oxazolone and Dermatitis

Nintedanib, a receptor tyrosine kinase (RTK) inhibitor has been developed as therapeutics for idiopathic pulmonary fibrosis and non-small lung cancer. We found that the expression levels of RTK, especially VEGFR1 is increased in skin biopsies of dermatitis patients from multiple independent datasets. Moreover, VEGFR1 is highly expressed by infiltrated cells in dermis from oxazolone (OXA) treated mice. Interestingly, nintedanib alleviates dermatitis symptom in OXA-induced animal model. Especially, levels of epidermis thickness, infiltrated immune cells including mast cells and eosinophils were decreased from mice cotreated with nintedanib and OXA compared with OXA treated mice. Moreover, serum IgE and Th2 cytokines including IL-4 and IL-13 were decreased by nintedanib treatment. These results suggest an evidence that nintedanib alleviates animal model of dermatitis.

Topics: Animals; Biomarkers; Biopsy; Cell Line; Cell Survival; Dermatitis; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Gene Expression; Immunoglobulin E; Indoles; Mice; Oxazolone; Protein Kinase Inhibitors; Skin; Vascular Endothelial Growth Factor Receptor-1

The therapeutic application of antimicrobial peptides (AMPs), a potential type of peptide-based biomaterial, is impeded by their poor antimicrobial activity and potential cytotoxicity as a lack of understanding of their structure-activity relationships. In order to comprehensively enhance the antibacterial and clinical application potency of AMPs, a rational approach was applied to design amphiphilic peptides, including head-to-tail cyclic, linear and D-proline antimicrobial peptides using the template (IR)

Topics: Adjuvants, Immunologic; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Antimicrobial Cationic Peptides; Biocompatible Materials; Cell Death; Dermatitis; Endotoxins; Hemolysis; Humans; Lipopolysaccharides; Male; Mice; Mice, Inbred ICR; Oxazolone; Peptides; Peptides, Cyclic; RAW 264.7 Cells

Keratinocytes have a pivotal role in the regulation of immune responses, but the impact of antigen presentation by these cells is still poorly understood, particularly in a situation where the antigen will be presented only in adult life. Here, we generated a transgenic mouse model in which keratinocytes exclusively present a myelin basic protein (MBP) peptide covalently linked to the major histocompatibility complex class II β-chain, solely under inflammatory conditions. In these mice, inflammation caused by epicutaneous contact sensitizer treatment resulted in keratinocyte-mediated expansion of MBP-specific CD4(+) T cells in the skin. Moreover, repeated contact sensitizer application preceding a systemic MBP immunization reduced the reactivity of the respective CD4(+) T cells and lowered the symptoms of the resulting experimental autoimmune encephalomyelitis. This downregulation was CD4(+) T-cell-mediated and dependent on the presence of the immune modulator Dickkopf-3. Thus, presentation of a neo self-antigen by keratinocytes in the inflamed, adult skin can modulate CD4(+) T-cell auto-aggression at a distal organ.

Topics: Adaptor Proteins, Signal Transducing; Animals; Autoantigens; CD4-Positive T-Lymphocytes; Cyclopropanes; Dermatitis; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Genes, MHC Class II; Intercellular Signaling Peptides and Proteins; Keratinocytes; Mice; Mice, Knockout; Mice, Transgenic; Myelin Basic Protein; Oxazoles; Skin

To investigate the role of cannabinoid receptor-2 (CB2) in allergic inflammation in CB2 knockout (CB2-KO) mice.. The swelling reaction of the pinna to various stimuli was compared between CB2-KO and wild-type (WT) mice in terms of edema and acanthosis.. Ear swelling induced by repeated application of 2,4-dinitrofluorobenzene in CB2-KO mice was significantly decreased compared with that in WT mice. In an ovalbumin model, pinna edema was significantly suppressed in CB2-KO mice in comparison with that in WT mice. The contribution of CB2 to edema was investigated in a more extreme dermatitis model using oxazolone. Delayed-type hypersensitivity reactions in this model were also suppressed in CB2-KO mice. In each of these three different allergic dermatitis models, there was a significant decrease in edema and acanthosis in CB2-KO mice compared with WT mice.. These results clearly demonstrate that CB2 and its endogenous ligands participate not only in the acute, edematous phase of allergic dermatitis, but also in the chronic irreversible acanthosis reaction.

