prostaglandin-d2 and Dermatitis--Atopic

Itching, or pruritus, can be defined as an unpleasant sensation that evokes the desire to scratch. Pruritus is most commonly associated with a primary skin disorder such as atopic dermatitis (AD), psoriasis, etc., and can have a major impact on the quality of life of those patients. Itch-induced scratching can further damage the skin barrier, leading to a worsening of symptoms. For that reason, it is important to manage pruritus. Topical glucocorticoids are commonly the first-line therapy in the management of AD and psoriasis patients. We found that topical glucocorticoids induce pruritus in mice under certain conditions. Topical glucocorticoids may induce pruritus in a mouse model of allergic contact dermatitis via inhibition of prostaglandin (PG)D

Topics: Administration, Topical; Animals; Dermatitis, Atopic; Disease Models, Animal; Glucocorticoids; Humans; Mast Cells; Mice; Patient Education as Topic; Pharmacists; Professional Role; Prostaglandin D2; Pruritus; Psoriasis; Skin

Topics: Animals; Behavior, Animal; Dermatitis, Atopic; Drug Design; Mice; Prostaglandin D2; Pruritus; Receptors, Prostaglandin

Prostaglandins (PGs) are potent eicosanoid lipid mediators derived from phospholipase-released arachidonic acid, which are involved in numerous homeostatic biological functions and inflammation. They are generated by the sequential action of cyclooxygenase isozymes and cell-specific PG synthases. Along with their role in inflammatory responses, recent accumulating evidence strongly suggests that PGs, including PGD2, are part of a complex regulatory network that modulates the immune system. PGD2 is the major prostanoid secreted by activated mast cells and has long been implicated in allergic diseases. The aim of this review is to discuss our current understanding of the mode of action of PGD2 during Th2-mediated inflammation. We also discuss recent findings, which suggest that PGD2 exerts important effects on both immune and inflammatory responses by targeting the D prostanoid receptor 1 on dendritic cells, the most potent antigen-presenting cells.

Topics: Animals; Dendritic Cells; Dermatitis, Atopic; Dermatitis, Contact; Humans; Inflammation; Lipids; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin; Th2 Cells

Antigen and cold dry air were used to challenge the upper and lower airways, skin, and conjunctiva. In each of these four systems an immediate and late-phase reaction to antigen is well characterized. Although the pattern of mediator release is different in these four areas, the degree of infiltration of basophils and eosinophils in the late-phase reaction appears to be constant. Of a number of drugs that can influence these mediators and cell responses, the steroids represent a typical mode of action. Steroids block the late-phase response and ablate the eosinophil and basophil infiltration. Although the effects of antihistamines appear to be similar, they do not appear to be caused by H1 antagonism; the mechanism of their action is unknown. This discussion will focus on these non-H1 antagonist effects of antihistamines in four challenge models, particularly the upper airways and skin.

Topics: Benzhydryl Compounds; Cetirizine; Cyproheptadine; Dermatitis, Atopic; Histamine H1 Antagonists; Histamine H2 Antagonists; Humans; Hydroxyzine; Prostaglandin D2; Rhinitis, Allergic, Seasonal; SRS-A; Terfenadine

Antigen and cold dry air were used to challenge the upper and lower airways, skin, and conjunctiva. In each of these four systems an immediate and late-phase reaction to antigen is well characterized. Although the pattern of mediator release is different in these four areas, the degree of infiltration of basophils and eosinophils in the late-phase reaction appears to be constant. Of a number of drugs that can influence these mediators and cell responses, the steroids represent a typical mode of action. Steroids block the late-phase response and ablate the eosinophil and basophil infiltration. Although the effects of antihistamines appear to be similar, they do not appear to be caused by H1 antagonism; the mechanism of their action is unknown. This discussion will focus on these non-H1 antagonist effects of antihistamines in four challenge models, particularly the upper airways and skin.

Topics: Benzhydryl Compounds; Cetirizine; Cyproheptadine; Dermatitis, Atopic; Histamine H1 Antagonists; Histamine H2 Antagonists; Humans; Hydroxyzine; Prostaglandin D2; Rhinitis, Allergic, Seasonal; SRS-A; Terfenadine

With a skin blister technique in which the mediators generated by the trauma of forming the blister are allowed to subside, we have collected human interstitial skin fluid during the course of allergic reactions to ragweed, and measured levels of histamine and prostaglandin D2 (PGD2). Of 18 ragweed-allergic individuals tested, 11 developed both an immediate and a late-phase reaction (LPR) with fivefold-elevated levels of histamine (40 ng/ml) at 30 minutes and a peak level of PGD2 (6.5 ng/ml) later at 2 1/2 hours after ragweed challenge. The other seven allergic individuals had immediate reactions without an LPR lesion and demonstrated somewhat smaller elevations of histamine (25 ng/ml) but much lower levels of PGD2 (1.6 ng/ml; p less than 0.05). The time course of appearance of these mediators was identical in both groups of patients. The fluids from unchallenged blisters of allergic and nonallergic patients and the fluids of nonallergic patients challenged with ragweed had similar levels of histamine, at the lower limit of detection, and undetectable PGD2 levels. The peak levels of PGD2 in allergic individuals correlated with the size of the LPR lesion (p less than 0.05). These data suggest that the LPR involves the secondary elaboration of mediators different from mediators responsible for the immediate manifestations of the allergic skin reaction.

