prostaglandin-d2 and Dermatitis--Allergic-Contact

Rebound is known to occur most typically when topical glucocorticoids are abruptly discontinued; however, its frequency and severity are poorly characterized. We previously created a novel murine model of topical glucocorticoid-induced pruritus; however, the mechanism underlying pruritus in this model has not been elucidated. Using this murine model, we aimed to determine the cause of augmentation of pruritus with a focus on the production of prostaglandin (PG) D(2). BALB/c mice with chronic allergic contact dermatitis induced by 5 weeks of repeated application of 2,4,6-trinitro-1-chlorobenzene (TNCB) were treated topically with dexamethasone for 5 weeks immediately after the elicitation of dermatitis and after ear-swelling and scratching behavior were measured. RBL-2H3 mast cells were used to investigate the effect of dexamethasone on degranulation or PGD(2) production in IgE/antigen-stimulated mast cells. The scratching behavior induced by TNCB was augmented by topical application of dexamethasone, but dexamethasone did not have any effect on scratching bouts in mice that had not been treated with TNCB. Topical dexamethasone reduced the PGD(2) level, which increase in TNCB-treated mice, to the baseline level. Moreover, dexamethasone significantly decreased the PGD(2) production in IgE/antigen-stimulated RBL-2H3 mast cells; however, the same concentration of dexamethasone did not have any effect on the degranulation of stimulated mast cells. Topical glucocorticoids may exacerbate pruritus in a mouse model of allergic contact dermatitis via inhibition of PGD(2) production in antigen-mediated activated mast cells in the skin.

Topics: Administration, Topical; Animals; Dermatitis, Allergic Contact; Dexamethasone; Disease Models, Animal; Disease Progression; Female; Glucocorticoids; Mast Cells; Mice; Mice, Inbred BALB C; Picryl Chloride; Prostaglandin D2; Pruritus

A FITC-induced allergic contact hypersensitivity model was used to investigate the role that the prostaglandin D(2) receptor-chemoattractant receptor-homologous molecule expressed on T(h)2 cells (CRTH2) plays in modulating cutaneous inflammation. Our results show that inhibition of CRTH2, achieved via administration of a potent, small molecule antagonist, Compound A (Cmpd A), effectively blocked edema formation and greatly reduced the inflammatory infiltrate and skin pathology observed in drug vehicle-treated animals. Gene expression analysis revealed that Cmpd A administration down-regulated the transcription of a wide range of pro-inflammatory mediators. This correlated with decreases in cytokine and chemokine protein levels, notably IL-4, IL-1beta, tumor necrosis factor-alpha, transforming growth factor-beta, GRO-alpha, MIP-2 and thymic stromal lymphopoietin (TSLP) in FITC-challenged ears. The administration of an anti-TSLP-neutralizing antibody was only partially effective in lowering the FITC-induced inflammatory infiltrate and cytokine production compared with the CRTH2 antagonist. Taken together, these data suggest that blockade of CRTH2 inhibits multiple pathways leading to cutaneous inflammation in this model. This suggests that CRTH2 antagonism may be a viable route for therapeutic intervention in allergic skin diseases, such as atopic dermatitis.

Topics: Animals; Cell Line; Cytokines; Dermatitis, Allergic Contact; Female; Fluorescein-5-isothiocyanate; Gene Expression; Humans; Mice; Mice, Inbred BALB C; Prostaglandin Antagonists; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin; Th2 Cells

PGD(2) plays roles in allergic inflammation via specific receptors, the PGD receptor designated DP and CRTH2 (chemoattractant receptor homologous molecule expressed on Th2 cells). We generated mutant mice carrying a targeted disruption of the CRTH2 gene to investigate the functional roles of CRTH2 in cutaneous inflammatory responses. CRTH2-deficent mice were fertile and grew normally. Ear-swelling responses induced by hapten-specific IgE were less pronounced in mutant mice, giving 35-55% of the responses of normal mice. Similar results were seen in mice treated with a hemopoietic PGD synthase inhibitor, HQL-79, or a CRTH2 antagonist, ramatroban. The reduction in cutaneous responses was associated with decreased infiltration of lymphocytes, eosinophils, and basophils and decreased production of macrophage-derived chemokine and RANTES at inflammatory sites. In models of chronic contact hypersensitivity induced by repeated hapten application, CRTH2 deficiency resulted in a reduction by approximately half of skin responses and low levels (63% of control) of serum IgE production, although in vivo migration of Langerhans cells and dendritic cells to regional lymph nodes was not impaired in CRTH2-deficient mice. In contrast, delayed-type hypersensitivity to SRBC and irritation dermatitis in mutant mice were the same as in wild-type mice. These findings indicate that the PGD(2)-CRTH2 system plays a significant role in chronic allergic skin inflammation. CRTH2 may represent a novel therapeutic target for treatment of human allergic disorders, including atopic dermatitis.

Topics: Animals; Chronic Disease; Dermatitis, Allergic Contact; Disease Models, Animal; Female; Immunoglobulin E; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin

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

Salmeterol is a long-acting beta2-agonist which in animal studies has been shown to possess anti-inflammatory effects on early (EAR) and late (LPR) phase allergic responses.. To evaluate the anti-inflammatory effects of intradermally injected salmeterol and salbutamol on clinical and biochemical EAR and LPR in human skin.. Measurement of wheal and flare reactions to allergen, codeine, and histamine, and LPR (induration) to allergen. Assessment of histamine and prostaglandin D2 (PGD2) release by microdialysis technique in EAR, and measurement of mediators in LPR by suction blister technique.. Both beta2-agonists inhibited allergen-induced histamine release and wheal and flare reactions with maximum inhibition of 40-50% at 10(-6) M, a concentration which reduced PGD2 synthesis by approximately 55%. Histamine release by codeine and skin reactions to codeine and histamine were not or only marginally reduced. Salmeterol and salbutamol (10(-6) M) inhibited clinical LPR at 6 h by 71% and 48%, Except for the clinical LPR, no statistical differences were found between the two drugs on any parameters. None of the drugs inhibited levels of histamine, tryptase, myeloperoxidase, or eosinophil cationic protein in LPR.. Salmeterol and salbutamol inhibited allergen-induced skin responses, and reduced mediator release in EAR but not LPR. In general, the anti-inflammatory effects of salmeterol did not differ from those induced by salbutamol.

Topics: Adrenergic beta-Agonists; Adult; Albuterol; Allergens; Dermatitis, Allergic Contact; Female; Histamine; Humans; Inflammation Mediators; Male; Poaceae; Pollen; Prostaglandin D2; Regression Analysis; Salmeterol Xinafoate; Skin Tests; Time Factors