oxazolone and Asthma

Cathelicidin has been reported to be multifunctional. The current study aimed to investigate the influences of exogenous cathelicidin-related antimicrobial peptide (CRAMP) on inflammatory responses in different disease models. In OVA-induced allergic airway inflammation, CRAMP significantly enhanced the infiltration of inflammatory cells and accumulation of proinflammatory Th2 cytokine IL-13 and IL-33 in bronchial alveolar lavage fluid (BALF), exacerbated lung tissue inflammation and airway goblet cell hyperplasia, and elevated OVA-specific IgE level in serum. In oxazolone-induced intestinal colitis, the expression levels of CRAMP and its receptor FPR2 significantly increased in comparison with those of TNBS-induced mice, vesicle and normal controls. Exogenous CRAMP significantly prevented the development of ulcerative colitis, evidenced by improved body weight regain, decreased colons weight/length ratio, elevated epithelial integrity, and ameliorated colon tissue inflammation. In addition, pro-inflammatory cytokines TNF-α, IL-1β, IL-4 and IL-13, as well as chemokines CXCL2 and CXCL5 for neutrophils recruitment were significantly decreased in CRAMP-treated mice, and epithelial repair-related factors MUC2 and Claudin1 were increased, determined by real time-PCR and ELISAs. The results indicated that although CRAMP has pro-inflammatory effects in airway, local application of exogenous CRAMP might be a potential approach for the treatment of ulcerative colitis.

Topics: Administration, Intranasal; Administration, Rectal; Animals; Antimicrobial Cationic Peptides; Asthma; Bronchoalveolar Lavage Fluid; Cathelicidins; Colitis, Ulcerative; Cytokines; Disease Models, Animal; Disease Progression; Female; Goblet Cells; Humans; Lung; Mice; Mice, Inbred BALB C; Ovalbumin; Oxazolone

Long-standing or repeated skin barrier damage followed by atopic dermatitis (AD) is the initial step of the atopic march that eventually progresses to respiratory allergies. Maintenance of an acidic pH in the stratum corneum (SC) is an important factor for normal skin barrier function. We performed this study to determine whether an oxazolone (Ox)-induced AD murine model can develop airway inflammation by topical application and nasal inhalation of a house dust mite, Dermatofagoides pteronyssinus (Dp), which is a novel 'atopic march animal model', and whether an acidic SC environment, made by repeated application of acidic cream, can interrupt this atopic march. During repeated treatment with Ox and Dp to make an atopic march murine model, acidic cream (pH 2.8) and neutral cream (pH 7.4) adjusted by citric acid and sodium hydroxide mixed with vehicle were applied twice daily. Repeated treatment with Ox and Dp to hairless mice induced AD-like skin lesions followed by respiratory allergy, defining it as an atopic march model. Acidic cream inhibited the occurrence of respiratory allergic inflammation as well as AD-like skin lesions. These results indicate that a novel atopic march animal model can be developed by repeated topical and nasal treatments with house dust mite on Ox-induced AD mice and that the acidification of SC could be a novel intervention method to block the atopic march.

Topics: Administration, Inhalation; Administration, Topical; Allergens; Animals; Antigens, Dermatophagoides; Asthma; Cytokines; Dermatitis, Atopic; Disease Models, Animal; Female; Hydrogen-Ion Concentration; Immunoglobulin E; Mice; Mice, Hairless; Oxazolone; Skin Cream; Thymic Stromal Lymphopoietin

Exposure to microbes during early childhood is associated with protection from immune-mediated diseases such as inflammatory bowel disease (IBD) and asthma. Here, we show that in germ-free (GF) mice, invariant natural killer T (iNKT) cells accumulate in the colonic lamina propria and lung, resulting in increased morbidity in models of IBD and allergic asthma as compared with that of specific pathogen-free mice. This was associated with increased intestinal and pulmonary expression of the chemokine ligand CXCL16, which was associated with increased mucosal iNKT cells. Colonization of neonatal-but not adult-GF mice with a conventional microbiota protected the animals from mucosal iNKT accumulation and related pathology. These results indicate that age-sensitive contact with commensal microbes is critical for establishing mucosal iNKT cell tolerance to later environmental exposures.

Topics: Aging; Animals; Animals, Newborn; Antigens, CD1d; Asthma; Bacteria; Chemokine CXCL16; Chemokine CXCL6; Colitis, Ulcerative; Colon; Disease Models, Animal; Disease Susceptibility; DNA Methylation; Germ-Free Life; Intestinal Mucosa; Intestines; Lung; Mice; Mice, Inbred C57BL; Natural Killer T-Cells; Oxazolone; Receptors, CXCR; Receptors, CXCR6; Specific Pathogen-Free Organisms

A recent paper suggests that reduced exposure to germs results in the expansion of a cell type called natural killer T cells, which predisposes to colitis and asthma. Such a scenario could explain the Hygiene Hypothesis, which has been a puzzle for decades.

