ovalbumin and Rhinitis

Eosinophilic chronic rhinosinusitis (ECRS) is predominantly characterized by nasal type 2 inflammation. The pathogenesis of this condition is complex. High levels of IL-17A are associated with eosinophil infiltration in some inflammatory diseases and contribute to the severity and insensitivity of corticosteroid therapy for chronic rhinosinusitis.. In the first experiment, we constructed a modified ECRS mouse model using four groups of mice: phosphate-buffered saline (PBS)-sensitized and nasal instillation (control); PBS-sensitized and Staphylococcus aureus enterotoxin B (SEB) nasal instillation after nasal tamponade (SEB group); ovalbumin (OVA)-sensitized and nasal instillation (OVA group); and OVA-sensitized combined with OVA and SEB nasal instillation after nasal tamponade (OVA + SEB group). In the second experiment, we examined the role of IL-17A by dividing the mice into four groups: control group; ECRS group; ECRS + anti-IL-17A group; and ECRS + IL-17A group. The latter two groups received intraperitoneal injections of anti-IL-17A antibody or IL-17A, respectively.. We constructed a modified ECRS mouse model (OVA + SEB group), where the IL-17A levels were upregulated in the nasal sinus of ECRS mice and the IL-17A levels were significantly correlated with eosinophil infiltration. We further demonstrated that IL-17A induced type 2 inflammation and eosinophil infiltration in the ECRS group of mice. In contrast, IL-17A neutralization attenuated type 2 inflammatory cytokine secretion and eosinophil infiltration.. OVA sensitization and unilateral nasal tamponade, combined with SEB and OVA alternate nasal instillation (OVA + SEB group), could be used to construct a more typical ECRS mouse model in which IL-17A enhanced the expression of type 2 cytokines and eosinophil infiltration.

Topics: Animals; Chronic Disease; Cytokines; Eosinophilia; Eosinophils; Inflammation; Mice; Nasal Polyps; Ovalbumin; Rhinitis; Sinusitis

Topics: Allergens; Animals; Cell Movement; Chronic Disease; Disease Models, Animal; Enterotoxins; Eosinophils; Humans; Lipopolysaccharides; Male; Nasal Mucosa; Neutrophil Infiltration; Ovalbumin; Rabbits; Rhinitis; Sinusitis; Staphylococcus aureus; Teichoic Acids

One subtype of chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by the development of a T-helper type 2 (Th2) response and eosinophilic infiltration. Here, we aimed to establish an eosinophilic CRSwNP murine model, which would be essential to understand the underlying pathogenesis and establish a treatment strategy. C57BL/6 mice were challenged intranasally with a mixture of an Aspergillus oryzae-derived protease (AP) and ovalbumin (OVA) for 6, 8, or 12 consecutive weeks (12 mice/group); control mice received the same volume of phosphate-buffered saline for 12 weeks (n = 12). Sinonasal samples were evaluated histologically, and interleukin (IL)-4, IL-5, IL-13, eotaxin, keratinocyte chemoattractant, and macrophage inflammatory protein-2 mRNA levels in sinonasal mucosa were measured by real-time PCR. Protein levels of Th2 cytokines, INF-γ, IL-17A, and chemokines in nasal lavage fluid, and total serum IgE were measured by ELISA. Greater eosinophil infiltration in the subepithelial layer was observed in the challenged groups, compared with the control group. Polypoid mucosal lesions were predominantly observed in the 12-week group, which also exhibited mucosal thickening on micro-CT scans. The IL-4, IL-5, and IL-13 mRNA and protein levels were elevated in the sinonasal mucosa and nasal lavage fluid. INF-γ and IL-17A were undetectable or not elevated relative to the control group levels. In contrast, eotaxin levels were particularly elevated in the sinonasal mucosa and nasal lavage fluid in the 12-week group. In conclusion, intranasal AP and OVA exposure successfully induced Th2-specific CRSwNP in a murine model.

Topics: Administration, Intranasal; Animals; Aspergillus; Chronic Disease; Cytokines; Disease Models, Animal; Eosinophilia; Instillation, Drug; Mice; Mice, Inbred C57BL; Nasal Polyps; Ovalbumin; Peptide Hydrolases; Rhinitis; Sinusitis

Chronic rhinosinusitis (CRS) is one of the most common chronic diseases in adults in both developing and developed countries. The etiology and pathogenesis of CRS remain poorly understood, and the disease is refractory to therapy in many patients. Mast cell activation has been demonstrated in the sinonasal mucosa of patients with CRS; however, the specific contribution of mast cells to the development and pathogenesis of this disease has not been established.. The objective of this study was to investigate the role of mast cells in the development of CRS.. C57BL/6 wild-type and C57BL/6-Kit(W-sh/W-sh) mast cell-deficient mice were immunized by intraperitoneal allergen injection and subsequent chronic low dose intranasal allergen challenges. The sinonasal phenotypes of these groups were then evaluated and compared to saline-treated controls using radiologic, histologic, and immunologic methods.. Wild-type mice exposed to chronic intranasal allergen developed many features seen in human CRS, including mucosal thickening, cystic changes, polyp development, eosinophilia, goblet cell hyperplasia, and mast cell activation. In contrast, sinonasal pathology was significantly attenuated in mast cell-deficient mice subjected to the same chronic allergen protocol. Specifically, tissue eosinophilia and goblet cell hyperplasia were reduced by approximately 50% compared to wild-type levels. Surprisingly, none of the mast cell-deficient mice subjected to chronic allergen challenge developed cystic changes or polypoid changes in the nose or sinuses.. These data identify a critical role for mast cells in the development of many features of a mouse model of eosinophilic CRS, suggesting that therapeutic strategies targeting mast cells be examined in humans afflicted with this disease.

