eosinophils and mast cells in the lesional skin of Cap-NC mice were lower than those in Conv-NC mice. Immunological studies showed that the capability of spleen T cells to produce both T-helper (Th) 1 (interferon-gamma) and Th2 [interleukin (IL)-5 and IL-13] cytokines was diminished in Cap-NC mice. Furthermore, serum levels of IL-18 were approximately twice higher in Conv-NC mice than in Cap-NC mice. CONCLUSIONS: These observations suggest that scratching behaviour contributes to the development of dermatitis by enhancing various immunological responses in the murine AD model, implying that prevention of the itch sensation and/or itch-associated scratching behaviour is an effective treatment for AD.     

The benefit of a ceramide‐linoleic acid‐containing moisturizer as an adjunctive therapy for a set of xerotic dermatoses

Atopic dermatitis (AD), chronic eczema, and pruritus hiemalis are a set of prevalent chronic xerotic skin disorders that share clinical features such as dryness, scales, and pruritus. A ceramide deficiency and defective epidermal functions are common in these diseases. This study was designed to assess the effect of ceramide‐linoleic acid (LA‐Cer)–containing moisturizer as an adjunctive therapy in the treatment of AD, chronic eczema, and pruritus hiemalis. In a 2‐month study, patients with one of these three diseases were divided into two groups. The control group was treated with mometasone furoate (0.1%) cream (MF), whereas the treatment group received 0.1% MF in combination with an LA‐Cer‐containing moisturizer. Capacitance and transepidermal water loss were measured in normal and lesional skin, along with Eczema Assessment Severity Index and pruritus scores at Weeks 0, 2, 4, and 8. The results showed that tropical applications of an LA‐Cer‐containing moisturizer in combination with a topical glucocorticoid accelerated the reestablishment of epidermal permeability barrier and the amelioration of pruritus in patients with AD and pruritus hiemalis. However, it did not provide the same effect for chronic eczema. Thus, the efficacy of this combination therapy for this set of xerotic disorders requires further evaluation.     

Repetitive scratching and noxious heat do not inhibit histamine-induced itch in atopic dermatitis

BACKGROUND: Repetitive scratching is the most common behavioural response to itch in atopic dermatitis (AD). Patients with chronic itch often report that very hot showers inhibit itch. We recently reported that scratching and noxious heat stimuli inhibit histamine-induced itch in healthy subjects. However, no psychophysical studies have been performed in AD to assess the effects of repetitive heat pain stimuli and scratching on histamine-induced itch. OBJECTIVES: To examine the effects of repetitive noxious heat and scratching on itch intensity in patients with AD using quantitative sensory testing devices. METHODS: Itch was induced with histamine iontophoresis in 16 patients with AD in both lesional and nonlesional skin as well as in 10 healthy subjects. Repetitive noxious heat and scratching were applied 3 cm distal to the area of histamine iontophoresis. Subjects rated their perceived intensity of histamine-induced itch with a computerized visual analogue scale. RESULTS: Our results demonstrate that repetitive noxious heat and scratching do not inhibit itch intensity in lesional and nonlesional AD skin but do so in healthy skin. Of note, both these stimuli increase itch intensity in lesional AD skin. CONCLUSIONS: Our results strongly suggest that scratching and noxious thermal stimuli have a different effect upon histamine-induced itch perception in patients with AD when compared with healthy controls. This difference may be associated with both peripheral and central sensitization of nerve fibres in AD.     