Topics: Adolescent; Adult; Antigens; Dermatitis, Atopic; Female; Histamine; Humans; Hypersensitivity, Delayed; Kinetics; Male; Middle Aged; Prostaglandin D2; Prostaglandins D; Skin Diseases, Vesiculobullous; SRS-A; Time Factors

Prostaglandin D

Topics: Biomarkers; Case-Control Studies; Child; Child, Preschool; Dermatitis, Atopic; Female; Humans; Male; Patient Acuity; Prostaglandin D2; Reference Values

The present study examined the efficacy of the topical 15d‑PGJ2‑poloxamer 407 hydrogel in an atopic dermatitis (AD) animal model. The 15d‑PGJ2 hydrogel was prepared and characterized. The examined rats possessed AD‑Like cutaneous lesions, which were induced using 2,4‑dinitrochlorobenzene, the rats were then treated with a hydrogel vehicle, 15d‑PGJ2 hydrogel or tacrolimus for 14 days. The rats were sacrificed and blood samples were collected to quantify the IgE levels. Subsequently, skin biopsies were stained with toluidine blue to identify mast cells and immunohistochemistry was performed for ROR‑γt and TNF‑α. Histological analyses demonstrated that 15d‑PGJ2 hydrogel significantly decreased mast cell infiltration (P<0.05) when compared with the AD‑group. Tacrolimus at 0.1% exhibited decreased mast cell infiltration; however, this difference was not statistically significant from the AD‑group. Topical 15d‑PGJ2 hydrogel and Tacrolimus 0.1% significantly reduced the serum levels of IgE (P<0.05) compared with the AD‑group. Immunohistochemistry revealed a significant decrease in ROR‑γt and TNF‑α positive cell expression (P<0.05) in the 15d‑PGJ2 hydrogel group compared with the AD‑group. In summary, topical administration of 15d‑PGJ2 hydrogel had a beneficial effect on AD symptoms, suggesting that this formulation may be a useful strategy for the treatment of AD.

Topics: Administration, Topical; Animals; Dermatitis, Atopic; Dinitrochlorobenzene; Hydrogels; Immunoglobulin E; Immunohistochemistry; Immunosuppressive Agents; Male; Mast Cells; Nuclear Receptor Subfamily 1, Group F, Member 3; Prostaglandin D2; Rats; Rats, Wistar; Skin; Tacrolimus; Tumor Necrosis Factor-alpha

Food allergy is immediate hypersensitive reactions to ingested foods. Since early diagnosis is effective for disease control, development of an objective diagnostic index is required. Using mediator-lipidomics, we found that levels of the urinary prostaglandin D

Topics: Animals; Asthma; Dermatitis, Atopic; Food Hypersensitivity; Humans; Hyperplasia; Intestines; Intramolecular Oxidoreductases; Lipocalins; Mast Cells; Mice; Mice, Inbred BALB C; Ovalbumin; Prostaglandin D2; Rhinitis, Allergic

Group 2 innate lymphoid cells (ILC2s) are a potential innate source of type 2 cytokines in the pathogenesis of allergic conditions. Epithelial cytokines (IL-33, IL-25, and thymic stromal lymphopoietin [TSLP]) and mast cell mediators (prostaglandin D. We sought to determine the role of cysLTs and their relationship with other ILC2 stimulators in the activation of human ILC2s.. For ex vivo studies, fresh blood from patients with atopic dermatitis and healthy control subjects was analyzed with flow cytometry. For in vitro studies, ILC2s were isolated and cultured. The effects of cysLTs, PGD. Human ILC2s expressed the LT receptor CysLT. CysLTs, particularly LTE

Topics: Adult; Cells, Cultured; Cytokines; Dermatitis, Atopic; Eicosanoic Acids; Epithelial Cells; Female; Humans; Immunity, Innate; Leukotriene E4; Lymphocytes; Male; Mast Cells; Prostaglandin D2; Th2 Cells

Topics: Asthma; Case-Control Studies; Child, Preschool; Creatinine; Dermatitis, Atopic; Dinoprostone; Female; Humans; Inflammation; Male; Prostaglandin D2; Prostaglandins; Respiratory Sounds; Urinalysis

Atopic dermatitis (AD) is a chronic and relapsing skin disorder with pruritic skin symptoms. We previously reported that dihomo-γ-linolenic acid (DGLA) prevented the development of AD in NC/Tnd mice, though the mechanism remained unclear.. We attempted to investigate the mechanism of preventive effect of DGLA on AD development in NC/Tnd mice.. The clinical outcomes of NC/Tnd mice that were given diets containing DGLA, arachidonic acid, or eicosapentaenoic acid were compared. Lipid mediator contents in the skin in each group were also quantified. In addition, release of lipid mediators from RBL-2H3 mast cells treated with either DGLA or prostaglandin D1 (PGD1) was measured. Furthermore, effect of PGD1 on gene expression of thymic stromal lymphopoietin (TSLP) in PAM212 keratinocyte cells was determined.. Only DGLA containing diet suppressed the development of dermatitis in vivo. By quantifying the 20-carbon fatty acid-derived eicosanoids in the skin, the application of DGLA was found to upregulate PGD1, which correlated with a better outcome in NC/Tnd mice. Moreover, we confirmed that mast cells produced PGD1 after DGLA exposure, thereby exerting a suppressive effect on immunoglobulin E-mediated degranulation. PGD1 also suppressed gene expression of TSLP in keratinocytes.. These results suggest that oral administration of DGLA causes preventive effects on AD development in NC/Tnd mice by regulating the PGD1 supply.

Topics: 8,11,14-Eicosatrienoic Acid; Administration, Cutaneous; Animals; Arachidonic Acid; Cell Degranulation; Cytokines; Dermatitis, Atopic; Dietary Supplements; Eicosapentaenoic Acid; Gene Expression; Mast Cells; Mice; Prostaglandin D2; Prostaglandins D; RNA, Messenger; Thymic Stromal Lymphopoietin; Up-Regulation

Thymic stromal lymphopoietin (TSLP) is produced by epidermal keratinocytes, and it induces Th2-mediated inflammation. TSLP expression is enhanced in lesions with atopic dermatitis, and is a therapeutic target. Antimycotic agents improve the symptoms of atopic dermatitis.. The objective of this study was to examine whether antimycotics suppress TSLP expression in human keratinocytes.. Normal human keratinocytes were incubated with polyinosinic-polycytidylic acid (poly I:C) plus IL-4 in the presence of antimycotics. TSLP expression was analyzed by ELISA and real time PCR. Luciferase assays were performed to analyze NF-κB activity. IκBα degradation was analyzed by Western blot analysis.. Poly I:C plus IL-4 increased the secretion and mRNA levels of TSLP, which was suppressed by an NF-κB inhibitor, and also enhanced NF-κB transcriptional activities and induced the degradation of IκBα in keratinocytes. The antimycotics itraconazole, ketoconazole, luliconazole, terbinafine, butenafine, and amorolfine suppressed the secretion and mRNA expression of TSLP, NF-κB activity, and IκBα degradation induced by poly I:C plus IL-4. These suppressive effects were similarly manifested by 15-deoxy-Δ-(12,14)-PGJ2 (15d-PGJ2), a prostaglandin D2 metabolite. Antimycotics increased the release of 15d-PGJ2 from keratinocytes and decreased the release of thromboxane B2, a thromboxane A2 metabolite. Antimycotic-induced suppression of TSLP production and NF-κB activity was counteracted by an inhibitor of lipocalin type-prostaglandin D synthase.. Antimycotics itraconazole, ketoconazole, luliconazole, terbinafine, butenafine, and amorolfine may suppress poly I:C plus IL-4-induced production of TSLP by inhibiting NF-κB via increasing 15d-PGJ2 production in keratinocytes. These antimycotics may block the overexpression of TSLP in lesions with atopic dermatitis.