Topics: Allergens; Animals; Chronic Disease; Disease Models, Animal; Eosinophilia; Goblet Cells; Hyperplasia; Mast Cells; Maxillary Sinus; Mice; Mice, Inbred C57BL; Nasal Polyps; Ovalbumin; Paranasal Sinuses; Rhinitis; Sinusitis; X-Ray Microtomography

Aqueous extract of Qu Feng Xuan Bi Formula (QFXBF, a Chinese herb formula) which composed of Radix Glycyrrhizae, Radix Glycyrrhizae Preparata, Paeonia sterniana Fletcher in Journ, Pheretima, Allium macrostemon Bunge, Astragalus membranaceus (Fisch) Bunge and Divaricate Saposhnikovia Root has been used in treatment of allergic rhinitis and asthma (ARA) as an approved hospital prescription for many years in Jiangsu Province Hospital of Traditional Chinese Medicine, China. The present study was designed to investigate the effect of the aqueous extract of QFXBF in the gene expression of Toll-like receptor 9 (TLR9) and the manners of immune modulation of T cell-associated interleukin (IL-4 and IL-13) in rat ARA models.. Fifty SD male rats were divided into five groups: not treated group, OVA only group (treated only with OVA), dexamethasone (DXM) group, low dose QFXBF group and high dose QFXBF group randomly (n=10 per group). Rat allergic rhinitis and asthma model was developed by ovalbumin (OVA) sensitization and nose infusion. Pathological changes of nasal tissue and lungs were examined by H&E staining. Gene expressions of TLR9, Stat 3, Jak-1 and C-Jun in nasal tissue were assayed by real-time polymerase chain reaction (RT-PCR). The serum and broncho-alveolar lavage fluid (BALF) levels of T cell-associated interleukin (IL-4 and IL-13) were determined by enzyme-linked immunosorbent assay (ELISA).. The ARA model was successfully established. Marked EOS count was observed in BALF from ARA models. The aqueous extract of QFXBF could reduce EOS levels and increase TLR9 expression, but did not affect the gene expression of Stat-3 and Jak-1 and C-Jun. The reduction of IL-13 concentration in serum from high dose QFXBF group was observed in BALF, albeit not significantly. Despite the not treated group, serum levels of IL-4 had significantly increased in other four groups (P<0.001, n=4-6) but made higher in low dose QFXBF group and DXM group (P<0.05, n=4-6).. This study originally provides the evidence that the aqueous extract of Qu Feng Xuan Bi Formula alone is effective in the treatment of anaphylactic rhinitis-asthma symptoms. The extract of Qu Feng Xuan Bi Formula was effective to reduce the eosophil recruitment to the lung. In addition it increased the IL-4 concentration in the BALF and expression of TLR9 in the nasal tissue. No alteration was observed in the IL-13 concentration in the BALF and expression of STAT-3, JAK-1 and C-Jun in nasal tissue. The results thereby scientifically provided mechanism of these aqueous extract of QFXBF in improvement of ARA and supported its clinical use.

Topics: Anaphylaxis; Animals; Asthma; Bronchoalveolar Lavage Fluid; Dexamethasone; Drugs, Chinese Herbal; Eosinophils; Gene Expression Regulation; Interleukin-13; Interleukin-4; Male; Ovalbumin; Plant Extracts; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Rhinitis; T-Lymphocytes; Toll-Like Receptor 9

Invariant natural killer T (iNKT) cells play important immunoregulatory functions in allergen-induced airway hyperresponsiveness and inflammation. To clarify the role of iNKT cells in allergic rhinitis (AR), we generated bone marrow-derived dendritic cells (BMDCs), which were pulsed by ovalbumin (OVA) and α-galactosylceramide (OVA/α-GalCer-BMDCs) and administered into the oral submucosa of OVA-sensitized mice before nasal challenge. Nasal symptoms, level of OVA-specific immunoglobulin (IgE), and T helper type 2 (Th2) cytokine production in cervical lymph nodes (CLNs) were significantly ameliorated in wild-type (WT) mice treated with OVA/α-GalCer-BMDCs, but not in WT mice treated with OVA-BMDCs. These anti-allergic effects were not observed in Jα18(-/-) recipients that lack iNKT cells, even after similar treatment with OVA/α-GalCer-BMDCs in an adoptive transfer study with CD4(+) T cells and B cells from OVA-sensitized WT mice. In WT recipients of OVA/α-GalCer-BMDCs, the number of interleukin (IL)-21-producing iNKT cells increased significantly and the Th1/Th2 balance shifted towards the Th1 dominant state. Treatment with anti-IL-21 and anti-interferon (IFN)-γ antibodies abrogated these anti-allergic effects in mice treated with α-GalCer/OVA-BMDCs. These results suggest that activation of iNKT cells in regional lymph nodes induces anti-allergic effects through production of IL-21 or IFN-γ, and that these effects are enhanced by simultaneous stimulation with antigen. Thus, iNKT cells might be a useful target in development of new treatment strategies for AR.

Topics: Animals; B-Lymphocytes; CD4-Positive T-Lymphocytes; Dendritic Cells; Epitopes; Female; Galactosylceramides; Hypersensitivity; Immunoglobulin E; Immunotherapy, Adoptive; Interferon-gamma; Interleukins; Lymph Nodes; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Natural Killer T-Cells; Ovalbumin; Rhinitis; Th1 Cells; Th2 Cells

This study was designed to find out the impact of micro-ecological environment on the incidence of allergic rhinitis after developing a model of allergic rhinitis on mice.. Sixty mice were randomly divided into GF group (n=30) and SPF group (n=30). Mice of GF group were fed in the germ-free environment and mice of SPF group were fed in the specific pathogen-free environment. Then each group were randomly divided into model group (20 mice) and control group (10 mice). Establish allergic rhinitis model in the mice of model group using ovalbumin (OVA) at the age of 6 weeks, observe and score the corresponding symptoms and signs that could been induced. Stain with hematoxylin eosin (HE) staining method for nasal mucosa to observe the morphological changes. Using enzyme linked immunosorbent assay to detect the concentration of IgE, IFN-γ and IL-4 in the peripheral blood serum.. The chi square test showed that the incidence of allergic rhinithis in the mice of GF group was significantly higher than that in the SPF group (P< 0. 05). HE staining showed that the nasal mucosas of allergic rhinitis positive reaction mice were highly congestive and edematous and had a large number of inflammatory cell infiltration, while there was no abnormal morphology of nasal mucosas in mice with no allergic rhinitis reaction. EOS counting displayed that the number of eosinophilic cells in nasal mucosa of positive allergic rhinitis reaction mice was increased significantly. The concentration of IgE and IL-4 in the serum of positive allergic rhinitis reaction mice was highly increased (P <0. 05), and IFN-γ was significantly decreased (P< 0.05).. The difference of micro-ecological environment may play a key role in the occurrence of allergic rhinitis in mice.

