Induction of scratching behaviour and dermatitis in various strains of mice cohabiting with NC/Nga mice with chronic dermatitis

BACKGROUND: NC/Nga (NC) mice with similar pathological and behavioural features as seen in human atopic dermatitis are used as a model of the disease. Under normal circumstances, spontaneous and persistent scratching occurs in NC mice and this can lead to the onset of skin inflammation. OBJECTIVES: We examined the induction of scratching behaviour in NC, BALB/c, ICR and C3H/HeN mice, and of dermatitis in NC and BALB/c mice, by cohabitation with mice with dermatitis. METHODS: NC, BALB/c, ICR and C3H/HeN mice were kept together with NC mice with chronic dermatitis (CNV-NC) for 2 weeks, and the numbers of scratching episodes were counted. NC and BALB/c mice were also kept together with CNV-NC mice for 24 weeks and the skin severity score was assessed. The score was assessed for a further 8 weeks after separation of these mice. RESULTS: The number of scratching episodes in NC, BALB/c, ICR and C3H/HeN mice was increased by cohabitation with CNV-NC mice. Cohabitation with CNV-NC mice led to dermatitis in both NC and BALB/c mice. The number of scratching episodes and the skin severity score in BALB/c mice were about half of those in NC mice. When cohabitation with CNV-NC mice stopped, the number of scratching episodes and the skin severity score decreased in BALB/c mice, but not in NC mice. Changes in the histopathological data of BALB/c mice supported the severity of skin inflammation. CONCLUSIONS: Our study demonstrates that scratching behaviour and dermatitis can be induced in various strains of mice by cohabitation with CNV-NC mice, and that cessation of cohabitation leads to a recovery in BALB/c mice but not in NC mice.     

Time course changes of scratching counts, dermatitis symptoms, and levels of cutaneous prostaglandins in NC/Nga mice

NC/Nga (NC) mice are known to develop dermatitis resembling atopic dermatitis (AD) in conventional (Conv) conditions, but not in specific pathogen-free (SPF) conditions. We reported that the ability of skin prostaglandin D(2) (PGD(2)) production, which might be the endogenous inhibitor of itching, was attenuated in skin-lesioned Conv-NC mice. We examined the age-related change in scratching, dermatitis symptoms, and skin PGs of SPF- and Conv-NC mice. In Conv-NC, PGD(2) increased at 7 weeks, at which scratching counts increased, but dermatitis did not develop. PGE(2), PGI(2) and PGF(2alpha) increased at 10 and 13 weeks, at which dermatitis developed. The ability to produce skin PGs was examined by measuring PGs after application of arachidonic acid or after mechanical scratching using a wire brush. In Conv-NC, PGD(2) production at 13 weeks was lower than at 7 weeks. In Conv-NC, hematopoietic PGD synthase (hPGDS) expression in the skin at 13 weeks was lower than at 7 weeks by Western blotting and immunohistochemical analysis. The increase of skin PGD(2) level in the early phase of the development of dermatitis is due to the stress of extensive scratching, but did not increase in spite of the stress of extensive scratching in the late phase, due to decreasing capacity of PGD(2) production attributable to decreasing hPGDS expression in Conv-NC mice. These results suggest that a decreased ability to produce skin PGD(2) production could enhance scratching and aggravate dermatitis in Conv-NC mice.     

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.     

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.     

Scratching behavior in spontaneous- or allergic contact-induced dermatitis in NC/Nga mice

NC/Nga mice have pathological and behavioral features similar to those seen in human atopic dermatitis. There are two known dermatitis models in NC/Nga mice, one being spontaneous-induced dermatitis under conventional conditions and the other 2,4,6-trinitrochlorobenzene (TNCB)-induced allergic contact dermatitis. However, there are significant differences in time course on development of dermatitis. We studied the role of scratching behavior (sign of itch) on the development of dermatitis on spontaneous- and TNCB-induced dermatitis. We measured scratching counts, transepidermal water loss (TEWL), and skin inflammation score, under conventional conditions or by applying 5% TNCB once a week for 6 weeks in NC/Nga mice. In spontaneous-induced dermatitis, scratching counts increased with the passage of time. The scratching counts were significantly increased only 1 week after housing the mice under conventional conditions, but no changes were observed in cases of TNCB-induced dermatitis. In spontaneous-induced dermatitis, TEWL and skin-inflammation score were gradually increased, time-dependently. On the other hand, in TNCB-induced dermatitis, these dependent values rapidly increased and reached a maximum only after 24 h TNCB application. These data suggest that pathogenesis of spontaneous- and allergic contact-induced dermatitis was clearly different. It will be of major interest to identify the pruritic mediators causing profound scratching behavior and scratching-induced aggravation of inflammation in the spontaneous-induced dermatitis, as opposed to the inflammatory mediators that cause contact allergic dermatitis without major scratching.     