Topics: Animals; Dermatitis; Disease Models, Animal; Edema; Hypersensitivity, Delayed; Inflammation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Ovalbumin; Oxazolone; Receptor, Cannabinoid, CB2

Transient receptor potential vanilloid type 1 (TRPV1) is a cation channel activated by diverse obnoxious stimuli like capsaicin, low pH or heat. Recently, it was revealed that TRPV1 might be deeply associated with skin permeability barrier function, suggesting that modulation of TRPV1 might be beneficial for the skin disorders with barrier damages.. We aimed to investigate whether the blockade of TRPV1 activation might accelerate skin barrier recovery and alleviate atopic dermatitis (AD)-like symptoms, employing a novel TRPV1 antagonist, PAC-14028.. TRPV1 antagonistic effects of PAC-14028 in human keratinocytes and skin were confirmed through capsaicin-evoked calcium influx assay and capsaicin-induced blood perfusion increase. Effects of PAC-14028 on skin barrier recovery were examined in vivo tape-stripping-induced barrier disruption in hairless mice. To determine the effects of PAC-14028 on AD, Dermatophagoides farina (Df)- and oxazolone (OXZ)-induced AD models were employed.. PAC-14028 could inhibit capsaicin-evoked calcium influx in keratinocytes at sub-micromolar concentrations. This potent TRPV1 antagonistic activity in keratinocytes was manifested in vivo as the blockade of capsaicin-induced blood perfusion increase, and the accelerated barrier recovery from tape-stripping-induced barrier damages in hairless mice. PAC-14028 could also attenuate dermatitis-associated barrier damages in Df and OXZ models as determined by lower TEWL (trans-epidermal water loss), reformation of neutral lipid layer and reversion of changes in loricrin and filaggrin expression. Importantly, along with accelerated recovery of skin barrier function, PAC-14028 alleviated the general AD-like symptoms, including serum IgE increase, mast cell degranulation, scratching behavior and clinical severity of dermatitis.. These results reflect that the blockade of TRPV1 activation can suppress the atopic dermatitis-like symptoms by accelerating skin barrier recovery.

Topics: Acrylamides; Animals; Calcium; Capsaicin; Dermatitis; Dermatitis, Atopic; Female; Filaggrin Proteins; Humans; Immunoglobulin E; Intermediate Filament Proteins; Lipids; Mast Cells; Membrane Proteins; Mice; Oxazolone; Perfusion; Permeability; Pyridines; Skin; TRPV Cation Channels

In contrast to the established role of blood vessel remodeling in inflammation, the biologic function of the lymphatic vasculature in acute inflammation has remained less explored. We studied 2 established models of acute cutaneous inflammation, namely, oxazolone-induced delayed-type hypersensitivity reactions and ultraviolet B irradiation, in keratin 14-vascular endothelial growth factor (VEGF)-C and keratin 14-VEGF-D transgenic mice. These mice have an expanded network of cutaneous lymphatic vessels. Transgenic delivery of the lymphangiogenic factors VEGF-C and the VEGFR-3 specific ligand mouse VEGF-D significantly limited acute skin inflammation in both experimental models, with a strong reduction of dermal edema. Expression of VEGFR-3 by lymphatic endothelium was strongly down-regulated at the mRNA and protein level in acutely inflamed skin, and no VEGFR-3 expression was detectable on inflamed blood vessels and dermal macrophages. There was no major change of the inflammatory cell infiltrate or the composition of the inflammatory cytokine milieu in the inflamed skin of VEGF-C or VEGF-D transgenic mice. However, the increased network of lymphatic vessels in these mice significantly enhanced lymphatic drainage from the ear skin. These results provide evidence that specific lymphatic vessel activation limits acute skin inflammation via promotion of lymph flow from the skin and reduction of edema formation.

Topics: Acute Disease; Adjuvants, Immunologic; Animals; Cytokines; Dermatitis; Disease Models, Animal; Edema; Humans; Hypersensitivity, Delayed; Keratin-14; Lymph; Lymphatic Vessels; Mice; Mice, Transgenic; Oxazolone; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor D; Vascular Endothelial Growth Factor Receptor-3

Chemokine receptor CCR4 is expressed by Th2 cells and is involved in the recruitment of inflammatory cells into the skin. We studied the effects of CCR4 deficiency in the murine model of oxazolone-induced contact hypersensitivity in CCR4-/- and wild-type (WT) mice. The inflammatory response in the skin at 24  hours post-elicitation was stronger in CCR4-/- mice compared with WT, evidenced by increased ear swelling and inflammatory cell infiltration. In addition, the mRNA expression levels of several cytokines, chemokines, chemokine receptors, and selectins in the skin of CCR4-/- mice were significantly elevated compared with WT mice. Time kinetic experiments during the sensitization and elicitation phases revealed that the number of CD3+CD4+ cells in CCR4-/- mice remained high longer during the sensitization phase and increased more rapidly during the elicitation phase compared with WT mice. These data demonstrate that the absence of CCR4 results in enhanced secondary immune response during allergic skin inflammation.