Topics: Animals; Disease Models, Animal; Environment; Incidence; Interleukin-4; Mice; Mice, Inbred BALB C; Nasal Mucosa; Ovalbumin; Rhinitis; Rhinitis, Allergic

Recent studies have suggested that upper airway inflammation has a strong impact on lower airway diseases. The purpose of this study was to assess whether nasal inflammation could exacerbate allergic asthma in a mouse model.. Mice were assigned to 4 groups: control (Cont), either rhinosinusitis (R) or allergic asthma (A) alone, and both rhinosinusitis and allergic asthma (R&A). Mice underwent induction of nasal inflammation (R and R&A) or sham surgery (Cont and A) on day 1. Mice in the A and R&A groups were sensitized to ovalbumin on days 1, 7, and 14, followed by aerosol challenge on days 18 to 20, whereas in the Cont and R groups only saline was administered. All mice were assessed for airway hyperresponsiveness (AHR) and were euthanized on day 21. The sera, bronchoalveolar lavage fluids (BALFs), and nasal and lung tissues were collected for further analyses.. Histology findings confirmed upper and lower airway inflammation in experimental mice. Significantly increased AHR and total serum immunoglobulin E (IgE) were observed in the R&A group when compared with those of the Cont, R, and A groups. Responses to IgG2a induction were also found in sera and BALFs from mice with rhinosinusitis (R and R&A). Higher levels of interleukin 4 (IL-4) and IL-13, and increased eosinophilic inflammation were detected in BALFs and lung tissues from the experimental groups when compared with those from the Cont group.. Our results confirm that upper airway inflammation could exacerbate allergic asthma, and provide support to the concept of "one airway, one disease.

Topics: Allergens; Animals; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Immunoglobulin E; Immunoglobulin G; Interleukin-13; Interleukin-4; Leukocyte Count; Lung; Male; Mice; Mice, Inbred BALB C; Nasal Cavity; Ovalbumin; Rhinitis; Sinusitis

Extra domain A-containing fibronectin (EDA-FN) is necessary for the development of allergen-induced lower airway fibrosis. The pathogenesis of fibrosis in allergic rhinitis has not been well studied.. To determine whether EDA-fibronectin is necessary for the development of nasal remodeling in a murine model of chronic allergic rhinitis and in human allergic rhinitis.. EDA(-/-) and wild-type (WT) C57Bl/6 mice were sensitized intraperitoneally and then challenged with inhaled ovalbumin (OVA) or saline for 2 and 5 weeks. Clinical signs of rhinitis and histological analysis of nasal tissue were evaluated. Immunohistological staining for EDA-FN was performed in human tissue of inferior nasal conchae from patients with allergic rhinitis and controls.. After 2 weeks of allergen exposure, only goblet cell hyperplasia and perivascular eosinophilia were observed. After 5 weeks, goblet cell number, thickening of the subepithelial layer, and extent and area of collagen deposition were increased in the nasal tissue of WT OVA (ovalbumin)-challenged mice as compared with saline controls (P < .0001, P < .0001, P = .018, and P = .03, respectively). Clinical signs of rhinitis were observed only in WT OVA-challenged mice. In the EDA(-/-) mice exposed to OVA, collagen deposition, collagen area, and subepithelial thickness showed no increase and were similar to saline control mice, whereas goblet cell hyperplasia was similar to WT OVA-challenged mice. EDA-FN expression was prominent in inferior conchae from patients with allergic rhinitis but was absent in control patients.. EDA-containing fibronectin is necessary for the development of nasal tissue fibrotic remodeling process in both murine and human allergic rhinitis.

Topics: Adult; Allergens; Animals; Collagen; Eosinophilia; Female; Fibronectins; Goblet Cells; Humans; Hyperplasia; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Nasal Mucosa; Ovalbumin; Rhinitis

Interleukin (IL) 17A, a key cytokine of T(H)17 cells, is a well-known proinflammatory cytokine. Despite the important role of T(H)17 cells in acute airway inflammation, the role of IL-17A in allergic rhinitis (AR) remains unclear.. To investigate the role of IL-17A in the allergic response in AR.. Wild-type BALB/c and IL-17A-deficient mice were immunized intraperitoneally and were challenged intranasally with ovalbumin. Allergic symptom scores, eosinophil infiltration, serum IgE level, and the levels of several cytokines in nasal lavage fluid and splenocyte supernatants were analyzed.. IL-17A levels increased significantly more in ovalbumin-sensitized wild-type mice than in the negative control group. IL-17A-deficient mice showed a significant decrease in allergic symptoms, serum IgE levels, and eosinophil infiltration into the nasal mucosa compared with wild-type mice. IL-17A-deficient mice also showed decreased histamine and cysteinyl leukotriene release. Bone marrow-derived mast cells from IL-17A-deficient mice showed significantly lower degranulation and secretion of tumor necrosis factor α. Moreover, IL-17A deficiency attenuated the IL-5 level in nasal lavage fluid and its production in response to ovalbumin but did not increase interferon γ production and its level in nasal lavage fluid. In addition, secretion of IL-17A from spleen cells induced the expression of proinflammatory cytokine messenger RNA in macrophages. The mean level of proinflammatory cytokines, including tumor necrosis factor α and IL-17, decreased in IL-17A-deficient mice.. These results suggest that IL-17A may partly contribute to the development of nasal allergic inflammation in an AR animal model and regulate AR via the activation of proinflammatory cytokines and modulation of T(H)2 cytokine.