Topics: Antifungal Agents; Cells, Cultured; Cytokines; Dermatitis, Atopic; Humans; Interleukin-4; Keratinocytes; NF-kappa B; Poly I-C; Prostaglandin D2; Recombinant Proteins; RNA, Messenger; Thymic Stromal Lymphopoietin

Aldo-keto reductase 1C3 (AKR1C3) has been shown to mediate the metabolism of sex hormones and prostaglandin D(2) (PGD(2)), a lipid mediator that promotes skin inflammation in atopic dermatitis (AD). As both have a role in skin function and pathology, we first sought to investigate the expression pattern of AKR1C3 in normal human epidermis. Immunofluorescence revealed a strong expression of AKR1C3 in the differentiated suprabasal layers compared with the basal layer. Western blot analysis and quantitative PCR confirmed that AKR1C3 expression was also upregulated in differentiation-induced primary human keratinocytes (PHKs). To investigate the functional role of AKR1C3 during PHK differentiation, its expression and activity (measured as PGD(2) reduction to 9α,11β-PGF(2) by ELISA) were impaired by small interfering RNA or 2'-hydroxyflavanone, respectively. Cytokeratin 10 (K10) and loricrin expression were then examined by western blot analysis, thus revealing altered expression of these differentiation markers. Finally, following an observation that the AD-associated mediator, PGD(2), upregulated AKR1C3 expression in PHKs, we used immunofluorescence to examine AKR1C3 expression in AD and psoriasis lesions. AKR1C3 was found to be upregulated in AD but not in psoriasis lesions compared with non-lesional skin. Our work demonstrates a function for AKR1C3 in differentiation-associated gene regulation and also suggests a role in supporting inflammation in AD.

Topics: 3-Hydroxysteroid Dehydrogenases; Aldo-Keto Reductase Family 1 Member C3; Biomarkers; Calcium; Cell Differentiation; Cells, Cultured; Dermatitis, Atopic; Epidermal Cells; Epidermis; Flavanones; Gene Expression Regulation; Humans; Hydroxyprostaglandin Dehydrogenases; Keratin-10; Keratinocytes; Membrane Proteins; Prostaglandin D2; RNA, Small Interfering; Up-Regulation

Cutaneous prostaglandin (PG) D₂ levels increase after scratching. Chemoattractant receptor-homologous molecule expressed on receptor on T(H)2 cells (CRTH2) mediates chemotaxis to PGD₂ and is expressed on T(H)2 cells and eosinophils, which infiltrate skin lesions in patients with atopic dermatitis.. We sought to examine the role of CRTH2 in a murine model of atopic dermatitis.. CRTH2(-/-) mice and wild-type control animals were epicutaneously sensitized by means of repeated application of ovalbumin (OVA) to tape-stripped skin for 7 weeks and then challenged by means of OVA application to tape-stripped previously unsensitized skin for 1 week. Skin histology was assessed by means of hematoxylin and eosin staining and immunohistochemistry. Cytokine mRNA expression was examined by means of quantitative RT-PCR. Levels of PGD₂, antibody, and cytokines were measured by means of ELISA.. PGD₂ levels significantly increased in skin 24 hours after tape stripping, although not in skin subjected to repeated sensitization with OVA. Allergic skin inflammation developed normally at sites of chronic epicutaneous sensitization with OVA in CRTH2(-/-) mice but was severely impaired in previously unsensitized skin challenged with OVA, as evidenced by significantly decreased skin infiltration with eosinophils and CD4(+) cells and impaired T(H)2 cytokine mRNA expression. Impaired skin inflammation at sites of acute OVA challenge in CRTH2(-/-) mice was not due to an impaired systemic response to epicutaneous sensitization because OVA-specific IgG1 and IgE antibody levels and OVA-driven splenocyte secretion of cytokines in these mice were comparable with those seen in wild-type control animals.. CRTH2 promotes allergic skin inflammation in response to cutaneous exposure to antigen in previously sensitized mice.

Topics: Administration, Cutaneous; Animals; Chemotaxis, Leukocyte; Dermatitis, Atopic; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Knockout; Ovalbumin; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin; Skin; Th2 Cells

Prostaglandin D(2) (PGD(2)) and its receptor chemoattractant receptor homologous molecule expressed on T(h)2 cells (CRTH2) have been implicated in the pathogenesis of numerous allergic diseases. We investigated the role of PGD(2) and CRTH2 in allergic cutaneous inflammation by using a highly potent and specific antagonist of CRTH2. Administration of this antagonist ameliorated cutaneous inflammation caused by either repeated epicutaneous ovalbumin or FITC sensitization. Gene expression and ELISA analysis revealed that there was reduced pro-inflammatory cytokine mRNA or protein produced. Importantly, the CRTH2 antagonist reduced total IgE, as well as antigen-specific IgE, IgG1 and IgG2a antibody levels. This reduction in antibody production correlated to reduced cytokines produced by splenocytes following in vitro antigen challenge. An examination of skin CD11c(+) dendritic cells (DC) showed that in mice treated with the CRTH2 antagonist, there was a decrease in the number of these cells that migrated to the draining lymph nodes in response to FITC application to the skin. Additionally, naive CD4(+) T lymphocytes co-cultured with skin-derived DC from CRTH2 antagonist-treated mice showed a reduced ability to produce a number of cytokines compared with DC from vehicle-treated mice. Collectively, these findings suggest that CRTH2 has a pivotal role in mediating the inflammation and the underlying immune response following epicutaneous sensitization.

