oxazolone and Chronic-Disease

T helper type 2 (Th2)-characterized inflammatory responses are highly dynamic processes initiated by epithelial cell damage resulting in remodelling of the tissue architecture to prevent further harm caused by a dysfunctional epithelial barrier or migrating parasites. This process is a temporal and spatial response which requires communication between immobile cells such as epithelial, endothelial, fibroblast and muscle cells and the highly mobile cells of the innate and adaptive immunity. It is further characterized by a high cellular plasticity that enables the cells to adapt to a specific inflammatory milieu. Incipiently, this milieu is shaped by cytokines released from epithelial cells, which stimulate Th2, innate lymphoid and invariant natural killer (NK) T cells to secrete Th2 cytokines and to activate dendritic cells which results in the further differentiation of Th2 cells. This milieu promotes wound-healing processes which are beneficial in parasitic infections or toxin exposure but account for increasingly dysfunctional vital organs, such as the lung in the case of asthma and the colon in ulcerative colitis. A better understanding of the dynamics underlying relapses and remissions might lead ultimately to improved therapeutics for chronic inflammatory diseases adapted to individual needs and to different phases of the inflammation.

Topics: Animals; Cellular Microenvironment; Chronic Disease; Disease Models, Animal; Humans; Inflammation; Neoplasms; Oxazolone; Th2 Cells

A decrease in the number of basophils in the peripheral blood, or basopenia, has been noted, reflecting the activity of chronic spontaneous urticaria (CSU). Infiltration of basophils into the skin has also been reported, but the mechanism of basopenia in CSU has not been clarified. The phenomenon of basopenia during the active phase of urticaria was confirmed, and basophil numbers increased following symptom improvement in 15 out of 17 patients treated with omalizumab and in 13 of 15 patients treated with antihistamines. Our examination by immunostaining also revealed basophil infiltration of the CSU lesions, as in previous reports, but since most of our patients were already taking oral steroids, it was not considered appropriate to examine the relationship between basophil numbers in tissue and peripheral blood. Then, we used mouse model of contact hypersensitivity with a single application of oxazolone, which is known to stimulate basophil infiltration, and investigated basophil counts in the skin, peripheral blood, and bone marrow. In this model, a decrease in peripheral blood basophil numbers was observed one day after challenge, but not after 2 days, reflecting supplementation from the bone marrow. Indeed, when cultured basophils expressing GFP were transplanted into the peripheral blood, GFP-positive basophil numbers in the peripheral blood remained low even after 2 days of challenge. Despite differences among species and models, these results suggest that one reason for the decrease of basophils in the peripheral blood in CSU may involve migration of circulating basophils into the skin.

Topics: Animals; Basophils; Chronic Disease; Chronic Urticaria; Mice; Omalizumab; Oxazolone; Urticaria

Inflammatory bowel diseases (IBDs) result in diarrhea and abdominal pain with further potential complications such as tissue fibrosis and stenosis. Animal models help in understanding the immunopathogenesis of IBDs and in the design of novel therapeutic concepts. Here we present an updated version of a protocol we published in 2007 for key models of acute and chronic forms of colitis induced by 2,4,6-trinitro-benzene sulfonic acid (TNBS), oxazolone and dextran sulfate sodium (DSS). This protocol update describes an adaptation of the existing protocol that modifies the technique. This protocol has been used to generate improved mouse models that better reflect the nature of IBDs in humans. In TNBS and oxazolone colitis models, topical administration of hapten reagents results in T-cell-mediated immunity against haptenized proteins and luminal antigens. By contrast, to generate DSS colitis models, mice orally receive DSS, causing death of epithelial cells, compromising barrier function and causing subsequent inflammation. The analysis of the acute colitis models can be performed within 1-2 weeks, whereas that of the chronic models may take 2-4 months. The strengths of the acute models are that they are based on the analysis of short-lasting barrier alterations, innate immune effects and flares. The advantages of the chronic models are that they may offer better insight into adaptive immunity and complications such as neoplasia and tissue fibrosis. The protocol requires basic skills in laboratory animal research.