Topics: Animals; Cell Line; Cytokines; Disease Models, Animal; Female; Humans; Hypersensitivity, Immediate; Immunoglobulin E; Inflammation; Interleukin-17; Macrophages; Mice; Mice, Inbred BALB C; Mice, Knockout; Nasal Mucosa; Ovalbumin; Rhinitis; Th2 Cells; Tumor Necrosis Factor-alpha

KOB03 is a polyherbal medicine consisting of five different herbs and has commonly been used for the treatment of various allergic diseases. However, its precise anti-allergic effect and mechanism remain unknown.. The aim of this study was to investigate the effect of KOB03 on allergic responses through the regulation of mast-cell mediated allergic inflammation.. To determine the effect of KOB03 on mast cell-mediated allergic reactions, we investigated the parameter changes of in vivo models such as compound 48/80-induced systemic anaphylaxis and ovalbumin (OVA)-induced allergic rhinitis, and the release of allergic inflammatory mediators such as histamine, immunoglobulin (Ig) E, and inflammatory cytokines via the MAPKs and NF-kappaB pathways.. The oral administration of KOB03 at doses of 100 and 200mg/kg inhibited histamine release and mortality in compound 48/80-induced anaphylactic rats. KOB03 also improved rhinitis symptoms, inhibited the histopathological changes of nasal mucosa, and decreased the serum levels of histamine, OVA-specific IgE and TNF-α in OVA-induced allergic rhinitis in mice. In vitro, KOB03 suppressed compound 48/80-induced histamine release by blocking mast cell degranulation. In addition, KOB03 inhibited the production of inflammatory cytokines such as TNF-α, IL-1β, IL-6 and IL-8 in PMA/A23187-stimulated HMC-1 mast cells by suppressing their gene expression and blocking the ERK1/2 and p38 MAPK and NF-κB pathways.. These results suggest that KOB03 has an anti-allergic effect by modulating mast cell-mediated allergic responses in allergic rhinitis.

Topics: Allergens; Animals; Anti-Allergic Agents; Cell Line; Cytokines; Histamine Release; Humans; Hypersensitivity, Immediate; Immunoglobulin E; Magnoliopsida; Male; Mast Cells; Mice; Mice, Inbred BALB C; Mitogen-Activated Protein Kinases; Nasal Cavity; NF-kappa B; Ovalbumin; p-Methoxy-N-methylphenethylamine; Phytotherapy; Plant Extracts; Plant Preparations; Rhinitis; RNA, Messenger

The anti-allergic effect of total bakkenolides from the rhizome of Petasites tricholobus (BAPT) was evaluated in an ovalbumin-induced allergic rhinitis model in male Wistar rats. The major components of the bakkenolide fraction are bakkenolide-D, bakkenolide-B, bakkenolide-IIIa and bakkenolide-IVa, which account for 60.04% of the total. The rats were treated with 40 mg/kg, 20 mg/kg, 10 mg/kg or 5 mg/kg BAPT, and 0.942 mg/kg loratadine and 0.5% gum tragacanth were used as positive and negative controls, respectively. The frequency of nose rubbing and sneezing was observed, the number of eosinophils infiltrating into the nasal tissue was counted, and serum levels of IL-4 and histamine were determined by ELISA. The results showed that BAPT had a beneficial effect on allergic rhinitis in ovalbumin-sensitized Wistar rats, which was evidenced by a significant decrease in the frequency of sneezing, the number of eosinophils infiltrating into the nasal tissue, and the serum levels of IL-4 and histamine. BAPT may therefore be a potential antiallergic drug.

Topics: Animals; Anti-Allergic Agents; Disease Models, Animal; Histamine; Immunoglobulin E; Interleukin-4; Male; Ovalbumin; Petasites; Rats; Rats, Wistar; Rhinitis; Sesquiterpenes

  Tumor necrosis factor (TNF)-α is a principal mediator of the acute inflammatory response, including allergic rhinitis. TNF-α inhibitors are widely used for the treatment of inflammatory conditions such as rheumatoid arthritis and inflammatory bowel diseases; however, the effects of TNF-α inhibitors on allergic rhinitis are not well established. We aimed to investigate the effects of infliximab, a TNF-α inhibitor, on allergic rhinitis in a mouse model..   BALB/c mice were sensitized with ovalbumin (OVA) and alum, and challenged intranasally with OVA. The TNF-α inhibitor, infliximab was administered intraperitoneally, and multiple parameters of allergic responses were evaluated to determine the effects of infliximab..   Infliximab reduced allergic symptoms and eosinophilic infiltration into the nasal mucosa. It also suppressed total and OVA-specific IgE levels, and inhibited local Th2 cytokine transcription in the nasal mucosa and systemic Th2 cytokine production by splenocytes. Furthermore, the expression of E-selectin, neither intercellular adhesion molecule 1 (ICAM-1) nor vascular cell adhesion molecule 1 (VCAM-1), in the nasal mucosa was suppressed in the infliximab-treated group when compared to the nontreated group..   This study shows that the TNF-α inhibitor infliximab induces anti-allergic effects by decreasing local and systemic Th2 cytokine (IL-4) production, total and OVA-specific IgE levels, adhesion molecule (E-selectin) expression, and eosinophil infiltration into the nasal mucosa in an allergic rhinitis model. Therefore, infliximab should be considered as a potential agent in treating allergic rhinitis.