Topics: Animals; Antigens, CD; CD4-Positive T-Lymphocytes; Cells, Cultured; Cytokines; Dendritic Cells; Dermatitis, Atopic; Female; Gene Expression; Immunoglobulins; Mice; Mice, Inbred BALB C; Ovalbumin; Prostaglandin Antagonists; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin; Up-Regulation

PentaHerbs formula (PHF) containing Cortex Moutan, root bark of Paeonia suffruticosa Andr. (Ranunculaceae), Cortex Phellodendri, bark of Phellodendron chinensis Schneid. (Rutaceae), Flos Lonicerae, flower of Lonicera japonica Thunb. (Capri-foliaceae), Herba Menthae, aerial part of Mentha haplocalyx Briq. (Labiatae) and Rhizoma Atractylodis, rhizome of Atractylodes lancea (Thunb.) DC. (Compositae) at the ratio of 2:2:2:1:2 was useful in the management of eczema.. Since the mechanism of action of PHF is not known, we aimed to investigate the actions of PHF on mast cell activation.. Effects of aqueous extracts of PHF and individual component herb on mediator release from rat peritoneal mast cells (RPMCs) and cytokine production from HMC-1 were investigated.. PHF, Cortex Moutan and Herba Menthae significantly attenuated histamine release and prostaglandin D(2) synthesis from RPMC activated by anti-IgE and compound 48/80 (p<0.05). While Flos Lonicerae and Rhizoma Atractylodis suppressed only mediator release from compound 48/80 activated RPMC, Cortex Phellodendri potentiated only anti-IgE induced mediator release (p<0.05). However, with the exception of Cortex Moutan, PHF and the other four component herbs failed to affect cytokine production in HMC-1.. Although individual herbs demonstrated different modulating effects on mast cells, inhibition of inflammatory mediator release from mast cells would contribute to the therapeutic efficacy of PHF.

Topics: Animals; Anti-Inflammatory Agents; Cell Line; Cytokines; Dermatitis, Atopic; Drugs, Chinese Herbal; Histamine; Humans; Male; Mast Cells; Medicine, Chinese Traditional; Peritoneum; Phytotherapy; Prostaglandin D2; Rats; Rats, Sprague-Dawley

TS-022, {4-[(1R, 2S, 3R, 5R)-5-Chloro-2-((S)-3-cyclohexyl-3-hydroxyprop-1-ynyl)-3-hydroxycyclopentyl] butylthio} acetic acid monohydrate, inhibits ADP-induced platelet aggregation, an effect significantly antagonized, as in the case of prostaglandin D(2) by the prostanoid DP(1) receptor antagonist (BW A868C). TS-022 is a prostanoid DP(1) receptor agonist, originally developed as a novel anti-pruritic drug for patients with atopic dermatitis. We examined the effects of TS-022 on experimental pruritus, cutaneous barrier disruption, and atopic dermatitis and in in vitro immune function tests. Topically applied TS-022 significantly suppressed scratching in skin-lesioned NC/Nga mice from a concentration of 2.5 nM, and this scratch-suppressive activity was significantly antagonized by BW A868C. Tacrolimus (FK-506) and dexamethasone, used as reference drugs for atopic dermatitis, also exhibited suppressive effects against scratching, but only at concentrations of 125 and 25,000 microM. TS-022 applied topically, once a day for 2 days, significantly accelerated repair of the cutaneous barrier disruption caused by mechanical scratching, from concentrations of 2.5 nM. This acceleration of repair of the disrupted cutaneous barrier by this drug was also significantly antagonized by BW A868C. FK-506 and dexamethasone showed no beneficial effects on the repair of the disrupted cutaneous barrier. Repeated topical application of 2.5 microM of TS-022 and 12.5 microM of FK-506 once a day for 6 weeks significantly improved the skin inflammation scores in the NC/Nga mice. In regard to the effects of TS-022 in vitro, the inhibitory activity of TS-022 against concanavalin A-induced cytokine production by splenocytes was marginal as compared with that of FK-506 or dexamethasone. These results suggest that the beneficial therapeutic effects of TS-022 in NC/Nga mice with atopic dermatitis are mediated by its suppressive effect on scratching and its effect of accelerating repair of the disrupted cutaneous barrier, both effects being attributable to its prostanoid DP(1) receptor agonistic activity.

Topics: Acetates; Animals; Antipruritics; Concanavalin A; Cyclohexanes; Cytokines; Dermatitis, Atopic; Dexamethasone; Humans; Hydantoins; Immunosuppressive Agents; Inflammation; Male; Mice; Platelet Aggregation; Prostaglandin D2; Pruritus; Receptors, Immunologic; Receptors, Prostaglandin; Skin; Sulfhydryl Compounds; Tacrolimus; Wound Healing

In atopic dermatitis, scratching of the skin as a reaction to itching causes injury to the skin, which, in turn, further increases the itching resulting in the establishment of the so-called itch-scratch circle. We have shown that prostaglandin (PG) D2 plays an inhibitory role against pruritus in mice with atopic-like dermatitis; therefore, we examined the relationship between scratching and the cutaneous PGD2 level using an artificial scratching model with a wire brush. Mechanical scratching induced a temporary increase of the skin PGs levels (PGE2, PGD2, 6-ketoPGF1alpha, PGF2alpha). The skin PGD2 level and the ability of PGD2 production decreased at 48 h after repeated scratch, compared to that of normal skin, not so after single scratch. Immunohistochemical analysis and Western blotting revealed a decrease in the levels of cyclooxygenase-1 (COX-1) and hematopoietic PGD synthase in mechanically scratched skin. The reduced ability of the skin for PGD2 production following mechanical scratching could be caused by this decrease in the expression levels of COX-1 and PGD2 synthase. The results suggest that repeated scratching in mice decreases the ability of the skin to produce PGD2, which is an endogenous mediator that inhibits pruritus, resulting in the establishment of the itch-scratch circle.