Topics: Animals; Chronic Disease; Colitis; Dextran Sulfate; Disease Models, Animal; Mice; Oxazolone; Trinitrobenzenesulfonic Acid

Accumulating evidence suggests that Toll-like receptor (TLR)-3 signaling is involved in non-infectious immune and inflammatory reactions as well as in viral infections. The skin of patients with atopic dermatitis (AD) is often infected with virus and bacteria, leading to the aggravation of atopic symptoms. These findings suggest TLR3 signaling may be involved in the pathogenesis of AD, but the exact role of TLR3 in AD remains to be defined.. The purpose of this study was to investigate the role of TLR3 in chronic contact hypersensitivity reactions induced by repeated elicitation, resembling the features of AD.. Wild-type (WT) and Toll-like receptor 3 knockout (Tlr3 KO) mice were sensitized, and chronic contact hypersensitivity reactions were elicited in their ear skin via repeated application of a hapten, 2,4,6-trinitro-1-chlorobenzene (TNCB) or oxazolone.. The Tlr3 KO mice exhibited less ear swelling, less leukocyte infiltration into the skin, and lower serum total IgE levels than WT mice after hapten challenge. The Tlr3 KO mice also displayed lower expression levels of inflammatory cytokines (interleukin (IL)-33, IL-4, IL-10, and interferon-ɤ in their TNCB-treated ear skin than WT mice.. These results showed that TLR3 deficiency suppressed the development of chronic contact hypersensitivity reactions, suggesting that TLR3 signaling may participate in the pathogenesis of AD.

Topics: Animals; Chronic Disease; Cytokines; Dermatitis, Allergic Contact; Disease Models, Animal; Humans; Immunoglobulin E; Leukocytes; Male; Mice; Mice, Inbred BALB C; Mice, Knockout; Oxazolone; Picryl Chloride; Signal Transduction; Skin; Toll-Like Receptor 3

Impaired immune responses in skin play a pivotal role in the development and progression of chemical-associated inflammatory skin disorders. In this study, we synthesized new flavonoid derivatives from macakurzin C, and identified in vitro and in vivo efficacy of a potent anti-inflammatory flavonoid, Compound 14 (CPD 14), with its underlying mechanisms. In lipopolysaccharide (LPS)-stimulated murine macrophages and IFN-γ/TNF-α-stimulated human keratinocytes, CPD 14 significantly inhibited the release of inflammatory mediators including nitric oxide (NO), prostaglandins, and cytokines (IC50 for NO inhibition in macrophages: 4.61μM). Attenuated NF-κB signaling and activated Nrf2/HO-1 pathway were responsible for the anti-inflammatory effects of CPD 14. The in vivo relevance was examined in phorbol 12-myristate 13-acetate (TPA)-induced acute skin inflammation and oxazolone-induced atopic dermatitis models. Topically applied CPD 14 significantly protected both irritation- and sensitization-associated skin inflammation by suppressing the expression of inflammatory mediators. In summary, we demonstrated that a newly synthesized flavonoid, CPD 14, has potent inhibitory effects on skin inflammation, suggesting it is a potential therapeutic candidate to treat skin disorders associated with excessive inflammation.

Topics: Acute Disease; Animals; Anti-Inflammatory Agents; Cell Line; Chronic Disease; Dermatitis, Atopic; Dinoprostone; Flavonoids; Heme Oxygenase-1; Humans; Interferon-gamma; Lipopolysaccharides; Male; Mice; Mice, Inbred BALB C; Mice, Inbred ICR; NF-E2-Related Factor 2; NF-kappa B; Nitric Oxide; Oxazolone; RAW 264.7 Cells; Tetradecanoylphorbol Acetate; Tumor Necrosis Factor-alpha

Allergic contact dermatitis is a chronic T cell-driven inflammatory skin disease that is caused by repeated exposure to contact allergens. Based on murine studies of acute contact hypersensitivity, mast cells (MCs) are believed to play a role in its pathogenesis. The role of MCs in chronic allergic contact dermatitis has not been investigated, in part because of the lack of murine models for chronic contact hypersensitivity. We developed and used a chronic contact hypersensitivity model in wild-type and MC-deficient mice and assessed skin inflammatory responses to identify and characterize the role of MCs in chronic allergic contact dermatitis. Ear swelling chronic contact hypersensitivity responses increased markedly, up to 4-fold, in MC-deficient Kit

Topics: Allergens; Animals; CD8-Positive T-Lymphocytes; Chronic Disease; Cytokines; Dermatitis, Contact; Disease Models, Animal; Immunologic Memory; Mast Cells; Mice; Mice, Transgenic; Oxazolone; Proto-Oncogene Proteins c-kit; Skin