Topics: Animals; Anti-Allergic Agents; Antibodies, Monoclonal; Cell Adhesion Molecules; Cytokines; Eosinophils; Hypersensitivity; Immunoglobulin E; Infliximab; Mice; Mice, Inbred BALB C; Nasal Mucosa; Ovalbumin; Rhinitis; Th2 Cells

New therapies are necessary to address inadequate asthma control in many patients. This study sets out to investigate whether hypoxia-inducible factor (HIF) is essential for development of allergic airway inflammation (AAI) and therefore a potential novel target for asthma treatment.. Mice conditionally knocked out for HIF-1β were examined for their ability to mount an allergic inflammatory response in the lung after intratracheal exposure to ovalbumin. The effects of treating wild-type mice with either ethyl-3,4-dihydroxybenzoate (EDHB) or 2-methoxyestradiol (2ME), which upregulate and downregulate HIF, respectively, were determined. HIF-1α levels were also measured in endobronchial biopsies and bronchial fluid of patients with asthma and nasal fluid of patients with rhinitis after challenge.. Deletion of HIF-1β resulted in diminished AAI and diminished production of ovalbumin-specific IgE and IgG(1) . EDHB enhanced the inflammatory response, which was muted upon simultaneous inhibition of vascular endothelial growth factor (VEGF). EDHB and 2ME antagonized each other with regard to their effects on airway inflammation and mucus production. The levels of HIF-1α and VEGF increased in lung tissue and bronchial fluid of patients with asthma and in the nasal fluid of patients with rhinitis after challenge.. Our results support the notion that HIF is directly involved in the development of AAI. Most importantly, we demonstrate for the first time that HIF-1α is increased after challenge in patients with asthma and rhinitis. Therefore, we propose that HIF may be a potential therapeutic target for asthma and possibly for other inflammatory diseases.

Topics: Adolescent; Adult; Allergens; Animals; Asthma; Basic Helix-Loop-Helix Transcription Factors; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Lung; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Ovalbumin; Respiratory Hypersensitivity; Rhinitis; Up-Regulation; Young Adult

We investigated the role of hematopoietic prostaglandin D synthase (H-PGDS) in biphasic nasal obstruction in allergic rhinitis using a new specific inhibitor, (N-methoxy-N-methyl)-4-(5-benzoylbenzimidazole-2-yl)-3,5-dimethylpyrrole-2-carboxamide hydrochloride (TAS-204). First, we developed a novel guinea pig model of allergic rhinitis. Guinea pigs sensitized to ovalbumin without adjuvant were challenged with intranasal exposure to ovalbumin once a week. After the 3rd antigen challenge, they exhibited biphasic nasal obstruction. Additionally, analysis of nasal lavage fluid revealed an increase in the level of prostaglandin D(2) in both early and late phases. Treatment with oral TAS-204 for 15 days during the period of antigen challenges suppressed increases in nasal airway resistance in both phases. It is noteworthy that the late phase nasal obstruction was almost completely abrogated by inhibiting H-PGDS alone. Eosinophil infiltration in nasal lavage fluid and nasal hyperresponsiveness to histamine was also reduced by TAS-204 administration. These findings suggest that H-PGDS plays a critical role in the development of allergic rhinitis, especially in the induction of late phase nasal obstruction.

Topics: Animals; Benzimidazoles; Dinoprostone; Disease Models, Animal; Eosinophils; Guinea Pigs; Histamine; Humans; Intramolecular Oxidoreductases; Leukotrienes; Lipocalins; Male; Nasal Lavage Fluid; Nasal Mucosa; Nasal Obstruction; Ovalbumin; Prostaglandin D2; Pyrroles; Rhinitis; Time Factors

To evaluate the function of Th17 cells in allergic rhinitis,through comparing the symptoms, pathology and and the quantity of Th1, Th2 and Th17 cytokine in normal mice, allergic rhinitis mice and allergic rhinitis mice with IL-17 antibody application.. Thirty BALB/c mice were randomly divided into three groups, control group, allergic rhinitis group, and therapy group. The allergic rhinitis model was induced by classical method with ovalbumin. The therapy group was treated with IL-17 antibody. The concentration of IL-17, IL-4 and IFN-gamma in serum was measured by enzyme-linked immunosorbent assay (ELISA). Nasal mucosal inflammation was evaluated by HE staining. The expression of RORgammat mRNA was measured by reverse transcription-polymerase chain reaction (RT-PCR).. The expression level of IL-17, IL-4 and RORgammat mRNA in allergic rhinitis group were significantly higher than those of control group and IL-17 antibody treated group (P < 0.05). While the expression level of IFN-gamma in allergic rhinitis group were significantly was lower than those of control group and IL-17 antibody treated group (P < 0.05). The inflammation reaction in therapy group abated with nasal mucosal HE staining.. The large quantity of Th2, Th17 cells were found in allergic rhinitis. It might be associated with the pathogenesis of allergic rhinitis. The control of Th17 cells expression may be an effective way to treat allergic rhinitis.

Topics: Animals; Disease Models, Animal; Female; Interferon-gamma; Interleukin-17; Interleukin-4; Male; Mice; Mice, Inbred BALB C; Ovalbumin; Rhinitis; Th17 Cells; Th2 Cells

Sublingual immunotherapy (SLIT) is effective in the treatment of a variety of allergic diseases, including bronchial asthma and rhinitis. However, how this local therapy exerts such wide effects is unclear. In this study, we comparatively examined the effect of SLIT on antigen-induced airway inflammation in bronchoalveolar and nasal cavities in mice.. Mice were treated sublingually with ovalbumin (OVA) once a day for 2 weeks. Subsequently, they were immunized with the corresponding antigen. Following intratracheal and nasal challenge with OVA, infiltration of inflammatory cells into the bronchoalveolar and nasal cavities was investigated in these mice.. Massive infiltration of eosinophils as well as neutrophils into the bronchoalveolar cavity was induced by intratracheal OVA challenge. Eosinophils accumulated in the nasal cavity, but the number of neutrophils did not significantly change in response to nasal antigen challenge. These antigen-induced airway inflammatory responses, including the increases in the numbers of eosinophils and/or neutrophils in the bronchoalveolar and nasal cavities, were clearly suppressed by SLIT.. This animal model displaying differential inflammatory responses in the bronchoalveolar and nasal cavities may be useful to elucidate the efficacy and mechanisms of SLIT against various allergic diseases.