Aggravation of atopic dermatitis‐like symptoms by consecutive low concentration of formaldehyde exposure in NC/Nga mice

Formaldehyde (FA) has been known to be associated with development of asthma (AS) and atopic dermatitis (AD). In this study, we investigated whether FA inhalation would affect the provocation or exacerbation of AD‐like symptoms. Atopic‐prone NC/Nga mice were exposed to low (0.2 ppm) and high (1.0 ppm) concentration of FA by inhalation. Combined exposure to low concentration of FA inhalation and topical house dust mite (HDM) stimulation significantly upregulated HDM‐induced total plasma IgE and IgG2a production, Th1‐, Th2‐, Th17‐related cytokine as well as COX‐2 mRNA expressions in the skin. Interestingly, independent FA inhalation, especially at low concentration (0.2 ppm), increased the skin mRNA expressions of IL‐13, IL‐17E/IL‐25 and COX‐2, even though it failed to induce AD‐like skin inflammation. In conclusion, we suggest that increased skin mRNA expressions of IL‐13, IL‐25/IL‐17E and COX‐2 by independent low concentration of FA exposure might be a key factor to exacerbate HDM‐mediated AD‐like skin inflammation.     

Topical E6005, a novel phosphodiesterase 4 inhibitor,attenuates spontaneous itch‐related responses in mice with chronic atopy‐like dermatitis

Atopic dermatitis is a chronic inflammatory cutaneous disease with difficult‐to‐treat pruritus. Although phosphodiesterase (PDE) 4 inhibitors have an anti‐inflammatory effect on inflammatory skin diseases, such as atopic dermatitis, their acute antipruritic activities remain unclear. Therefore, in this study, we examined whether E6005, a novel PDE4 inhibitor, has antipruritic activity in dermatitis, using a mouse model of atopic dermatitis (NC/Nga mice). A single topical application of E6005 inhibited spontaneous hind‐paw scratching, an itch‐associated response and spontaneous activity of the cutaneous nerve in mice with chronic dermatitis. The cutaneous concentration of cAMP was significantly decreased in mice with chronic dermatitis, and this decrease was reversed by topical E6005 application. These results suggest that E6005 increases the cutaneous concentration of cAMP to relieve dermatitis‐associated itching. Thus, E6005 may be a useful therapy for pruritic dermatitis such as atopic dermatitis.     

A single dose of interleukin‐31 (IL‐31) causes continuous itch‐associated scratching behaviour in mice

We investigated the effects of a single dose of mouse interleukin‐31 (IL‐31) on scratching behaviour in comparison with spontaneous skin‐lesion‐ or serotonin (5‐HT)‐ induced scratching behaviour in NC/Nga and BALB/c mice. Intradermal (i.d.) injection of IL‐31 caused a gradual increase in long‐lasting scratching (LLS, over 1.5 s) about 3 h after administration followed by a gradual decrease for over 24 h after administration. I.d. injection of IL‐31 significantly increased the total LLS counts/24 h but not short‐lasting scratching (SLS, 0.3–1.5 s). In skin‐lesioned NC/Nga mice, the LLS but not SLS counts were significantly higher than those in non‐skin‐lesioned NC/Nga mice. We also investigated 5‐HT‐induced scratching in BALB/c mice, SLS but not LLS increased immediately after the injection and then decreased to baseline after at 20 min. These results suggest that IL‐31 may participate in the sensation of itching and promote scratching behaviour in skin‐lesioned NC/Nga mice, an animal model of atopic dermatitis (AD).     

COX-1 inhibition enhances scratching behaviour in NC/Nga mice with atopic dermatitis

NC/Nga (NC) mice, spontaneously develop an eczematous atopic dermatitis (AD)-like skin lesion when kept under conventional condition (Conv), but not under specific pathogen-free (SPF) conditions, have been thought to be an animal model of AD. We have previously shown that PGD(2) and arachidonic acid inhibited the scratching behaviour of NC mice, while indomethacin enhanced it. This study was designed to assess the role of cyclooxygenase (COX)-1 and COX-2 in the itch-related scratching behaviour of NC mice. We examined the expression of COX in the skin using real-time PCR and Western blotting and the effects of SC-560 (a COX-1 selective inhibitor) or NS-398 (a COX-2 selective inhibitor) on scratching behaviour in relation to skin prostaglandin (PG) levels in NC mice. COX-1 mRNA expression was unchanged and protein expression decreased in Conv NC mice compared with that of SPF mice. By contrast, COX-2 mRNA and protein expression increased in Conv NC mice. SC-560 increased scratching behaviour and significantly reduced skin PGD(2), PGE(2) and PGF(2alpha) levels, but NS-398 did not have effects on scratching and skin PG level. Moreover, the topical application of PGD(2), which might be the endogenous inhibitor of itching, suppressed the SC-560-induced enhancement of scratching behaviour by NC mice. These results suggest COX-1-coupled skin PGD(2) biosynthesis plays a physiological role in inhibiting regulation of pruritus in NC mice with AD.     