Skin inflammation plays a central role in the pathophysiology and symptoms of diverse chronic skin diseases including atopic dermatitis (AD). In this study, we examined if caffeic acid phenethyl ester (CAPE), a skin-permeable bioactive compound from propolis, was protective against skin inflammation using in vitro cell system and in vivo animal disease models. CAPE suppressed TNF-α-induced NF-κB activation and expression of inflammatory cytokines in human keratinocytes (HaCaT). The potency and efficacy of CAPE were superior to those of a non-phenethyl derivative, caffeic acid. Consistently, topical treatment of CAPE (0.5 %) attenuated 12-O-tetradecanoylphorbol-13-acetate(TPA)-induced skin inflammation on mouse ear as CAPE reduced ear swelling and histologic inflammation scores. CAPE suppressed increased expression of pro-inflammatory molecules such as TNF-α, cyclooxygenase-2 and inducible NO synthase in TPA-stimulated skin. TPA-induced phosphorylation of IκB and ERK was blocked by CAPE suggesting that protective effects of CAPE on skin inflammation is attributed to inhibition of NF-κB activation. Most importantly, in an oxazolone-induced chronic dermatitis model, topical application of CAPE (0.5 and 1 %) was effective in alleviating AD-like symptoms such as increases of trans-epidermal water loss, skin thickening and serum IgE as well as histologic inflammation assessment. Collectively, our results propose CAPE as a promising candidate for a novel topical drug for skin inflammatory diseases.

Topics: Acute Disease; Animals; Caffeic Acids; Cell Line; Chronic Disease; Cyclooxygenase 2; Dermatitis, Atopic; Disease Models, Animal; Humans; Immunoglobulin E; Inflammation; Keratinocytes; Mice; Mice, Inbred Strains; NF-kappa B; Oxazolone; Phenylethyl Alcohol; Propolis; Skin; Tetradecanoylphorbol Acetate; Tumor Necrosis Factor-alpha; Water Loss, Insensible

Even with the widespread clinical use of cannabinoid receptor (CBR) stimulating compounds, such as palmitoylethanolamine, the role of CBR agonists on inflammatory skin diseases is not yet fully understood. This study was performed to investigate the effects of CBR agonists on skin inflammation, using acute and chronic inflammation animal models.. The effectiveness of the newly synthesized cannabinoid receptor 1 (CB1R) agonists was determined using in vitro assays. Markers for epidermal permeability barrier function and skin inflammation were measured, and histological assessments were performed for evaluation.. Topical application of CB1R-specific agonist significantly accelerated the recovery of epidermal permeability barrier function and showed anti-inflammatory activity in both acute and chronic inflammation models. Histological assessments also confirmed the anti-inflammatory effects, which is consistent with previous reports.. All of the results suggest that topical application of CB1R-specific agonist can be beneficial for alleviating the inflammatory symptoms in chronic skin diseases, including atopic dermatitis.

Topics: Acute Disease; Administration, Cutaneous; Animals; Cannabinoid Receptor Agonists; Chronic Disease; Dermatitis, Atopic; Dermatitis, Contact; Disease Models, Animal; Fatty Acids, Unsaturated; Female; Mice, Inbred BALB C; Oxazolone; Permeability; Propanolamines; Receptor, Cannabinoid, CB1; Skin; Skin Physiological Phenomena; Tetradecanoylphorbol Acetate; Water Loss, Insensible

The development of chronic allergic dermatitis in early life has been associated with increased onset and severity of allergic asthma later in life. However, the mechanisms linking these two diseases are poorly understood. In this study, we report that the development of oxazolone-induced chronic allergic dermatitis, in a mouse model, caused enhanced OVA-induced allergic asthma after the resolution of the former disease. Our findings show that oxazolone-induced dermatitis caused a marked increase in tissue mast cells, which persisted long after the resolution of this disease. Subsequent OVA sensitization and airway challenge of mice that had recovered from dermatitis resulted in increased allergic airway hyperreactivity. The findings demonstrate that the accumulation of mast cells during dermatitis has the detrimental effect of increasing allergic airway hypersensitivity. Importantly, our findings also show that exposure to a given allergen can modify the immune response to an unrelated allergen.