Topics: Animals; Cyclooxygenase 1; Cyclooxygenase 2; Dermatitis, Atopic; Intramolecular Oxidoreductases; Lipocalins; Male; Membrane Proteins; Mice; Mice, Inbred BALB C; Prostaglandin D2; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Pruritus; Skin

TS-022 is a prostanoid DP(1) receptor agonist, originally developed as a novel anti-pruritic drug for atopic dermatitis. The drug has been shown to suppress scratching and improve the skin inflammation in the NC/Nga (NC) mouse, a model of atopic dermatitis. Corticosteroids are commonly used as effective agents for the treatment of atopic dermatitis. We examined the anti-pruritic efficacy of TS-022 in NC mice cohabited with skin-lesioned NC mice, which showed spontaneous scratching without skin lesions in the early phase and chronic itching with severe dermatitis in the late phase, in comparison with that of dexamethasone. We have previously reported that prostaglandin D(2) might have a physiological role in the inhibition of pruritus. While after 2 weeks of cohabitation with skin-lesioned NC mice (early phase of dermatitis, characterized by the appearance of spontaneous scratching), topically applied TS-022 exhibited a weak anti-pruritic effect in the NC mice, after 6 weeks of cohabitation (late phase, characterized by both chronic scratching and dermatitis), the drug exerted potent anti-pruritic activity. In contrast, dexamethasone exerted potent anti-pruritic effect in both the early and late phases. Indomethacin aggravated the scratching in the early phase, but had no effect in the late phase. The skin prostaglandin D(2) level was significantly increased in the early phase, to subsequently declined and return to the basal level in the late phase. The cutaneous ability for prostaglandin D(2) production following topical application of arachidonic acid or mechanical scratching was decreased in the late phase. Moreover, the expression level of the prostanoid DP(1) receptor in the skin was increased in the late phase. These findings suggest that the potent anti-pruritic activity of TS-022 in the late phase might be attributable to the decrease of endogenous prostaglandin D(2) production and increase of prostanoid DP(1) receptor expression.

Topics: Acetates; Animals; Anti-Inflammatory Agents; Antipruritics; Arachidonic Acid; Cyclohexanes; Dermatitis, Atopic; Dexamethasone; Gene Expression Regulation; Male; Mice; Prostaglandin D2; Pruritus; Receptors, Prostaglandin; Skin; Sulfhydryl Compounds; Water Loss, Insensible

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.

Topics: Animals; Behavior, Animal; Blotting, Western; Cyclooxygenase 1; Cyclooxygenase 2; Dermatitis, Atopic; Intramolecular Oxidoreductases; Lipocalins; Male; Mice; Mice, Inbred BALB C; Prostaglandin D2; Pruritus; Skin; Specific Pathogen-Free Organisms; Stress, Mechanical

Dermal microdialysis, a relatively noninvasive technique, allows investigation of the changes in cellular mediators released during cutaneous allergic responses. This technique was used to evaluate the effect of cyclosporin A, an immunosuppressive drug used for treatment of canine atopic dermatitis, on the cutaneous release of two pro-inflammatory mediators following intradermal allergen challenge. Four beagle dogs spontaneously sensitized to Ascaris suum were treated for 1 month with oral cyclosporin A. At days 0, 15 and 30 of the treatment, dialysis probes were inserted into the skin of the back, and 20 microL of A. suum antigen was injected intradermally at each site. At timed intervals, dialysate was collected and assayed for histamine and prostaglandin D(2) and the wheal area was measured. Mean histamine concentration and wheal area were significantly lower at days 15 and 30 of treatment, compared with day 0. However, prostaglandin D(2) concentration was not significantly reduced. The inhibition in histamine release after intradermal challenge, by cyclosporin, confirms its anti-inflammatory action in the dog. Dermal microdialysis provides a useful tool for investigating canine allergic reactions and their modulation by drugs.

Topics: Administration, Oral; Animals; Ascaris suum; Cyclosporine; Dermatitis, Atopic; Dermatologic Agents; Dog Diseases; Dogs; Female; Histamine; Histamine Release; Immunosuppressive Agents; Microdialysis; Prostaglandin D2; Time Factors

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.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Blotting, Western; Carrageenan; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Dermatitis, Atopic; Edema; Mice; Nitrobenzenes; Prostaglandin D2; Pruritus; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; Sulfonamides

Allergic pathologies are often associated with IgE production, mast cell activation, and eosinophilia. PGD2 is the major eicosanoid, among several inflammatory mediators, released by mast cells. PGD2 binds to two membrane receptors, D prostanoid receptor (DP)1 and DP2, endowed with antagonistic properties. In humans, DP2 is preferentially expressed on type 2 lymphocytes, eosinophils, and basophils and mediates chemotaxis in vitro. Although not yet supported by in vivo studies, DP2 is thought to be important in the promotion of Th2-related inflammation. Herein, we demonstrate that mouse eosinophils express both DP1 and DP2 and that PGD2 exerts in vitro chemotactic effects on eosinophils through DP2 activation. Furthermore, 13,14-dihydro-15-keto-PGD2, a specific DP2 agonist not only increases eosinophil recruitment at inflammatory sites but also the pathology in two in vivo models of allergic inflammation: atopic dermatitis and allergic asthma. By contrast, DP1 activation tends to ameliorate the pathology in asthma. Taken together, these results support the hypothesis that DP2 might play a critical role in allergic diseases and underline the interest of DP2 antagonists in human therapy.

Topics: Animals; Asthma; Base Sequence; Chemotaxis, Leukocyte; Dermatitis, Atopic; DNA; Eosinophilia; Eosinophils; Female; Gene Expression; Humans; Hypersensitivity; In Vitro Techniques; Inflammation; Mice; Mice, Inbred BALB C; Mice, Transgenic; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin; RNA, Messenger

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.