Increased scratching counts depend on a decrease in ability of cutaneous prostaglandin D2 biosynthesis in NC/Nga mice with atopic dermatitis

Spontaneous and 2,4,6-trinitrochlorobenzene (TNCB)-induced dermatitis models using NC/Nga mice have been recognized as animal models of atopic dermatitis. We reported that scratching behavior leads to dermatitis in a spontaneous dermatitis but not in a TNCB-induced dermatitis. Prostaglandin D2 (PGD2) suppressed the scratching behavior of NC/Nga mice, suggesting that PGD2 plays a physiological role on inhibiting pruritus. We studied whether there was a difference in skin PG contents between spontaneous and TNCB-induced dermatitis. Spontaneous dermatitis was induced by cohabitation with NC/Nga mice having severe skin lesions. TNCB-induced dermatitis was caused by applications of TNCB. PGD2, PGE2, 6keto-PGF1alpha, and PGF2alpha contents in the skin were examined using enzyme-immunoassay kits. For studying ability to produce skin PGs, PG contents were evaluated after topical treatment of arachidonic acid (AA) or mechanical scratching. In spontaneous dermatitis, PGE2, 6keto-PGF1alpha, and PGF2alpha contents increased with dermatitis, but only PGD2 did not do so. In TNCB-induced dermatitis, PGD2, PGE2, 6keto-PGF1alpha, and PGF2alpha increased. Determination of skin PG contents after AA treatment or mechanical scratching revealed that skin PGD2 production of conventional group of spontaneous dermatitis was lower than the specific pathogen-free group. It seemed that ability of skin PGD2 production was attenuated in spontaneous dermatitis. These results suggest that enhancement of scratching behavior in spontaneous dermatitis was caused by the defect of ability to produce PGD2, which plays a physiological role in inhibiting pruritus, resulting in development of dermatitis.     

Oral supplementation with Lactobacillus rhamnosus CGMCC 1.3724 prevents development of atopic dermatitis in NC/NgaTnd mice possibly by modulating local production of IFN‐γ

Abstract: Prevalence of allergies has increased during the last two decades. Alteration of the gut microbiota composition is thought to play a crucial role in development of atopic diseases. Oral administration of probiotics has been reported to treat and/or prevent symptoms of atopic diseases in infants, but the results are still controversial. We investigated the potential efficacy of dietary interventions by a probiotic strain on prevention and treatment of atopic dermatitis (AD) in a human‐like AD model, NC/NgaTnd mice by perinatal administration. Pregnant NC/NgaTnd mice were orally treated with the probiotic strain Lactobacillus rhamnosus CGMCC 1.3724 (LPR), which was followed by treatment of pups until 12 weeks of age. LPR‐treated mice exhibited significant lower clinical symptoms of dermatitis, reduced scratching frequency, lower levels of plasma total Immunoglobulin E and higher levels of interferon‐γ in skin biopsies, compared with untreated mice. The protective effect was also observed when mice started to be treated at weaning time (5 weeks of age) even with limited supplementation period of 2 weeks. However, treatment of mice with the probiotic starting 1 week after the onset of the disease (8 weeks of age) had limited effects. The usefulness of LPR for primary prevention of AD was supported.     