Topics: Administration, Sublingual; Animals; Antigens; Bronchitis; Bronchoalveolar Lavage Fluid; Desensitization, Immunologic; Eosinophils; Female; Mice; Mice, Inbred BALB C; Nasal Lavage Fluid; Neutrophils; Ovalbumin; Rhinitis; Vaccination

Neurokinins are known to induce neurogenic inflammation related to respiratory diseases. The effects of CS-003 ([1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[benzo[c]thiophene-1(3H),4'-piperidine]-(2S)-oxide hydrochloride]), a novel triple neurokinin receptor antagonist, on several respiratory disease models were evaluated in guinea pigs. As we have already shown that CS-003 is intravenously effective, we first determined if CS-003 was orally effective. CS-003 dose-dependently inhibited substance P-induced tracheal vascular hyperpermeability, neurokinin A- and neurokinin B-induced bronchoconstriction with ID(50) values of 3.6, 1.3 and 0.89 mg/kg (p.o.), respectively. CS-003 (10 mg/kg, p.o.) inhibited the number of coughs induced by capsaicin aerosol (P<0.01) and the antitussive effect was comparable to that of codeine. CS-003 (10 mg/kg, p.o.) also inhibited airway hyperresponsiveness to methacholine chloride in ovalbumin-induced asthma models (P<0.01), a milder one and a severer one. On the other hand, montelukast (10 mg/kg, p.o.), a leukotriene receptor antagonist, significantly inhibited the hyperresponsiveness only in the milder model (P<0.05). In an ovalbumin-induced rhinitis model, oral administration of CS-003 inhibited nasal blockade in a dose-dependent manner and the inhibitory effect was comparable to that of dexamethasone (10 mg/kg, p.o.). CS-003 (i.v.) also dose-dependently inhibited cigarette smoke-induced bronchoconstriction, tracheal vascular hyperpermeability and mucus secretion. These data show that CS-003, a potent orally active triple neurokinin receptor antagonist, may be useful for the treatment of respiratory diseases associated with neurokinins, such as allergic asthma, allergic rhinitis, chronic obstructive pulmonary disease and cough.

Topics: Administration, Oral; Animals; Asthma; Bronchoconstriction; Capillary Permeability; Capsaicin; Cough; Cyclic S-Oxides; Disease Models, Animal; Guinea Pigs; Male; Morpholines; Mucus; Nicotiana; Ovalbumin; Pulmonary Disease, Chronic Obstructive; Receptors, Tachykinin; Respiratory Tract Diseases; Rhinitis; Smoke; Trachea

Traditional therapies for asthma and allergic rhinitis (AR) such as corticosteroids and antihistamines are not without limitations and side effects. The use of complementary and alternative approaches to treat allergic airways disease, including the use of herbal and dietary supplements, is increasing but their efficacy and safety are relatively understudied. Previously, we have demonstrated that gamma-tocopherol (gammaT), the primary form of dietary vitamin E, is more effective than alpha-tocopherol, the primary form found in supplements and tissue, in reducing systemic inflammation induced by non-immunogenic stimuli.. We used allergic Brown Norway rats to test the hypothesis that a dietary supplement with gammaT would protect from adverse nasal and pulmonary responses to airway allergen provocation.. Ovalbumin (OVA)-sensitized Brown Norway rats were treated orally with gammaT before intranasal provocation with OVA. Twenty-four hours after two challenges, histopathological changes in the nose, sinus and pulmonary airways were compared with gene expression and cytokine production in bronchoalveolar lavage fluid and plasma.. We found that acute dosing for 4 days with gammaT was sufficient to provide broad protection from inflammatory cell recruitment and epithelial cell alterations induced by allergen challenge. Eosinophil infiltration into airspaces and tissues of the lung, nose, sinus and nasolacrimal duct was blocked in allergic rats treated with gammaT. Pulmonary production of soluble mediators PGE(2), LTB(4) and cysteinyl leukotrienes, and nasal expression of IL-4, -5, -13 and IFN-gamma were also inhibited by gammaT. Mucous cell metaplasia, the increase in the number of goblet cells and amounts of intraepithelial mucus storage, was induced by allergen in both pulmonary and nasal airways and decreased by treatment with gammaT.. Acute treatment with gammaT inhibits important inflammatory pathways that underlie the pathogenesis of both AR and asthma. Supplementation with gammaT may be a novel complementary therapy for allergic airways disease.

Topics: Animals; Antioxidants; Asthma; Bronchoalveolar Lavage Fluid; Cytokines; Dietary Supplements; Eosinophilia; gamma-Tocopherol; Gene Expression; Hyperplasia; Hypersensitivity; Lung; Male; Nasal Mucosa; Ovalbumin; Paranasal Sinuses; Rats; Rats, Inbred BN; Respiratory Mucosa; Respiratory Tract Diseases; Rhinitis

The relative contributions of the allergen-specific early-phase nasal response and nonspecific nasal response and mast cells to the pathophysiology of allergic rhinitis are not well defined.. To determine the contributions of specific reactivity, nonspecific reactivity, and mast cells to the development of early-phase and late-phase responses using a mouse model of allergic rhinitis.. Sensitized wild-type and FcvarepsilonRI-deficient (FcvarepsilonRI-/-) mice were exposed to allergen for 3, 5, or 12 days. As indicators of nasal reactivity, respiratory frequency and nasal resistance were monitored.. Sensitized mice exposed to 3 days of nasal allergen challenge showed a nonspecific early-phase response. As the number of allergen exposures increased, there was progressive diminution in nonspecific responses with increased allergen-specific early-phase responses and a late-phase response. Sensitized FcvarepsilonRI-/- mice did not develop nonspecific nasal responses or late-phase responses, but transfer of in vitro-differentiated wild-type mast cells into FcvarepsilonRI-/- mice restored nonspecific early-phase nasal responses but not the late-phase response.. These data identify the nonspecific nasal response as a major contributor to the early-phase response, especially during initial allergen exposure, and is dependent on mast cells. Increasing allergen exposure results in increasing allergen-specific responses, converting the nonspecific early-phase response to a late-phase response that is allergen-specific and mast cell-independent.