Topics: Animals; Bronchial Hyperreactivity; Cell Count; Chronic Disease; Dermatitis, Atopic; Disease Models, Animal; Disease Progression; Mast Cells; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Ovalbumin; Oxazolone; Respiratory Hypersensitivity; Tissue Distribution

We investigated the effects of gabapentin and pregabalin on the itch-associated response in a mouse model of chronic dermatitis induced by the repeated application of 4-ethoxymethylene-2-phenyl-2-oxazolin-5-one (oxazolone). Challenging the mice with oxazolone-induced chronic dermatitis with the oxazolone evoked severe and transient scratching behavior until 1 h after the application of oxazolone. Thereafter, a more mild and continuous scratching behavior was also observed for at least 8 h. Both severe and continuous scratching behaviors were suppressed by systemic injection of gabapentin and pregabalin. This effect of these compounds was correlated with its affinity for the α₂δ subunit of voltage-gated Ca²(+) channels. Intrathecal injection, but not peripheral treatment, with gabapentin inhibited the scratching behavior in this model. Gabapentin failed to suppress the scratching behavior induced by the intradermal injection of compound 48/80 in normal mice. The expression of the α₂δ-1 subunit in dorsal root ganglion (DRG) from mice following repeated application of oxazolone was significantly higher than that from normal mice. These results suggest that gabapentin and pregabalin show an anti-pruritic activity through α₂δ-subunit binding, and the up-regulation of the α₂δ-1 subunit in DRG may therefore play an important role in its anti-pruritic activity.

Topics: Amines; Animals; Calcium Channels; Chronic Disease; Cyclohexanecarboxylic Acids; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Eruptions; Gabapentin; gamma-Aminobutyric Acid; Ganglia, Spinal; Injections, Spinal; Male; Mice; Mice, Inbred BALB C; Oxazolone; Pregabalin; Rats; Rats, Sprague-Dawley; Severity of Illness Index; Time Factors; Up-Regulation; Urticaria

The incidence of chronic allergic dermatitis is rapidly increasing. Regulatory control of this disease has not been adequately explored. Here we report that mast cell-derived interleukin-2 (IL-2) contributes to the suppression of chronic allergic dermatitis. Mice deficient in IL-2 production, or deficient in mast cells (Kit(W-sh/W-sh)), showed exacerbated dermatitis upon repeated oxazolone challenge when compared to their wild-type counterparts. Adoptive transfer of wild-type, but not Il2(-/-), mast cells into Kit(W-sh/W-sh) mice dampened the inflammatory response. During the course of disease, mast cell expansion occurred at the site of inflammation and also in the spleen, where production of IL-2 by mast cells was markedly enhanced. In the absence of mast cell IL-2 production, the ratio of activated to regulatory T cells at the site of inflammation was increased. Thus, MC-derived IL-2 contributes to the maintenance of suppression in chronic allergic skin inflammation.

Topics: Animals; Chronic Disease; Dermatitis, Atopic; Immunoglobulin E; Interleukin-2; Mast Cells; Mice; Mice, Knockout; Oxazolone; Spleen

Xanthohumol (XN) and its related compounds were evaluated for their effects on modulating the production of interleukin (IL)-12, the most important factor driving T helper 1 immune responses. XN showed the strongest inhibitory effect on IL-12 production in macrophages stimulated by lipopolysaccharide (LPS) or LPS/interferon-gamma. Xanthohumol 4'-O-beta-D-glucopyranoside (XNG) inhibited IL-12 production less effectively than XN. Isoxanthohumol and 8-prenylnaringenin showed comparatively lower inhibitory effects on IL-12 production than XNG. (2S)-5-methoxy-8-prenylnaringenin 7-O-beta-D-glucopyranoside did not exert any effect on IL-12 production. We then tested how these compounds affected NF-kappaB binding activity to the kappaB site in the nucleus. The compounds inhibited kappaB binding in macrophages with the same potency order as IL-12 inhibition. Furthermore, we investigated whether XN, which showed the most effective reduction of IL-12 production, attenuated skin inflammation. Chronic allergic contact dermatitis, an experimental model for psoriasis, was used to determine the anti-inflammatory effects of XN in vivo. XN treatment reduced the degree of ear thickening induced by oxazolone. Taken together, XN might be effective as an anti-inflammatory agent to reduce skin inflammation by inhibiting IL-12 production.