Topics: Administration, Topical; Animals; Arachidonic Acid; Dermatitis, Atopic; Mice; Mice, Inbred Strains; Nitrobenzenes; Physical Stimulation; Prostaglandin D2; Prostaglandins; Pruritus; Skin; Water Loss, Insensible

The mobilization of Langerhans cells (LCs) from epithelia to the draining lymph nodes is an essential process to initiate primary immune responses. We have recently shown that in mice, PGD2 is a potent inhibitor of epidermal LC emigration. In this study, we demonstrate that activation of the D prostanoid receptor 1 (DP1) impedes the TNF-alpha-induced migration of human LCs from skin explants and strongly inhibits the chemotactic responses of human LC precursors and of maturing LCs to CC chemokine ligands 20 and 19, respectively. Using a murine model of atopic dermatitis, a chronic Th2-type allergic inflammatory disease, we demonstrate that the potent DP1 agonist BW245C dramatically decreases the Ag-specific T cell activation in the skin draining lymph nodes and markedly prevents the skin lesions following repeated epicutaneous sensitization with OVA. Interestingly, analysis of the local response indicates that BW245C treatment strongly reduces the recruitment of inflammatory cells into the dermis and disrupts the Th1/Th2 balance, probably through the increased production of the immunoregulatory cytokine IL-10, in the skin of sensitized mice. Taken together, our results suggest a new function for DP1 in the regulation of the immune and inflammatory responses. We propose that DP1 activation by specific agonists may represent a strategy to control cutaneous inflammatory Th2-associated diseases.

Topics: Adjuvants, Immunologic; Animals; Cell Migration Inhibition; Chemotaxis, Leukocyte; Culture Techniques; Dermatitis, Atopic; Disease Models, Animal; Down-Regulation; Epitopes, T-Lymphocyte; Female; Growth Inhibitors; Humans; Langerhans Cells; Lymph Nodes; Mice; Mice, Inbred BALB C; Mice, Transgenic; Ovalbumin; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin; RNA, Messenger; T-Lymphocyte Subsets; Th1 Cells; Th2 Cells; Up-Regulation

Chemoattractant receptor-homologous molecule expressed on Th2 lymphocytes, CRTH2, is a cognate receptor for prostaglandin (PG) D(2) and, in humans, is suggested to play a functional role in Th2-dependent allergic inflammation. While peripheral blood leukocytes expressing high levels of surface CRTH2 have been detected in disease, little is known of the functional significance of CRTH2 in disease etiology. We have utilized a Th2-dependent murine model of FITC-induced contact hypersensitivity to assess the role, if any, CRTH2-PGD(2) may play in the elicitation or maintenance of such pathobiology. Expression of both PGD(2) and CRTH2 in lesional skin was paralleled by the release of the chemoattractants LTB(4) and the chemokine KC, as well as a profuse dermal neutrophilic and eosinophilic infiltrate, closely paralleling the acute inflammatory pathology observed in human atopic dermatitis. A small molecule CRTH2 antagonist, but not a selective PGD(2)R (DP) receptor antagonist, was able to completely abrogate these responses. Inflammatory cascades mediated by CRTH2 ligation may therefore represent an important early step in the elicitation and maintenance of Th2-dependent skin inflammation.

Topics: Animals; Carbazoles; Chemokine CXCL1; Chemokines; Chemokines, CXC; Cytokines; Dermatitis, Allergic Contact; Dermatitis, Atopic; Eosinophils; Female; Inflammation; Leukotriene B4; Mice; Mice, Inbred BALB C; Neutrophil Activation; Neutrophils; Platelet Aggregation Inhibitors; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin; Signal Transduction; Sulfonamides; Th2 Cells

NC/Nga mice have similar pathological and behavioral features of human atopic dermatitis and are used as a model of the disease. Under conventional circumstances, spontaneous and persistent scratching is frequent and can lead to the onset of skin inflammation. We examined the effects of several prostanoids and their related compounds on the scratching behavior of NC/Nga mice. Among them, topically applied prostaglandin D2, prostaglandin E1, prostaglandin E2 and prostaglandin I2 significantly suppressed the scratching, the order of inhibitory activities being prostaglandin D2>>prostaglandin I2>prostaglandin E1=prostaglandin E2. Prostaglandin D2 metabolite, prostaglandin J2 also significantly suppressed the scratching but not so 13,14-dihydro-15-keto-prostaglandin D2, and 15-deoxy-Delta12,14-prostaglandin J2. The order of the inhibitory activities of these prostaglandin D2 metabolites depended on affinity of the prostanoid DP1 receptor but not on the DP2 receptor (chemoattractant receptor-homologous molecule expressed on T helper2 cells, CRTH2) and PPAR-gamma receptors. Likewise, topically applied arachidonic acid significantly suppressed the scratching while indomethacin enhanced it. Pretreatment of arachidonic acid increased the skin prostaglandins (prostaglandin D2, prostaglandin E2, prostaglandin F2alpha and 6-keto-prostaglandin F1alpha) contents, but indomethacin decreased the prostaglandin D2 and prostaglandin E2 contents. On the other hand, prostaglandin D2 and indomethacin had no apparent effects on histamine-induced scratching of ICR mice. These results suggested that prostaglandin D2 plays a physiological role in inhibiting pruritus of NC/Nga mice via their specific prostanoid DP1 receptors, and that prostaglandin D2 and/or a prostanoid DP1 receptor agonist may have therapeutic effects for cases of consecutive skin inflammation.

Topics: 6-Ketoprostaglandin F1 alpha; Alprostadil; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Behavior, Animal; Dermatitis, Atopic; Dinoprost; Dinoprostone; Dose-Response Relationship, Drug; Epoprostenol; Histamine; Indomethacin; Male; Mice; Mice, Inbred ICR; Mice, Inbred Strains; Prostaglandin D2; Prostaglandins; Pruritus; Receptors, Prostaglandin; Skin; Time Factors

Prostaglandin D2 is known to be the major prostanoid produced by allergen-activated mast cells, but its role in the formation of allergic diseases is not well established because of complexity of its receptor system and lack of appropriate inhibitors. We have recently identified a new-type prostaglandin D2 receptor, named CRTH2. Studies with normal subjects have shown that CRTH2 appears to be selectively expressed by T helper 2 cells but not T helper 1 cells among circulating CD4+ lymphocytes. The exact correlation between CRTH2 and T helper 2 cells in various disease settings and the impact of CRTH2-mediated prostaglandin D2 activities on various T helper 2 responses in vivo still remain to be elucidated, however. In this study, we investigated the correlation between CRTH2 and T helper 2 cells among circulating CD4+ lymphocytes in normal adults and patients with atopic dermatitis, a T-helper-2-involving disease. The results showed that virtually all CRTH2+CD4+ lymphocytes had a pure T helper 2 phenotype and formed not all but a large proportion of circulating T helper 2 cells for both normal and atopic dermatitis subjects. In chemotaxis assays, peripheral blood CRTH2+CD4+ lymphocytes were significantly attracted by prostaglandin D2 as well as by a typical T-helper-2-attracting chemokine, thymus and activation regulated chemokine, whereas they showed little chemotactic migration toward typical T-helper-1-attracting chemokines, macrophage inflammatory protein 1beta and interferon-gamma-inducible protein 10. Furthermore, in atopic dermatitis patients, a preferential increase of CRTH2+ cells was noted within the disease-related cutaneous lymphocyte-associated antigen-positive, but not the cutaneous lymphocyte-associated antigen-negative, CD4+ lymphocyte compartment. Our results suggest the involvement of the prostaglandin D2/CRTH2 system in both normal and pathogenic T helper 2 responses.