Itch-associated scratching contributes to the development of dermatitis and hyperimmunoglobulinaemia E in NC/Nga mice

Atopic dermatitis (AD) is related to immunoglobulin E (IgE) production, and a type-1 and type-2 helper T cell (Th1/Th2) imbalance has been hypothesized as the aetiology. While itching and scratching are important factors in the development of dermatitis, the mechanisms underlying these phenomena are poorly understood. We investigated the relationship between scratching, transepidermal water loss (TEWL), signs of dermatitis and serum Ig levels in NC/Nga mice, a model of AD. We also sensitized specific pathogen-free (SPF)-NC/Nga mice and BALB/c mice to mite antigen to determine the effects of IgE overproduction on scratching and investigated the involvement of mast cells and T/B cells in the induction of scratching using WBB6F1-W/W(v) mice and C.B.17/Icr-scid mice. Under conventional conditions, the scratch counts increased, followed by increases in TEWL and the inflammation score in NC/Nga mice that were not kept under SPF conditions. However, no change was observed in scratching, TEWL, or signs of dermatitis in mite antigen-sensitized SPF-NC/Nga and BALB/c mice, although the serum total IgE, IgG(1) and IgG(2a) levels increased. The scratch count increased significantly in both the WBB6F1-W/W(v) mice and C.B.17/Icr-scid mice when they were co-housed with skin-lesioned NC/Nga mice, raised under conventional conditions. These results show that IgE overproduction results from itch-associated scratching-induced dermatitis in NC/Nga mice.     

Anti-interleukin-31-antibodies ameliorate scratching behaviour in NC/Nga mice: a model of atopic dermatitis

Background:  Interleukin-31 (IL-31), a novel cytokine, is upregulated in atopic dermatitis skin lesions in humans and skin lesions in the NC/Nga mice, a murine model for atopic dermatitis.
Objective:  Here, we investigated the effect of a monoclonal IL-31 antibody on scratching behaviour, weight gain and dermatitis in NC/Nga mice.
Methods:  Mice were divided into three groups, n  =   10 in each group. Mice were given monoclonal IL-31 rat-anti-mouse antibody 10 mg/kg or albumin intraperitoneally every fifth day for seven weeks. In addition, the mice in one group were not exposed to any form of intervention. The dermatitis score was clinically assessed twice a week. The scratching behaviour was automatically detected and objectively evaluated.
Results:  Intervention with IL-31 antibody 10 mg/kg intraperitoneally every fifth day in NC/Nga mice from age 7 weeks reduced the scratching behaviour, but did not have any impact on weight gain or dermatitis.
Conclusion:  IL-31 antibody reduces scratching behaviour in an atopic dermatitis-like murine model during the onset of clinical skin manifestations. Our findings suggest IL-31 antibody as a new potential therapeutic approach for pruritus in atopic dermatitis and other pruritic diseases.     

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.     

Role of scratch-induced cutaneous prostaglandin D production on atopic-like scratching behaviour in mice