Topics: Allergens; Ambrosia; Animals; Hypersensitivity; Immunoglobulin E; Mice; Mice, Inbred BALB C; Mice, Mutant Strains; Nasal Provocation Tests; Ovalbumin; Rhinitis; Time

These studies aimed to outline the in vitro and in vivo histamine H(1) receptor antagonistic activity and safety pharmacology of SUN-1334H, a new potent antihistamine agent under clinical development.. In vitro antihistamine activity and selectivity of SUN-1334H was evaluated in a panel of receptor and enzyme assays and functional assays using isolated tissues. In vivo antihistamine and antiallergy efficacy were assessed following oral administration of SUN-1334H in histamine-induced bronchoconstriction in guinea pigs, skin wheal in beagle dogs and ovalbumin-induced rhinitis (sneezing, vascular permeability and intranasal pressure) in guinea pigs. Cardiovascular safety was assessed by CHO-K1/human ether-à-go-go related gene (hERG) K(+) current assay, dog telemetry and guinea-pig ECG. CNS safety was assessed by functional observational battery in rats and pentobarbital-induced sedation and pentylenetetrazol-induced convulsions in mice. The effect on intestinal motility was assessed in rats.. In vitro receptor binding assays showed that SUN-1334H had high histamine H(1) receptor binding affinity with an inhibition constant value of 9.7 nmol/L and either no or insignificant affinity with a panel of receptors and enzymes. In functional assays, SUN-1334H caused potent inhibition of histamine-induced contractions of isolated guinea-pig ileum with an IC(50) (half the maximal inhibitory concentration) of 0.198 micromol/L. In contrast, SUN-1334H had no significant effect on isolated tissue contractions induced by cholinergic, H(2)-histaminergic, serotonergic, adrenergic receptor agonists or BaCl(2). In studies of animal models of histamine-mediated disorders, SUN-1334H potently inhibited histamine-induced bronchospasm over 24 hours following oral administration and completely suppressed histamine-induced skin wheal in beagle dogs and ovalbumin-induced rhinitis in guinea pigs. In CHO-K1/hERG cells, SUN-1334H did not modulate hERG K(+)-currents at concentrations as high as 100 micromol/L. Cardiovascular and CNS function and intestinal motility were not altered at doses several-fold greater than those required for efficacy, indicating a good safety profile of the drug.. SUN-1334H is a potent, orally active, highly selective H(1) receptor antagonist with a long duration of action in its preclinical profile. It has potential for the treatment of disorders involving histamine as a mediator.

Topics: Acetates; Animals; Bronchoconstriction; CHO Cells; Cricetinae; Cricetulus; Dogs; Electrocardiography; Female; Guinea Pigs; Heart Rate; Histamine H1 Antagonists; Male; Mice; Ovalbumin; Piperazines; Rats; Rats, Sprague-Dawley; Rhinitis

Epithelial cell-derived thymic stromal lymphopoietin (TSLP) is a master switch for asthma or atopic dermatitis by inducing a dendritic cell-mediated Th2-type allergic inflammation. Allergic rhinitis is also pathologically characterized by Th2-type allergic inflammation. This study demonstrates that mast cells regulate the epithelial TSLP expression in allergic rhinitis. TSLP expression was found to be up-regulated predominantly in the nasal epithelium in the ovalbumin (OVA)-sensitized and -nasally challenged mouse model of allergic rhinitis, which was abolished in mast cell-deficient WBB6F1-W/W(v) in comparison with control WBB6F1-+/+ mice. Similarly, the epithelial TSLP expression was reduced in Fc receptor gamma chain (FcgammaR)-deficient mice, where the high-affinity IgE receptor (FcepsilonRI) is not expressed on mast cells, in comparison with control C57BL/6 mice. Furthermore, the administration of neutralizing TSLP antibody during the challenge phase of OVA inhibited the development of allergic rhinitis. These results suggest that the direct stimulation of epithelial cells by antigens alone may not be sufficient to induce TSLP expression in the nasal epithelium, and that mast cell regulation of epithelial TSLP expression, possibly via FcepsilonRI, plays an important role in the development of allergic rhinitis.

Topics: Animals; Antibodies; Behavior, Animal; Cell Count; Cytokines; Disease Models, Animal; Epithelial Cells; Female; Goblet Cells; Mast Cells; Mice; Mice, Inbred C57BL; Mice, Knockout; Nasal Mucosa; Ovalbumin; Proto-Oncogene Proteins c-kit; Receptors, IgG; Respiratory Hypersensitivity; Rhinitis; Thymic Stromal Lymphopoietin

Allergic rhinitis (AR) is one of the most common chronic diseases. Although current medications are highly effective in controlling its symptoms, they do not reverse the allergen-specific hypersensitivities that underlie the disease. Immunoglobulin E is a key mediator of AR, and preventing its production is clinically important. In this study, we developed an efficient needleless intranasal protein delivery system using the hemagglutinating virus of Japan envelope vector (HVJ-E). Intranasal delivery of ovalbumin (OVA) once a week for 3 weeks using this system enhanced OVA-induced interferon-gamma production by murine splenocytes. This treatment also attenuated the OVA-induced release interleukin-4 (IL-4) and IL-5 from splenocytes and the production of plasma OVA-specific immunoglobulin E in OVA-sensitive AR model mice. Thus, allergen-containing HVJ-E may be useful for noninvasive treatment of AR.