Effects of tacrolimus ointment on facial eruption, itch, and scratching in patients with atopic dermatitis

The action of tacrolimus ointment on pruritus in atopic dermatitis is still unclear. In this open study we investigated both the relationship between the severity of eruptions and the degree of itch and scratching in patients with atopic dermatitis and the effects of topical tacrolimus on these symptoms. Seventy adults with moderate to severe atopic dermatitis with facial eruptions that were recalcitrant to topical steroids applied a 0.1% tacrolimus ointment twice per day after discontinuation of topical steroid. The eruption scores and an assessment of the itch and scratching were recorded for 12 weeks. Oral antihistamine was prescribed at least one month before the study and continued unchanged during the study in each patient. The percentage reduction in the score of itch and scratching after two weeks (n=59) was significantly higher than in the score of eruption. Although there was no significant relationship between the severity of the eruptions and the degree of itch and scratching during steroid application, a relationship became significant after four weeks (n=59) of tacrolimus use by a one-factor ANOVA analysis. This suggests that tacrolimus ointment is effective for the itch and scratching in cases where degrees might be discrepant from the severity of eruptions in patients with recalcitrant facial eruptions of AD.     

Topical acidic cream prevents the development of atopic dermatitis‐ and asthma‐like lesions in murine model

Long‐standing or repeated skin barrier damage followed by atopic dermatitis (AD) is the initial step of the atopic march that eventually progresses to respiratory allergies. Maintenance of an acidic pH in the stratum corneum (SC) is an important factor for normal skin barrier function. We performed this study to determine whether an oxazolone (Ox)‐induced AD murine model can develop airway inflammation by topical application and nasal inhalation of a house dust mite, Dermatofagoides pteronyssinus (Dp), which is a novel ‘atopic march animal model’, and whether an acidic SC environment, made by repeated application of acidic cream, can interrupt this atopic march. During repeated treatment with Ox and Dp to make an atopic march murine model, acidic cream (pH 2.8) and neutral cream (pH 7.4) adjusted by citric acid and sodium hydroxide mixed with vehicle were applied twice daily. Repeated treatment with Ox and Dp to hairless mice induced AD‐like skin lesions followed by respiratory allergy, defining it as an atopic march model. Acidic cream inhibited the occurrence of respiratory allergic inflammation as well as AD‐like skin lesions. These results indicate that a novel atopic march animal model can be developed by repeated topical and nasal treatments with house dust mite on Ox‐induced AD mice and that the acidification of SC could be a novel intervention method to block the atopic march.     

Does therapeutic intervention in atopic dermatitis normalize epidermal Notch deficiency?

This viewpoint presents a unifying concept for the treatment of atopic dermatitis (AD) that is based on the improvement of deficient Notch signalling, which appears to represent the fundamental epithelial defect of AD resulting in epidermal and immunological barrier dysfunction. One study of AD patients demonstrated a marked epidermal deficiency of Notch receptors and several mouse models with genetically suppressed Notch signalling exhibit dry skin, signs of scratching, skin barrier abnormalities, increased transepidermal water loss and Th2 cell‐mediated immunological changes closely resembling human AD. Notch signalling is critically involved in the differentiation of regulatory T cells, in the feedback inhibition of activated innate immunity, in the repression of activating protein‐1 (AP‐1), the regulation of late epidermal differentiation associated with filaggrin‐ and stratum corneum barrier lipid processing, in aquaporin 3‐ and claudin‐1 expression and in keratinocyte‐mediated release of thymic stromal lymphopoietin (TSLP), which promotes Th2‐driven immune responses with TSLP‐ and IL‐31‐mediated stimulation of cutaneous sensory neurons involved in the induction of itch. Translational evidence will be provided that all major therapeutic regimens employed for the treatment of AD such as glucocorticoids, calcineurin inhibitors and UV radiation may converge in the upregulation of impaired Notch signalling, the proposed pathogenic defect of AD.     