NC/Nga mice are known to develop scratching dermatitis akin to atopic dermatitis, under conventional (Conv), but not under the specific-pathogen-free (SPF) condition. In this study, we examined the effects of mechanical-scratching on the spontaneous scratching counts (sign of itching), in relation to the cutaneous prostaglandin D2 (PGD2) levels in NC/Nga or BALB/c mice. Mechanical-scratching increased the cutaneous barrier damage and PGD2 levels in both strain mice under the SPF condition. By 4 weeks of cohabitation with the skin-lesioned NC/Nga mice, both the increase in the spontaneous scratching and development of dermatitis score were higher in the Conv-NC/Nga than in the Conv-BALB/c mice. At this time-point, the cutaneous PGD2 level induced by mechanical-scratching was significantly lower in the Conv-NC/Nga when compared with that in the SPF-NC/Nga mice, and that in the Conv-BALB/c was almost equal to that in the SPF-BALB/c mice. With mechanical scratches, the cohabitation-induced scratching was suppressed in the Conv-BALB/c, but not in the Conv-NC/Nga mice. These results suggest that the scratch-induced cutaneous PGD2 inhibits scratching and the subsequent development of dermatitis in BALB/c, while the impaired scratch-induced cutaneous PGD2 production in the NC/Nga mice resulted in no suppression of scratching, and aggravated the dermatitis.     

A method to induce stable atopic dermatitis-like symptoms in NC/Nga mice housed with skin-lesioned mice

BACKGROUND: Itching is a characteristic symptom in various forms of dermatosis, especially atopic dermatitis; consequently it is a major diagnostic criterion. All features are similar to events seen in patients, hence NC/Nga mice are considered to be a suitable model of human atopic dermatitis. However, there were data spreads in commencing time and the degree of skin lesions in NC/Nga mice. OBJECTIVES: In the present study, we attempted to improve experimental conditions to induce stable skin lesions and to establish a more appropriate method. Methods NC/Nga mice were kept together with skin-lesioned mice during the experiment period (mixed-NC mice). The dermatitis scores of face, ears and rostral back were assessed. Scratching behaviour was measured using an apparatus, MicroAct (Neuroscience, Tokyo, Japan). Transepidermal water loss (TEWL) and serum total IgE levels were also measured. To observe the presence of mites, the skin of the rostral backs of the mixed-NC mice was stripped using cellulose tape. We also investigated the effects of fipronil (Wako, Osaka, Japan), an acaricidal compound, on skin lesions and scratching behaviour of these mixed-NC mice. RESULTS: In mixed-NC mice, skin lesions appeared from 2 weeks, worsened gradually and reached peak levels of a dermatitis score in 8 weeks. Scratching behaviour increased significantly from day 3. TEWL also increased from day 3, but total IgE increased from day 7. Mites were observed on the rostral backs of mixed-NC mice from day 3, and all mice had these mites on day 28. Giving pretreatment with fipronil (Wako), the skin lesions and scratching behaviour of mixed-NC mice was significantly suppressed. CONCLUSIONS: The findings of the present study suggest that the method of being kept together with skin-lesioned mice can induce stable skin lesions and scratching behaviour at an early stage, without skin lesions. This method could help investigate a more stable evaluation of the effects on symptoms of atopic dermatitis, and mechanisms of the itching. It was considered that parasitism of mites, not allergic reactions, was the pathogenesis of skin lesions and scratching behaviour in mixed-NC mice.     

Immunomodulatory effects of ultraviolet B irradiation on atopic dermatitis in NC/Nga mice

BACKGROUND: Atopic dermatitis (AD) is a common pruritic inflammatory skin disease, which occurs primarily in childhood. Recently, narrow-band ultraviolet B (UVB) phototherapy has been used to treat AD, but the mechanism involved is unknown. In this study, we investigated whether UVB irradiation influences AD in the NC/Nga mouse. METHODS: The mice were separated into three groups: control, AD-control (immunized with mite antigens), and AD+UVB-irradiated (immunized with mite antigens and UVB irradiation) groups. The mice in the irradiation group were exposed to 1 kJ/m(2)/day twice a week from 6 to 12 weeks of age. Animals in the control and AD-control groups were shaved, but not irradiated. RESULTS: In the AD+UVB-irradiated group, the atopy score, ear thickness, and total immunoglobulin E (IgE) were increased in comparison with the AD-control group. On day 40, the levels of interleukin (IL)-4, IL-5, and IL-10 in the spleen lymphocytes were significantly increased compared with the AD-control group, resulting in a marked decrease of the interferon (IFN)-gamma/IL-4 ratio compared with the AD-control group. In addition, the levels of IL-6, tumor necrosis factor (TNF)-alpha, and NO(x) production by peritoneal macrophages were significantly elevated. CONCLUSION: These results indicate that UVB irradiation promotes the development of AD-like skin lesions in NC/Nga mice.     