Topics: Animals; Cells, Cultured; Chronic Disease; Dermatitis, Allergic Contact; Female; Flavonoids; Humans; Interferon-gamma; Interleukin-12; Lipopolysaccharides; Macrophage Activation; Macrophages; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Models, Animal; NF-kappa B; Oxazolone; Propiophenones; Protein Binding; Psoriasis

Prolactin-induced protein (PIP) has been shown to bind to CD4 and is speculated to block CD4-HLA-DR interaction. However, the immunomodulatory effect of PIP on chronic allergic contact dermatitis (ACD) remains to be elucidated.. To define the role of PIP during the immunoresponse.. Using a low-dose oxazolone-induced mouse chronic ACD model, expression of PIP was examined immunohistologically. Furthermore, effects of continued exposure to a peptide mimicking the major binding site of PIP (amino acids 106-132) for CD4 was examined in a mouse chronic ACD model.. We clarified that keratinocytes, dermal infiltrating cells and spleen infiltrating mononuclear cells are positively stained with anti-PIP antibody. The PIP peptide significantly downregulated oxazolone-induced mouse ACD compared with controls. We also found that inflammation of the control ear, to which the PIP peptide had not been applied, was also suppressed in a synchronized manner in the late phase of ACD.. These findings suggest that PIP might have a local and systemic immunosuppressive effect in mouse chronic ACD.

Topics: Adjuvants, Immunologic; Administration, Topical; Animals; Carrier Proteins; Chronic Disease; Dermatitis, Allergic Contact; Disease Models, Animal; Ear; Glycoproteins; Immunohistochemistry; Immunosuppressive Agents; Membrane Transport Proteins; Mice; Oxazolone; Skin; Spleen

Licochalcone, a constituent of licorice, has antitumor, antimicrobial, and anti-inflammatory effects. Recently, licochalcone E was isolated from the roots of Glycyrrhiza inflata and its biological functions are not fully examined. In this study, we investigated its ability to modulate production of IL-12p40, a common subunit of IL-12 and IL-23. Licochalcone E dose-dependently inhibited IL-12p40 production from lipopolysaccharide-stimulated RAW264.7 macrophage cells. The repressive effect was mapped to a region in the IL-12 gene promoter containing a binding site for NF-kappaB. Furthermore, licochalcone E decreased binding to the NF-kappaB site in RAW264.7 macrophage cells. Using a chronic allergic contact dermatitis model induced by repeated application of oxazolone, we showed that licochalcone E inhibited the increased IL-12p40 expression and ear thickness induced by oxazolone. Taken together, licochalcone E inhibits IL-12p40 production and has therapeutic potential to reduce skin inflammation.

Topics: Animals; Anti-Inflammatory Agents; Cells, Cultured; Chalcones; Chronic Disease; Dermatitis, Allergic Contact; Down-Regulation; Female; Interleukin-12 Subunit p40; Macrophages; Mice; Mice, Inbred C57BL; NF-kappa B; Oxazolone; Promoter Regions, Genetic

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Chronic Disease; Cyclooxygenase 2; Dermatitis, Atopic; Female; I-kappa B Proteins; Lithospermum; Mice; NF-kappa B; NF-KappaB Inhibitor alpha; Nitric Oxide Synthase Type II; Oxazolone; Phytotherapy; Plant Extracts; Prednisolone; Skin

The diterpene compounds, centipedic acid (CA) and 12-acetoxyhawtriwaic acid lactone (AHAL, tanabalin) isolated from the flower buds of Egletes viscosa LESS. (Asteraceae) were evaluated on acute and chronic models of mouse ear dermatitis. A single topical application of CA (0.125; 0.25 and 0.5 mg/ear) or AHAL (0.125, 0.25, 0.5 mg/ear) immediately before 12-O-tetradecanoylphorbol-13-acetate (TPA, 2.5 mug/ear) caused a dose-related significant inhibition of ear inflammatory edema and influx of polymorphonuclear cells, as evidenced by a decrease in ear thickness and reduced myeloperoxidase (MPO) activity and tumor necrosis factor-alpha (TNF-alpha) in ear tissue homogenates. The maximal obtained inhibition for both ear edema and neutrophil influx were almost similar to that of topically applied dexamethasone (0.05 mg/ear). The extent of inhibitions for the respective treatments of CA (0.5 mg/ear), AHAL (0.5 mg/ear), or dexamethasone (0.05 mg/ear) were in the order of 63%, 61% and 81% for the ear edema, and 90%, 95% and 95% for the neutrophil influx. Also, at similar doses, both diterpenes and dexamethasone effectively inhibited the delayed-type hypersensitivity reaction induced by repeated topical application of 1% oxazolone (OXA, 20 microl/ear), as evidenced by significant decreases in ear thickness and interferon-gamma (INF-gamma) levels in ear tissue. Histopathological analysis revealed a marked decrease in epidermal hyperplasia and neutrophil infiltration in animals pretreated with CA or AHAL, in a manner similar to dexamethasone. These data provide evidence for the anti-dermatitis effect of Egletes viscosa diterpenes, by mechanisms that involve a reduced neutrophil influx and decreased production of inflammatory cytokines, TNF-alpha and IFN-gamma.