Topics: Adjuvants, Immunologic; Animals; CD3 Complex; CD4 Antigens; Dermatitis; Dermatitis, Contact; Disease Models, Animal; Edema; Interleukin-13; Mice; Mice, Mutant Strains; Oxazolone; Receptors, CCR4; T-Lymphocytes, Regulatory; Up-Regulation

CD47 on the surface of T cells was shown in vitro to mediate either T cell activation or, in the presence of high amounts of thrombospondin (TSP), T cell apoptosis. We report here that CD47-deficient mice, as well as TSP-1 or TSP-2-deficient mice, sustain oxazolone-induced inflammation for more than four days, whereas wild-type mice reduce the inflammation within 48 h. We observe that prolonged inflammation in CD47-, TSP-1-, or TSP-2-deficient mice is accompanied by a local deficiency of T cell apoptosis. Finally, we show that upon activation normal T cells increase the expression of the proapoptotic Bcl-2 family member BNIP3 (Bcl-2/adenovirus E1B 19-kDa interacting protein) and undergo CD47-mediated apoptosis. This finding is consistent with our previous demonstration of a physical interaction between BNIP3 and CD47 that inhibits BNIP3 degradation by the proteasome, sensitizing T cells to CD47-induced apoptosis. Overall, these results reveal an important role in vivo for this new CD47/BNIP3 pathway in limiting inflammation by controlling the number of activated T cells.

Topics: Animals; Apoptosis; CD47 Antigen; Dermatitis; Inflammation; Membrane Proteins; Mice; Mice, Mutant Strains; Mitochondrial Proteins; Oxazolone; Proteasome Endopeptidase Complex; T-Lymphocytes; Thrombospondin 1; Thrombospondins

The effects of the main constituent ginsenoside Re in ginseng and its metabolite, ginsenoside Rh1, were investigated in 12-O-tetradecanoylphorbol 13-acetate (TPA)- and oxazolone-induced mouse ear dermatitis models. Ginsenoside Rh1 potently suppressed the TPA- and oxazolone-induced swellings as well as mRNA expression levels of cyclooxygenase-2, IL-1beta and TNF-alpha, although these were only weakly inhibited by ginsenoside Re.

Topics: Administration, Cutaneous; Animals; Dermatitis; Disease Models, Animal; Dose-Response Relationship, Drug; Ginsenosides; Keratolytic Agents; Mice; Mice, Inbred ICR; Oxazolone; Panax; Phytotherapy; Plant Roots; Tetradecanoylphorbol Acetate

We set out to establish the in vivo histamine H(1) receptor antagonistic (antihistaminic) and antiallergic properties of bilastine.. In vivo antihistaminic activity experiments consisted of measurement of: inhibition of increase in capillary permeability and reduction in microvascular extravasation and bronchospasm in rats and guinea pigs induced by histamine and other inflammatory mediators; and protection against lethality induced by histamine and other inflammatory mediators in rats. In vivo antiallergic activity experiments consisted of measurement of passive and active cutaneous anaphylactic reactions as well as type III and type IV allergic reactions in sensitised rodents.. In the in vivo antihistaminic activity experiments, bilastine was shown to have a positive effect, similar to that of cetirizine and more potent than that of fexofenadine. The results of the in vivo antiallergic activity experiments showed that the properties of bilastine in this setting are similar to those observed for cetirizine and superior to fexofenadine in the model of passive cutaneous anaphylactic reaction. When active cutaneous anaphylactic reaction experiments were conducted, bilastine showed significant activity, less potent than that observed with cetirizine but superior to that of fexofenadine. Evaluation of the type III allergic reaction showed that of the antihistamines only bilastine was able to inhibit oedema in sensitised mice, although its effect in this respect was much less potent than that observed with dexamethasone. In terms of the type IV allergic reaction, neither bilastine, cetirizine nor fexofenadine significantly modified the effect caused by oxazolone.. The results of our in vivo preclinical studies corroborate those obtained from previously conducted in vitro experiments of bilastine, and provide evidence that bilastine possesses antihistaminic as well as antiallergic properties, with similar potency to cetirizine and superior potency to fexofenadine.