Effect of topical application and intraperitoneal injection of oregonin on atopic dermatitis in NC/Nga mice

Please cite this paper as: Effect of topical application and intraperitoneal injection of oregonin on atopic dermatitis in NC/Nga mice. Experimental Dermatology 2010; 19 : e37–e43. Abstract: The diarylheptanoid, oregonin (ORE), which was isolated from the bark of Alnus japonica Steudel that grows natively in Korea, has been known to exert antioxidative, anti‐inflammatory, anti‐cancer and immune response inhibitory effects. The antioxidative effect of ORE was observed on the superoxide and 1,1‐diphenyl‐2‐picrylhydrazyl radical, as well as on the expression of inducible nitric oxide synthase and cyclooxygenase‐2 in lipopolysaccharide‐treated RAW264.7 macrophages. The statistically significant inhibitory action of ORE against production of cytokines induced by bacterial products or by interleukin (IL)‐1β, free radicals and nitrogen species, and a corresponding increase in cellular calcium concentration because of ORE were confirmed in bone marrow and spleen dendritic cells that are known to play important functions in the development and advancement of atopic dermatitis (AD). It was thus expected that ORE would exert a beneficial effect in the treatment of AD. A study on the pharmaceutical benefits of ORE against AD has not yet been conducted in vivo. We therefore used an in vivo AD animal model, namely the NC/Nga mice, and by applying ORE onto the animals through skin application as well as intraperitoneal injection, we attempted to evaluate the benefits of ORE in this system. Evaluation of ORE was conducted by following the SCORE method to score the effect, as well as by measuring the Th2 cytokines IL‐4, IL‐5 and IL‐13 levels from serum and lymphocytes, and IgE and eosinophil levels from serum. Additionally, the expression of mRNA and protein levels was estimated using real‐time polymerase chain reaction and Western blotting analysis. The following categories of clinical evaluation, Th2 cytokines IL‐4, IL‐5 and IL‐13 values, serum IgE levels, serum eosinophil levels, and mRNA and protein expression levels of iNOS and COX‐2, were evaluated from topical application and intraperitoneal injection groups of ORE. The effects of ORE on AD in NC/Nga mice were confirmed as being similar to the positive control group, while a significant difference with the negative control group was observed. The results presented in this report suggest that ORE might be beneficial in the treatment of AD.     

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.     

Therapeutic and prophylactic effects of PUVA photochemotherapy on atopic dermatitis-like lesions in NC/Nga mice

BACKGROUND: Psoralens and ultraviolet A radiation (PUVA) photochemotherapy has been used for severe cases of atopic dermatitis (AD). To understand the mechanisms of action is important for the choice of treatments. AD-like lesions can be induced experimentally in NC/Nga mice. OBJECTIVES: To evaluate clinically and histologically the therapeutic and prophylactic effects of PUVA on AD-like dermatitis using NC/Nga mice. METHODS: PUVA therapy was performed with intraperitoneal injection of 4 mg/kg of 8-methoxypsoralen (8-MOP) and 4 J/cm(2)-UVA irradiation before and after development of AD-like lesions in NC/Nga mice which had been maintained in a conventional room (Conv-NC/Nga mice). Clinical skin conditions were evaluated periodically by a clinical severity score defined. Lesions were histologically examined in haematoxylin-eosin or toluidine blue-stained sections. Plasma levels of total IgE were measured at various time points. RESULTS: In Conv-NC/Nga mice infested with mite, AD-like lesions started to develop at 8 week of age and thereafter increased in severity score. PUVA therapy at lower does than minimal phototoxic dose suppressed the development of dermatitis and was also therapeutically effective against established lesions. Proliferation of dermal mast cells in AD-like lesions was suppressed, but IgE hyperproduction was not changed after PUVA. CONCLUSIONS: These observations suggest that PUVA photochemotherapy reveals not only therapeutic but also prophylactic effects on human AD.     