Topics: Adult; Allergens; CD4-Positive T-Lymphocytes; Chemokines; Chemotaxis, Leukocyte; Dermatitis, Atopic; Flow Cytometry; Humans; Immunophenotyping; Prostaglandin D2; Receptors, Cell Surface; Receptors, Immunologic; Receptors, Prostaglandin; Severity of Illness Index; Th2 Cells

We investigated the influence of vitamin E on mediator activity and release in a canine mastocytoma cell line (C2) as a model for canine atopic dermatitis. Cells were incubated without and with vitamin E (100 microm) for 24 h. The histamine and prostaglandin D2 (PGD2) release as well as the chymase and tryptase activity were measured. To stimulate the PGD2 and histamine release, cells were incubated with the wasp venom peptide mastoparan (50 microm) for 30 or 45 min. Nonstimulated as well as mastoparan-stimulated histamine and PGD2 release was reduced significantly in vitamin E-treated cells. The activity of chymase tended to decrease, but the tryptase activity of C2 cells was not influenced by vitamin E. These results indicate that vitamin E decreased the production and release of inflammatory mediators in C2 cells, suggesting that vitamin E might have a possible beneficial effect in inflammatory diseases.

Topics: Animals; Cell Line; Chymases; Dermatitis, Atopic; Dog Diseases; Dogs; Histamine; Histamine Release; Intercellular Signaling Peptides and Proteins; Mast Cells; Peptides; Prostaglandin D2; Serine Endopeptidases; Tryptases; Vitamin E; Wasp Venoms

The mediators produced from a type I allergic reaction have not yet been able to explain the pathogenesis of atopic dermatitis (AD).. The purpose of this study was to elucidate the involvement of leukotriene (LT) B4 produced from a type I allergic reaction in the pathogenesis of AD.. The release of LTB4 was measured both in vitro, in passively sensitized and antigen-challenged human skin slices, as well as in vivo, in skin chambers on patients with AD.. LTB4 was released from in vitro human skin by stimulation of the antigen (54.9 +/- 14.6 pg/g wet weight of skin by antigen challenge and 28.0 +/- 11.1 pg/g in control skin, P <.002). Antigen-specific release of LTB4 and histamine was also observed in vivo in nonlesional skin from the patients with AD by using the skin chamber technique.. LTB4 release during type I allergic reaction in human skin has been determined in vitro. The released LTB4 possibly contributes to cellular response at the acute inflammatory lesion of AD.

Topics: Adolescent; Adult; Allergens; Animals; Chemotaxis, Leukocyte; Child; Dermatitis, Atopic; Dust; Female; Histamine Release; Humans; Leukotriene B4; Male; Middle Aged; Mites; Neutrophils; Prostaglandin D2; Skin

Skin mast cells have been proposed to be involved in the pathogenesis of acute and chronic phases of atopic dermatitis (AD). The aim of the present study was to investigate the significance of different mast cell mediators during acute exacerbation of this frequent skin disease. Plasma levels from 19 patients with AD were screened for elevation of the mast cell-specific protease tryptase, the biogene amine histamine, and the arachidonic acid metabolite prostaglandin D2. None of the patients showed elevated plasma levels of these three mediators, whereas the mean serum IgE level was strongly elevated. We conclude that the investigated mediators are either only active on the cutaneous level or that other mediators are responsible for the development of the acute eczematous and pruritic skin reactions. Alternatively, the assays could have been insufficiently sensitive since some studies have demonstrated increased plasma histamine levels, e.g. after food challenge of such patients.

Topics: Acute Disease; Adolescent; Adult; Aged; Chymases; Dermatitis, Atopic; Eosinophils; Female; Histamine; Humans; Immunoglobulin E; Leukocyte Count; Male; Mast Cells; Osmolar Concentration; Prostaglandin D2; Reference Values; Serine Endopeptidases; Tryptases

Basophils have been implicated as a source of histamine and pro-inflammatory eicosanoids in atopic dermatitis. However, mechanisms regulating basophil mediator release are not understood. An H3 receptor involved in the control of histamine synthesis and release has been identified in nervous tissue. In this study we have investigated 1) release of histamine, leukotriene C4, and prostaglandin D2 from anti-immunoglobulin E (IgE)-stimulated basophils of adults with atopic dermatitis and unaffected individuals and 2) specific H3 receptor-dependent basophil mediator release, using an H3 receptor agonist and antagonist. Basophil-rich leukocyte fractions were prepared by dextran sedimentation of venous blood from 19 patients with atopic dermatitis (five male, 14 female, mean age 30.6 years, range 19-59 years) and 15 unaffected individuals (five male, 10 female, mean age 27.6 years, range 19-50 years). Anti-IgE (0.78-78.0 micrograms/ml) stimulation of basophils induced a concentration-dependent release of histamine and leukotriene C4, but not prostaglandin D2. Histamine release was maximally induced by 7.8 micrograms/ml anti-IgE with no significant (Mann-Whitney U test) difference between atopic basophils (n = 17; 43.65 +/- 4.16% mean +/- SEM) and normal basophils (n = 13; 52.23 +/- 4.39%). LTC4 release was maximal from atopic basophils incubated with 2.6 micrograms/ml anti-IgE (n = 5; 0.99 +/- 0.29 pg/10(6) cells) and from normal basophils incubated with 0.78 microgram/ml anti-IgE (n = 5; 25.38 +/- 5.79 pg/10(6) cells). Anti-IgE-stimulated release of leukotriene C4 from atopic basophils was significantly less than from normal basophils at all concentrations (p < 0.05). Basophils were co-incubated with anti-IgE (2.6 and 7.8 micrograms/ml) and either the H3 receptor agonist, (R)alpha-methylhistamine (10(-8) and 10(-7) M), or the H3 receptor antagonist thioperamide (10(-6) and 10(-5) M). Neither drug modulated anti-IgE-induced release of histamine (atopics, n = 10; normals, n = 8). These results indicate 1) that basophils from adults with atopic dermatitis release the same amount of histamine as, but less leukotriene C4 than, basophils of unaffected adults and 2) that H3 receptors are not involved in anti-IgE release of histamine from basophils. These data do not support a role for increased basophil release of histamine as a mediator in the itch and erythema of atopic dermatitis in adults.