Topics: Animals; Benzimidazoles; Bradykinin; Bronchial Spasm; Capillary Permeability; Cetirizine; Dermatitis; Dose-Response Relationship, Drug; Guinea Pigs; Histamine; Histamine Antagonists; Hypersensitivity; Male; Mice; Molecular Structure; Oxazolone; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H1; Serotonin; Structure-Activity Relationship; Terfenadine; Time Factors

CD1d-restricted T-cells are activated by glycolipids presented by the major histocompatibility complex class-Ib molecule CD1d, found on the surface of antigen-presenting cells (APC). This interaction between APC, most notably dendritic cells (DC), and CD1d-restricted T-cells is an important regulatory step in the initiation of adaptive immune responses. It is well known that DC play a crucial role in the induction of contact hypersensitivity (CHS), a frequently studied form of in vivo T-cell-mediated immunity. In this study, we show that CD1d-restricted T-cells are also necessary for CHS, because both wild-type mice treated systemically or topically with CD1d glycolipid antagonists and CD1d-restricted T-cell-null mice have markedly diminished CHS responses. Thus, pharmacologic antagonists of CD1d can be used as effective inhibitors of CHS, a prototype for a variety of delayed-type tissue hypersensitivity responses.

Topics: Administration, Topical; Animals; Antigen Presentation; Antigens, CD1; Antigens, CD1d; Cell Line; Dendritic Cells; Dermatitis; Dermatitis, Contact; Dose-Response Relationship, Drug; Glycolipids; Hypersensitivity; Killer Cells, Natural; Major Histocompatibility Complex; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Oxazolone; Phosphatidylethanolamines; Polyethylene Glycols; Receptors, Antigen, T-Cell

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

Recruitment of antigen-specific T cells into the skin is a critical initiating event during immune responses to many parasites and tumors as well as T cell-mediated, cutaneous, allergic responses and autoimmune diseases. Mechanisms directing T cell trafficking into skin remain largely undefined. Here, we show that cutaneous contact with reactive antigen induces KC/CXC chemokine ligand 1 production and neutrophil infiltration in an antigen, dose-dependent manner. The intensity of neutrophil infiltration into cutaneous antigen challenge sites, in turn, controls the number of antigen-primed T cells recruited into the site and the magnitude of the immune response elicited. The absence of responses in immune animals challenged with suboptimal doses of antigen is overcome by manipulating neutrophil infiltration that then directs antigen-primed T cell infiltration into the challenge site. This inflammation also directs T cells primed to one antigen (dinitrofluorobenzene) into the site when challenged with a completely different antigen (oxazolone). These results identify the intensity of neutrophil infiltration into cutaneous, antigen-deposition sites as a critical parameter for the level of antigen-primed T cell recruitment to mediate the adaptive immune response. This interplay between the innate and adaptive responses suggests a strategy to modulate, in a positive or negative manner, antigen-primed T cell infiltration into cutaneous inflammation sites.

Topics: Adaptation, Physiological; Animals; Antigen Presentation; Antigens; CD8-Positive T-Lymphocytes; Chemokine CXCL1; Chemokines, CXC; Dermatitis; Dinitrofluorobenzene; Dose-Response Relationship, Drug; Female; Haptens; Immunity, Innate; Intercellular Signaling Peptides and Proteins; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neutrophil Infiltration; Neutrophils; Oxazolone; Skin

ETH615 (4-[2-quinolylmethoxy]-N-[3-fluorobenzyl]-phenylaminometh yl-4-benzoic acid) is a potent inhibitor of leukotriene biosynthesis in A23187-stimulated leukocytes, and of IL-8 gene expression in LPS-stimulated PBMC. It shows anti-inflammatory activity in a canine model of dermal inflammation. A topical formulation is present in phase II clinical trials. In the present study the effect of ETH615 on oxazolone-induced acute inflammation and phorbol ester-induced chronic inflammation in the mouse ear was investigated. Betamethasone (0.04 mg/ear) and ETH615 (1-1.5 mg/ear) significantly inhibited both the oedema formation and the PMN infiltration. The cream and ointment formulations of ETH615 developed for clinical studies were equally active. ETH615 is thus an anti-inflammatory agent in these murine models of dermatosis.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Betamethasone; Dermatitis; Disease Models, Animal; Ear; Edema; Gene Expression; Interleukin-8; Leukotriene B4; Mice; Oxazolone; Peroxidase; Quinolines; T-Lymphocytes; Tetradecanoylphorbol Acetate