Effect of pedunculagin investigated by non‐invasive evaluation on atopic‐like dermatitis in NC/Nga mice

Background/purpose: Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disorder that is becoming increasingly prevalent. Experimental animal models have been an indispensable tool for studying its pathological mechanisms and for in vivo testing of novel therapeutic approaches. AD‐like lesions can be induced experimentally in NC/Nga mice. Pedunculagin, an ellagitannin purified from the Manchurian alder, Alnus hirsuta var. microphylla, Betulaceae, is a novel immunomodulator. To evaluate the effect of pedunculagin for AD‐like lesions in NC/Nga mice, using clinical and non‐invasive methods. Methods: AD‐like lesions were induced in NC/Nga mice using 2,4,6‐trinitrochlorobenzene (TNCB). A cream containing 0.1% or 0.5% pedunculagin was applied to the positive treatment group, and the base cream without pedunculagin was applied to the negative treatment group. The control group did not receive any kind of topical agents. We evaluated the therapeutic efficacy of pedunculagin for AD by statistical evaluation of the clinical severity score using non‐invasive biomedical engineering tools before treatment, and 1 day, 3 days, 1 week, 2 weeks and 4 weeks afterwards. Results: An AD‐like skin rash was successfully induced using TNCB in NC/Nga mice. The group receiving higher concentrations of pedunculagin showed faster and greater improvement. Conclusion: Our results suggest that remedies made from natural materials like pedunculagin are now showing promise for medical applications, and many new studies are expected to explore this potential.     

Inhibitory effects of Rumex japonicus Houtt. on the development of atopic dermatitis-like skin lesions in NC/Nga mice

BACKGROUND: Rumex japonicus Houtt. (RJH) is one of the herbs used in Eastern countries for the treatment of atopic dermatitis (AD). It has been shown to have an antioxidative effect in human skin disease. OBJECTIVES: To examine whether RJH extract (RJH-E) suppresses the development of AD-like skin lesions in NC/Nga mice, which are induced by the repeated application of picryl chloride (PC). METHODS: The efficacy of RJH-E in NC/Nga mice was assessed by measuring symptom severity, scratching behaviour, Staphylococcus aureus numbers on an ear, and serum levels of IgE, interleukin (IL)-4 and interferon (IFN)-gamma. RESULTS: Oral administration of RJH-E to NC/Nga mice treated with PC inhibited the development of AD-like skin lesions as exemplified by a significant decrease in total skin symptom severity scores, and a decrease in hypertrophy, hyperkeratosis and infiltration of inflammatory cells in the skin. The scratching behaviour and numbers of S. aureus, which are known to be exacerbated in AD, were also significantly reduced by RJH-E. No significant change was observed in the serum levels of IFN-gamma, whereas IgE and IL-4 levels were significantly reduced by RJH-E. CONCLUSIONS: These results suggest that RJH-E inhibits the development of AD-like skin lesions in NC/Nga mice by suppressing the T-helper 2 cell response. Our results indicate that RJH treatment could provide an effective alternative therapy for the management of AD.     

Time‐dependent progression from the acute to chronic phases in atopic dermatitis induced by epicutaneous allergen stimulation in NC/Nga mice

Atopic dermatitis (AD) is a complicated skin condition influenced by genetic background and environmental factors. In this study, we applied Dermatophagoides farinae body extract (DfE) to the barrier‐disrupted skin of NC/Nga mice twice a week for 8 weeks to identify the clinical and immunological factors in AD progression. Repeated application of the DfE to the skin of NC/Nga mice showed the similar consequences for the natural course of progression in human AD, histologically and immunologically. We confirmed that the AD‐like skin lesions in NC/Nga mice did not last for the whole period of our experiment in spite of repeated topical applications of DfE twice a week. Topical DfE stimulation increased the skin mRNA expressions of Th1‐, Th2‐ and Th17‐related cytokines in the acute phase. The expression patterns of IL‐4 and IL‐13 in splenic T cells and skin lesions were consistent with the time course alterations of clinical features of AD‐like skin symptoms. We also showed that there was a remission phase either just before or right after the chronic phase in this experimental model. Interestingly, splenic T‐cell‐derived IL‐5 expression began to increase in the chronic phase, while skin‐derived IL‐5 mRNA expression increased in the acute phase. In conclusion, our results suggest that we should pay attention to the characteristics of each stage of AD progression and choose a suitable corresponding stage of animal model not only to elucidate the pathogenesis of AD but also to develop and evaluate therapeutic drugs for 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.