Topics: Acute Disease; Administration, Topical; Animals; Anti-Inflammatory Agents; Asteraceae; Chronic Disease; Dermatitis, Contact; Diterpenes; Ear, External; Fatty Acids, Unsaturated; Flowers; Furans; Interferon-gamma; Lactones; Male; Mice; Oxazolone; Peroxidase; Skin; Tetradecanoylphorbol Acetate; Tumor Necrosis Factor-alpha

Some evidence exists that peripheral neutrophils from patients with chronic periodontitis generate higher levels of reactive oxygen species (ROS) after Fcgamma-receptor stimulation than those from healthy controls. We hypothesized that peripheral neutrophils in periodontitis also show both hyper-reactivity to plaque organisms and hyperactivity in terms of baseline, unstimulated generation and release of ROS. Peripheral neutrophils from chronic periodontitis patients and age/sex/smoking-matched healthy controls (18 pairs) were assayed for total ROS generation and extracellular ROS release, with and without stimulation (Fcgamma-receptor and Fusobacterium nucleatum), using luminol and isoluminol chemiluminescence. Assays were performed with and without priming with Escherichia coli lipopolysaccharide (LPS) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Phox gene expression (p22, p47, p67, gp91) was investigated using reverse transcription-polymerase chain reaction (RT-PCR). Neutrophils from patients produced higher mean levels of ROS in all assays. Total generation and extracellular release of ROS by patients' cells were significantly greater than those from controls after FcgammaR-stimulation, with (P = 0.023) and without (P < or = 0.023) priming with GM-CSF. Differences in unstimulated total ROS generation were not significant. By contrast, patients' cells demonstrated greater baseline, extracellular ROS release than those from controls (P = 0.004). This difference was maintained after priming with LPS (P = 0.028) but not GM-CSF (P = 0.217). Phox gene expression was similar in patient and control cells at baseline and stimulation with F. nucleatum (3 h) consistently reduced gp91(PHOX) transcripts. Our data demonstrate that peripheral neutrophils from periodontitis patients exhibit hyper-reactivity following stimulation (Fcgamma-receptor and F. nucleatum) and hyperactivity in terms of excess ROS release in the absence of exogenous stimulation. This hyperactive/-reactive neutrophil phenotype is not associated with elevated phox gene expression.

Topics: Adult; Antigens, Bacterial; Case-Control Studies; Chronic Disease; Endotoxins; Female; Fusobacterium nucleatum; Gene Expression Regulation; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Lipopolysaccharides; Male; Middle Aged; Neutrophil Activation; Neutrophils; Oxazoles; Periodontitis; Phosphoproteins; Reactive Oxygen Species; Receptors, IgG; Reverse Transcriptase Polymerase Chain Reaction

Chronic contact hypersensitivity (CH) models induced by repeated hapten exposure exhibit chronic dermatitis and immunological abnormalities resembling atopic dermatitis. To assess the contribution of endothelial selectins (P- and E-selectins) to cutaneous chronic inflammation, chronic CH responses were assessed in mice lacking P- or E-selectin. Elicitation with oxazolone on the ears of P-selectin(-/-) mice 7 days after the sensitization induced a typical delayed-type hypersensitivity response similar to that found in wild-type mice. By contrast, a significant increase in ear swelling was observed in E-selectin(-/-) mice 36 to 48 hours after first elicitation. E-selectin(-/-) mice showed augmented P-selectin up-regulation, and administration of anti-P-selectin monoclonal antibody significantly inhibited the enhanced ear response, suggesting that the enhanced ear-swelling response in E-selectin(-/-) mice resulted from compensatory increase in P-selectin expression. In the late phase of chronic CH, acceleration of ear swelling was significantly reduced in both E- and P-selectin(-/-) mice relative to wild-type littermates. Thus, the loss of P- or E-selectin suppressed inflammatory responses during the chronic phase of the chronic models, whereas early-phase inflammatory responses were exacerbated by E-selectin blockade. Collectively, P- and E-selectins cooperatively regulate CH response, although their roles may be different depending on the phase of the reaction.