Topics: Animals; Calmodulin; Dermatitis; Fluorescein-5-isothiocyanate; Fluoresceins; Fluorescent Dyes; Humans; Interleukin-1; Oxazolone; Phospholipases A; Picryl Chloride; Platelet Activating Factor; Thiocyanates

Ciclosporin is clinically effective in a variety of inflammatory skin diseases. We have therefore studied the effects of the drug on cutaneous inflammation in mice. Ciclosporin inhibited the inflammatory response to 12-O-tetradecanoylphorbol-13-acetate (TPA) and to the contact sensitising agent oxazolone when applied topically to mouse skin. The drug had no effect on arachidonic acid-induced inflammation. The protein synthesis inhibitor cycloheximide showed a similar profile of activity. Ciclosporin, like actinomycin D but unlike cycloheximide, was only effective in inhibiting the inflammatory response to TPA if given 0.5 h before, but not 2 h, after TPA. These results suggest that the anti-inflammatory activity of ciclosporin in the skin is due to an effect on the production of proinflammatory proteins.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Arachidonic Acids; Cycloheximide; Cyclosporins; Dactinomycin; Dermatitis; Female; Hypersensitivity, Delayed; Mice; Mice, Inbred Strains; Neutrophils; Oxazolone; Peroxidase; Protein Synthesis Inhibitors; Skin; Tetradecanoylphorbol Acetate

The effects of high molecular weight dextran sulphate (DXS) on the migration of 125I-labelled deoxyuridine-labelled peripheral lymphoblasts (stimulated by oxazolone) were studied in vivo by injecting the drug (50 mg/kg) subcutaneously in recipients, and by following the fate of oxazolone-stimulated peripheral lymphocytes treated in vitro with DXS in non-treated syngeneic recipients. Both types of experiments demonstrate that DXS considerably reduces lymphoblast extravasation in skin sites inflamed either by non-immune causes or by DTH. Our results also demonstrate that oxazolone-stimulated peripheral lymphocytes, after in vitro treatment with DXS, are unable to transfer antigen-specific contact hypersensitivity to unsensitized recipients. The results obtained suggest that the drug acts on both T effector cells and lymphoblasts.

Topics: Animals; Cell Movement; Dermatitis; Dextran Sulfate; Dextrans; Erythrocytes; Female; Hypersensitivity, Delayed; Immunization, Passive; Lymphocytes; Male; Mice; Mice, Inbred Strains; Oxazolone

The biochemical and biological profile of a topical anti-inflammatory agent, 2,3-dihydro-6-[3-(2-hydroxymethyl)phenyl-2-propenyl]-5-benzofuranol (L-651,896 inhibited the 5-lipoxygenase of rat basophilic leukemia cells with an IC50 of 0.1 microM and leukotriene synthesis by human PMN and mouse macrophages with IC50 values of 0.4 and 0.1 microM respectively. L-651,896 also inhibited prostaglandin E2 synthesis by mouse peritoneal macrophages (IC50 = 1.1 microM). This compound inhibited ram seminal vesicle cyclooxygenase activity at considerably higher concentrations, and this effect was directly related to substrate concentration. When applied topically to the mouse ear, L-651,896 lowered elevated levels of leukotrienes associated with arachidonic acid-induced skin inflammation and delayed hypersensitivity induced by oxazolone. However, while L-651,896 inhibited the increased vascular permeability induced by arachidonic acid, it had no effect on the edema associated with the immune-based response to oxazolone in the same tissue. Thus, it is possible that leukotrienes may play a role in some but not all inflammatory responses.

Topics: Administration, Topical; Animals; Anti-Inflammatory Agents; Arachidonate Lipoxygenases; Benzofurans; Dermatitis; Dinoprostone; Humans; Hypersensitivity, Delayed; Leukemia, Experimental; Lipoxygenase Inhibitors; Macrophages; Neutrophils; Oxazolone; Prostaglandin-Endoperoxide Synthases; Prostaglandins E; SRS-A