The characteristics of nocturnal scratching in adults with atopic dermatitis

Patients with atopic dermatitis (AD) are known to suffer from nocturnal itch, and the resultant scratching may worsen the skin lesions. We observed nocturnal scratching for 112 nights in 35 adult patients with AD, using an infrared video camera system. To quantify the amount of scratching, we counted scratching bouts lasting more than 5 s and calculated the duration of all the scratching bouts (total scratching time, TST). The percentage of TST in the total recording time (TST%) was used as an index of nocturnal scratching. Mean +/- SD TST% was 14.3 +/- 13.9 for patients with severe AD, 6.2 +/- 3.7 for those with moderate AD and 0.7 +/- 0.4 for those with mild AD. The higher TST% in the severely affected group was attributed mainly to a longer duration rather than a higher frequency of bouts. Patients scratched more in the first third of the night than in the later two-thirds. Both the group of patients whose disease distribution pattern was generalized and those who showed a head-neck-shoulder type distribution scratched their heads, faces and necks for longer than other parts of the body. Repeated measurement performed on individual subjects resulted in a similar TST% when there was little change in skin lesions. TST% reduced by 15 +/- 21% when the patients showed marked improvement. The measurement of nocturnal scratching helps to evaluate the severity of itch in AD. In addition, the infrared video successfully detected the location and nature of nocturnal scratching in AD.     

Adipose‐derived stem cells attenuate atopic dermatitis‐like skin lesions in NC/Nga mice

There is an unmet need in novel therapeutics for atopic dermatitis (AD). We examined the effects of autologous adipose‐derived stem cells (ADSCs) on AD‐like skin lesions induced by the application of 2,4‐dinitrochlorobenzene (DNCB) in NC/Nga mice. Autologous ADSCs and ADSC‐conditioned medium (ADSC‐CM) were injected intralesionally three times. Clinical severity and histopathologic findings were compared in sham naïve control, saline‐treated, ADSC‐treated, ADSC‐CM‐treated and 2.5% cortisone lotion‐applied animals. The severity index, skin thickness, mast cell number, as well as expression levels of thymic stromal lymphopoietin, CD45, chemoattractant receptor‐homologous molecule, chemokine ligand 9 and chemokine ligand 20 were significantly lower in mice treated with ADSC, ADSC‐CM, or 2.5% cortisone lotion. Tissue levels of interferon‐γ as well as serum levels of interleukin‐33 and immunoglobulin E levels were also decreased in those groups. We conclude that autologous ADSCs improved DNCB‐induced AD‐like skin lesions in NC/Nga mice by reducing inflammation associated with Th2 immune response and interferon‐γ.     

Amelioration of atopic‐like skin conditions in NC/Tnd mice by topical application with distilled Alpinia intermedia Gagnep extracts

Alpinia intermedia, a perennial plant that belongs to the Zingiberaceae family, has been used in folk medicine for a long time in the southern region of Japan. Because skin care is an effective approach that enables patients to manage their atopic dermatitis (AD), various herbal ingredients with few adverse effects have been evaluated for use in AD patients in recent years. In this study, we examined whether distilled extracts obtained from A. intermedia were beneficial for AD‐like skin conditions in NC/Tnd mice. Topical application with the A. intermedia extracts significantly reduced the severity of AD, transepidermal water loss and scratching behavior in the mice. Supplementation of the extracts to cell cultures suppressed the expression of Tslp mRNA in PAM212 keratinocytes, degranulation in bone marrow‐derived cultured mast cells (BMCMC), and neurite outgrowth in PC12 cells and dorsal root ganglia. In addition, the component analysis revealed that β‐pinene was a major constituent of the A. intermedia extracts. The inhibitory effects of β‐pinene both in vivo and in vitro were also demonstrated. These results indicate that topical application with the A. intermedia extract to the skin of NC/Tnd mice improved the condition of the skin by suppressing multiple inflammatory responses. The extracts may become novel skin‐care remedies for AD patients.