Topics: Adjuvants, Immunologic; Animals; Chronic Disease; Dermatitis, Atopic; Dermatitis, Contact; E-Selectin; Immunohistochemistry; Inflammation; Mice; Mice, Inbred C57BL; Oxazolone; P-Selectin; Reverse Transcriptase Polymerase Chain Reaction

The effect of a main constituent ginsenoside Rg5 isolated from red ginseng and its metabolite ginsenoside Rh3 in a chronic dermatitis model was investigated. Ginsenosides Rg5 and Rh3 suppressed swelling of oxazolone-induced mouse ear contact dermatitis. These ginsenosides also reduced mRNA expressions of cyclooxygenase-2, interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma. The inhibition of ginsenoside Rh3 was more potent than that of ginsenoside Rg5. These findings suggest that ginsenoside Rh3 metabolized from ginsenoside Rg5 may improve chronic dermatitis or psoriasis by the regulation of IL-1beta and TNF-alpha produced by macrophage cells and of IFN-gamma produced by Th cells.

Topics: Animals; Chronic Disease; Cyclooxygenase 2; Dermatitis, Contact; Female; Ginsenosides; Interferon-gamma; Interleukin-1beta; Mice; Mice, Inbred ICR; Oxazolone; Tumor Necrosis Factor-alpha

This paper studies the disturbances in ionic secretion in the colon of rats with different models of acute and chronic colitis measured as changes in short-circuit current. The aim was to verify whether the reported inhibition of basal and stimulated secretion in the trinitrobenzene sulfonic acid and mytomicin C models are applicable to experimental colitis as such. All models showed remarkable similarity in ion transport as determined in Ussing chambers, with downregulated basal as well as carbachol evoked secretion. The EC(50) of carbachol was unchanged in all cases. Iodoacetamide and oxazolone colitis models were notable exceptions in that the dose response curves for carbachol were unaltered compared to controls. The reason is unclear but seems to be unrelated to either interferon gamma or interleukin 4 levels or to the severity of the inflammatory response.

Topics: Acetic Acid; Acute Disease; Alkylating Agents; Animals; Animals, Genetically Modified; Chloramines; Chronic Disease; Colitis; Dextran Sulfate; Disease Models, Animal; Epithelial Cells; Female; HLA-B27 Antigen; Indicators and Reagents; Iodoacetamide; Ions; Oxazolone; Patch-Clamp Techniques; Rats; Trinitrobenzenesulfonic Acid

During the screening program to discover antipsoriatic agents from natural products, ginseng was found to show inhibitory activity in oxazolone-induced mouse ear dermatitis. Therefore, the effects of a main constituent ginsenoside Rb1 isolated from ginseng and its metabolite compound K on oxazolone-induced mouse ear dermatitis were investigated. Compound K at concentrations of 0.02% and 0.05% also potently suppressed mouse ear swelling by 54% and 76% at 16 days, respectively, although ginsenoside Rb1 did not significantly show the inhibitory activity. The compound K also significantly reduced the levels of mRNA of cyclooxygenase (COX)-2, IL-1beta, TNF-alpha, IFN-gamma and IL-4 increased in oxazolone-applied mouse ears. Based on these findings, the compound K may improve contact dermatitis or psoriasis by the regulation of COX-2 produced by macrophage cells and interferon-gamma and IL-4 induced by Th cells.

Topics: Animals; Cell Line; Chronic Disease; Cyclooxygenase 1; Cyclooxygenase 2; Dermatitis, Contact; Dinoprostone; Female; Ginsenosides; Macrophages; Membrane Proteins; Mice; Mice, Inbred ICR; Nitric Oxide; Oxazolone; Prostaglandin-Endoperoxide Synthases; Psoriasis; RNA, Messenger

To evaluate the antipsoriatic effect of Chunghyuldan (CHD, Daio-Orengedokuto in Japanese), which exhibited anti-inflammatory and antiischemic actions, the inhibitory activity of CHD metabolized with and without human intestinal microflora was investigated in oxazolone-induced mouse ear dermatitis. The CHD and metabolized CHD (MCHD) at concentrations of 0.1% also potently suppressed mouse ear swelling by 52.7% and 63.2% at 16 d, respectively. The antipsoriatic effect between CHD and MCHD was not significantly different, although that of CHD weakly increased by the metabolism of human intestinal microflora. Both CHD and MCHD also potently reduced the mRNA levels of cyclooxygenase (COX)-2, interferon (IFN)-gamma and IL-4 increased in oxazolone-applied mouse ears, but weakly inhibited that of IL-1beta and TNF-alpha. Based on these findings, CHD may improve contact dermatitis or psoriasis by the regulation of COX-2 produced by macrophage cells and IFN-gamma and IL-4 produced by Th cells.