Topics: Adult; Antibodies, Anti-Idiotypic; Basophils; Dermatitis, Atopic; Eicosanoids; Female; Histamine Release; Humans; Male; Middle Aged; Prostaglandin D2; Receptors, Histamine; Receptors, Histamine H3; SRS-A

Food hypersensitivities contribute to disease exacerbation in a sub-group of children with atopic dermatitis (AD). It has been shown that only selected foods are capable of causing clinical reactions when ingested, whereas other foods, to which the patient is equally sensitive by skin-prick testing, may be tolerated. The purpose of this study was to examine the cutaneous late-phase response (LPR) to food antigens in food-allergic patients with AD and to determine if the skin reacted differently to 'relevant foods' (foods eliciting positive skin-prick tests and positive oral challenges) than to 'non-relevant foods' (foods eliciting positive skin tests but negative oral challenges). Using blister chambers adfixed to the skin, six children with AD were challenged epicutaneously with foods to which they had previously been shown to be sensitive. Histamine and PGD2 were measured hourly for 10-12 hr in parallel with quantitation of the cellular traffic. There appeared to be no difference in any of the measured parameters between relevant foods and non-relevant foods, and the patterns of the LPR cells and mediators were similar to those previously described with aero-allergens in patients with respiratory allergy. Histamine rose to 13.0 +/- 24 ng/ml (P < 0.005) during the first hours, declined to < 1 ng/ml by the fifth hour, and then rose a second time to 6.72 +/- 3.4 ng/ml (P < 0.05) during the 12th hour. PGD2 rose to an average of 312 pg/ml (P < 0.05) during the first 3 hr followed by a decline to baseline.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Child; Dermatitis, Atopic; Female; Food; Food Hypersensitivity; Histamine Release; Humans; Hypersensitivity, Delayed; Leukocyte Count; Male; Prostaglandin D2; Skin; Skin Tests

Since the biochemical events leading to cutaneous inflammation in atopic dermatitis and psoriasis are unknown, we studied the levels of arachidonic acid-derived mediators of inflammation as well as histamine in the suction blister fluid obtained from lesional and nonlesional skin of patients with these dermatoses. Mediator levels were determined radioimmunologically. Skin from healthy controls and uninvolved skin from patients contained very low or unmeasurable levels of the 5-lipoxygenase metabolite of arachidonic acid, leukotriene (LT) B4. In contrast, higher levels of LTB4-like immunoreactivity were detected in suction blister fluid from lesional atopic dermatitis skin, and even higher concentrations occurred in psoriasis lesions. LTB4-like immunoreactivity from atopic dermatitis suction blister fluid cochromatographed on reverse-phase high-pressure liquid chromatography with authentic LTB4, thus excluding cross-reaction of the LTB4-antibody with arachidonic acid or monohydroxyeicosatetraenoic acids. In contrast, suction blister concentrations of the cyclooxygenase metabolite of arachidonic acid prostaglandin (PG) E2 showed no significant differences between lesional and nonlesional patient skin and healthy control skin. PGD2 determined as a stable metabolite could not be detected in these samples. Histamine concentrations in lesional skin were within normal range. The elevated levels of the potent proinflammatory and immunomodulating mediator LTB4 could be involved in the pathogenesis of cutaneous inflammation in atopic dermatitis and psoriasis. In addition, they might explain the therapeutic efficiency of glucocorticosteroids, which among other actions inhibit the release of arachidonic acid from phospholipid stores by blocking the enzyme phospholipase A2. However, the specificity of disease expression in atopic dermatitis and psoriasis must be due to factors other than cutaneous LTB4 elevation.

Topics: Adolescent; Adult; Aged; Arachidonic Acid; Arachidonic Acids; Dermatitis, Atopic; Dinoprostone; Female; Histamine; Humans; Leukotriene B4; Male; Middle Aged; Prostaglandin D2; Prostaglandins D; Prostaglandins E; Psoriasis; Skin

We have studied NK cell activity in atopic and non-atopic subjects using a standard 51Cr-release assay and K562 target cells. In atopics (AT) with allergic rhinitis and/or asthma, NK cell activity was similar to that in non-atopic (N) subjects, whilst patients with severe atopic eczema (AE) had depressed NK cell activity compared to AT or N subjects. In addition, circulating T-cell numbers and Con A responsiveness was decreased in AE, although neither parameter was correlated with decreased NK cell activity. However, decreased NK cell activity in atopic eczema was positively correlated with decreased numbers of Fc gamma + lymphocytes (P = 0.01) and decreased effector: target cell binding (P = 0.05), and negatively correlated with increased monocytes in AE (P = 0.09). AE NK cell activity was equally or more sensitive to the inhibitory effects of drugs such as dibutyryl cyclic AMP, prostaglandins (PG) D2,E2 and histamine. The relative percentage increase in NK cell activity by the interferon inducer poly I:C was similar in AE patients and controls. The results suggest that reduced numbers of circulating NK cells and pre-NK cells account for the depressed level of NK cell activity in subjects with severe atopic eczema.

Topics: Adult; Dermatitis, Atopic; Dinoprostone; Female; Humans; Indomethacin; Killer Cells, Natural; Leukocyte Count; Lymphocyte Activation; Male; Middle Aged; Poly I-C; Prostaglandin D2; Prostaglandins D; Prostaglandins E; Receptors, Fc; T-Lymphocytes