Topics: Animals; Asthma; Cell Proliferation; Colitis; Environmental Exposure; Humans; Hygiene Hypothesis; Hypersensitivity; Interleukins; Metagenome; Mice; Natural Killer T-Cells; Oxazolone; Specific Pathogen-Free Organisms

A piperidinyl chlorotriazine (PCT) derivative, used as a plastic UV-stabilizer, caused an outbreak of occupational asthma. We verified, in BALB/c mice, the sensitizing potential of PCT in comparison to a known respiratory sensitizer (toluene diisocyanate [TDI]) and a known dermal sensitizer (oxazolone), using three different methods in order to evaluate the validity of current models of sensitization. These included the local lymph node assay (LLNA) and the mouse IgE test. In addition, respiratory hyper-reactivity was assessed following a novel protocol involving dermal sensitization (20 microl of a 3% solution on each ear for three days) and intranasal challenge (0.1% or 1%, 10 microl per nostril on day 10), followed, after 24 h, by a methacholine challenge (using whole-body plethysmography), bronchoalveolar lavage, and histology. PCT was also used for structure-activity relationship (SAR) models for (respiratory) sensitization. High concentrations of PCT (10 and 20%) resulted in significant responses in the local lymph node assay (LLNA; stimulation indices (SI) of 2.7 +/- 0.9 and 3.2 +/- 0.6, respectively). The mouse IgE test was positive with 20% PCT only. Methacholine responsiveness was increased only in previously sensitized mice receiving a challenge with TDI or PCT. However, there was no evidence for pulmonary inflammation. The SAR studies indicated that PCT could be a respiratory sensitizer. Based on an approved test protocol such as the LLNA and the mouse IgE test, PCT proved to be a weak sensitizer when compared to TDI and oxazolone. However, in a protocol involving an intranasal challenge, PCT appeared to be a respiratory sensitizer of similar potency to TDI.

Topics: Adjuvants, Immunologic; Administration, Cutaneous; Allergens; Animals; Asthma; Bronchoalveolar Lavage; Dermatitis, Allergic Contact; Dose-Response Relationship, Drug; Female; Immunoglobulin E; Local Lymph Node Assay; Lung; Lymph Nodes; Methacholine Chloride; Mice; Mice, Inbred BALB C; Occupational Exposure; Oxazolone; Piperidines; Predictive Value of Tests; Structure-Activity Relationship; Toluene 2,4-Diisocyanate; Triazines

Inducible costimulator (ICOS) and B7-related protein-1 (B7RP-1) constitute a receptor-ligand pair involved in T cell costimulation. In this study, the stimulatory effects of B7RP-1 on cellular and humoral immune responses were investigated giving mice a construct with the extracellular domain of murine B7RP-1 fused with human IgG1 Fc (B7RP-1-Fc). B7RP-1-Fc stimulated contact hypersensitivity (CH) given near either the time of sensitization or challenge with oxazolone. When given near challenge time, B7RP-1-Fc stimulated CH more than a construct containing the extracellular domain of murine B7.2 and Fc (B7.2-Fc). B7RP-1-Fc increased the number of cells in lymph nodes draining the skin sensitized with oxazolone, especially activated T cells. B7RP-1-Fc also increased the ability of the cells in these lymph nodes to induce CH when transfused into naive mice. B7RP-1-Fc stimulated the production of anti-keyhole limpet hemocyanin (KLH) Ab, increasing anti-KLH IgG, IgG2a, and IgE, whereas B7.2-Fc did not affect this production. B7RP-1-Fc also increased the number of cells in lymph nodes draining the skin immunized with KLH and their production of IFN-gamma, IL-4, and IL-10 in response to KLH. Finally, B7RP-1-Fc increased the presence of eosinophils in the bronchoalveolar lavage and lungs of mice sensitized and challenged with OVA so to mount an asthmatic reaction. B7RP-1-Fc stimulates both cellular and humoral immune responses in vivo by increasing number and function of T and B cells reacting to Ag exposure.

Topics: Abatacept; Adjuvants, Immunologic; Administration, Cutaneous; Animals; Antigens, CD; Antigens, Differentiation; Asthma; B-Lymphocytes; B7-1 Antigen; B7-2 Antigen; Bronchoalveolar Lavage Fluid; CTLA-4 Antigen; Dermatitis, Contact; Drug Administration Schedule; Drug Combinations; Female; Hemocyanins; Humans; Immunoconjugates; Immunoglobulin Fc Fragments; Immunoglobulin G; Inducible T-Cell Co-Stimulator Ligand; Injections, Intraperitoneal; Lymph Nodes; Lymphocyte Count; Membrane Glycoproteins; Mice; Mice, Inbred BALB C; Oxazolone; Recombinant Fusion Proteins; Skin; Spleen; T-Lymphocytes