Topics: Animals; Chronic Disease; Dermatitis; Drug Eruptions; Drugs, Chinese Herbal; Female; Mice; Mice, Inbred BALB C; Oxazolone

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

Topics: Adjuvants, Immunologic; Animals; Anti-Inflammatory Agents, Non-Steroidal; Chronic Disease; Cytokines; Dermatitis, Contact; Dibenzoxepins; Gene Expression Regulation; Granulocyte-Macrophage Colony-Stimulating Factor; Histamine H1 Antagonists, Non-Sedating; Immunoglobulin E; Male; Mice; Mice, Inbred BALB C; Nerve Growth Factor; Olopatadine Hydrochloride; Oxazolone; RNA, Messenger

An analysis was conducted of the cytokine profile and inflammatory response in oxazolone sensitized mouse skin. Following exposure to oxazolone, the intralesional production of inflammatory cytokines was demonstrable at the levels of both mRNA and protein. An initial challenge led to a transient increase in tumor necrosis factor-alpha production followed predominately by the T helper (Th)1 cytokine, interferon-gamma. There was a minimal production of interleukin-4, a Th2 cytokine. Continued exposure to oxazolone led to a downregulation of interferon-gamma and an upregulation of interleukin-4 production. A strong relationship was found between interleukin-4 and the inflammatory response, as measured by ear thickness. Similar experiments conducted in mast cell-deficient mice revealed reduced neutrophil influx but only minor changes in cytokine profile. An irritant response induced by chronic exposure of mouse skin to phorbol ester did not reveal any significant interferon-gamma or interleukin-4 response but was characterized by a tumor necrosis factor-alpha response that correlated with the inflammatory response. These observations suggest that the major source of interferon-gamma and interleukin-4 in the oxazolone response may be the infiltrating lymphocytes; whereas the tumor necrosis factor-alpha may result from the local irritation seen with both oxazolone and phorbol ester. At the end of 4 wk of chronic exposure to oxazolone, it was found that serum IgE levels had significantly increased. Histologic analysis of the skin lesion revealed that a mixed infiltrate including eosinophils developed upon repeat exposure to oxazolone. These findings are consistent with an early predominate Th1 response that is reduced and largely replaced with a Th2 response upon chronic T cell activation.

Topics: Animals; Chronic Disease; Dermatitis, Contact; Immunoglobulin E; Interferon-gamma; Interleukin-4; Male; Mast Cells; Mice; Mice, Inbred BALB C; Oxazolone; Tetradecanoylphorbol Acetate; Tumor Necrosis Factor-alpha

A technique of delayed-type hypersensitivity (DTH) skin reaction to a contact sensitizing agent, oxazolone, was used to assess the effects of uremia on cell-mediated immunity in chronically uremic mice and, for comparison, sham-operated and normal controls. The first objective was to establish that DTH responses are reduced in animals with renal failure. To do this, mice were made uremic by a combination of electrocoagulation of the entire surface of one kidney and subsequent contralateral nephrectomy; studies included biochemical and hematological evaluation using blood urea nitrogen level and hemoglobin concentration as routine indices to assess the degree and consequence of uremia, respectively. The second objective was to apply the technique to observe and compare changes during uremic states of varying severity and duration. A modest, although significant, decrease in both the induction and maintenance of DTH responses was observed in the mice with severe renal failure only (BUN above 100 mg/dl). This immunosuppressive effect was manifest early and persisted unchanged throughout the entire observation period (3-9 weeks). This study presents new evidence that severe uremia readily produces in the mouse sustained, albeit mild, changes in cell-mediated immunity. Furthermore the ability to elicit DTH skin reaction in the chronically uremic mouse offers a versatile system for studying changes in cell-mediated immunity occurring during uremia with a broad range of potential applicability.

Topics: Animals; Chronic Disease; Female; Hemoglobins; Hypersensitivity, Delayed; Immune Tolerance; Immunity, Cellular; Leukocyte Count; Mice; Mice, Inbred Strains; Oxazolone; Platelet Count; Skin Tests; Uremia

Topics: Animals; Antibody Formation; Antigens; Chronic Disease; Echinococcosis; Echinococcus; Immunity, Cellular; Isoantigens; Lymph Nodes; Male; Mice; Oxazolone; Spleen