Topics: Administration, Intranasal; Allergens; Animals; Cattle; Cytokines; Disease Models, Animal; Health; Immunoglobulin E; Interferon-gamma; Male; Mice; Mice, Inbred BALB C; Nasal Mucosa; Needles; Ovalbumin; Rhinitis; Sendai virus; Spleen; Th1 Cells; Th2 Cells; Time Factors

Although many studies regarding airway remodeling in asthma have been reported, only a few studies have investigated airway remodeling in allergic rhinitis.. To determine whether repetitive allergen challenge could induce airway remodeling in the nose and evaluate the effect of steroids using a murine model of allergic rhinitis.. To develop a mouse model of airway remodeling, ovalbumin-sensitized mice were repeatedly exposed to inhaled ovalbumin administration twice a week for 1 month and 3 months. Matched control mice were challenged with phosphate-buffered saline, and the treatment group received intraperitoneal dexamethasone injection. Trichrome, periodic acid-Schiff, hematoxylin-eosin, and immunohistochemical staining against matrix metalloproteinase 9 and tissue inhibitors of metalloproteinase 1 were performed to nasal and lung tissues, and the level of transforming growth factor beta in the nasal lavage fluid was analyzed.. Repetitive ovalbumin challenge for 3 months induced circumferential peribronchial fibrosis in the lung. In the nose, subepithelial fibrosis, increased matrix metalloproteinase 9 and tissue inhibitors of metalloproteinase 1 expression, goblet cell hyperplasia, and submucous gland hypertrophy were observed compared with the control group. Features of airway remodeling were more prominent in the lung tissue. Administration of dexamethasone significantly inhibited these histologic changes.. Airway remodeling associated with long-term allergen challenge can occur in the nasal mucosa and the lung. Steroid treatment prevents airway inflammation in response to acute allergen challenge, as well as airway remodeling by long-term allergen challenge.

Topics: Allergens; Animals; Anti-Inflammatory Agents; Dexamethasone; Fibrosis; Hypersensitivity; Immunohistochemistry; Lung; Matrix Metalloproteinase 9; Mice; Mice, Inbred BALB C; Nasal Mucosa; Ovalbumin; Rhinitis; Tissue Inhibitor of Metalloproteinase-1; Transforming Growth Factor beta

Nasal airway remodeling exists in allergic rhinitis, but it appears to be far less extensive than in asthma. However, there has been little study about nasal airway remodeling and no study using mice models. It has been reported that airway hyperresponsiveness decreased after prolonged allergen challenge in a chronic murine asthma model together with the progression of remodeling. However, there has been no study of the relation of remodeling and airway responsiveness in nasal allergy. Therefore, we have undertaken this investigation to characterize nasal airway structural changes after prolonged allergen challenge and to examine the relationship between nasal airway hyperresponsivity and remodeling.. We prepared murine allergic rhinitis for ovalbumin. Mice were subsequently challenged three times a week with ovalbumin from day 19 to days 53, 88, and 130. We examined allergen-induced nasal symptoms and objective nasal hyperresponsiveness using the enhanced pause system. Moreover, the pathologic changes were investigated after allergen challenge.. The extended allergen challenge protocol caused significant nasal airway remodeling. Specifically, remodeling was characterized by goblet cell hyperplasia and deposition of collagen in the submucosal area. Allergen-induced nasal hyperresponsiveness was first increased but gradually decreased in nasal symptoms and Penh after prolonged allergen challenge.. We have demonstrated that a remodeling of nasal mucosa in a murine allergic rhinitis model prolonged allergen exposure. Moreover, prolonged allergen exposure induced a reduction of nasal hyperresponsiveness together with a progression of nasal remodeling.

Topics: Adaptation, Physiological; Allergens; Analysis of Variance; Animals; Collagen; Goblet Cells; Male; Mice; Mice, Inbred BALB C; Nasal Mucosa; Ovalbumin; Rhinitis

Listeriolysin O (LLO) derived from Listeria monocytogenes is highly capable of inducing interleukin (IL)-12, IL-18 and interferon (IFN)-gamma, and facilitates the generation of Th1 cells. We have recently shown that recombinant LLO (rLLO) inhibits generation of ovalbumin (OVA)-specific Th2 immune response by skewing maturation of antigen-specific T cells into Th1 cells. In the present study, we investigated the effect of rLLO on the effector phase of Th2-dependent allergic rhinitis in BALB/c mice sensitized with OVA. In mice sensitized intraperitoneally and challenged intranasally with OVA, nasal allergic symptoms such as sneezing and nose-scratching were observed at a high frequency. A high titre of anti-OVA IgE antibody was detected in sera and a large number of eosinophils migrated into the nasal tissue. However, rLLO treatment during the intranasal challenge inhibited the allergic symptoms, production of anti-OVA IgE antibody and eosinophil infiltration. Though rLLO did not affect antigen-specific cytokine production from splenic CD4(+) T cells, rLLO significantly suppressed OVA-specific IL-4 and IL-5 production from nasal mononuclear cells. We further found that rLLO inhibited the recruitment of CD4(+) T cells in nasal mucosa, and diminished the transcription and cell surface expression of CCR4 on splenic CD4(+) T cells. Moreover, rLLO was able to inhibit the passive cutaneous anaphylaxis reaction mediated by anaphylactic antibodies (IgE and IgG(1)) and mast cells. Taken together, these data showed that rLLO suppresses the effector phase of allergic rhinitis by inhibition of Th2 cell recruitment to nasal mucosa and type I allergic reaction.

Topics: Animals; Bacterial Toxins; CD4-Positive T-Lymphocytes; Cytokines; Down-Regulation; Female; Heat-Shock Proteins; Hemolysin Proteins; Immunity, Mucosal; Interleukin-12; Listeria monocytogenes; Mice; Mice, Inbred BALB C; Nasal Mucosa; Ovalbumin; Passive Cutaneous Anaphylaxis; Receptors, CCR4; Receptors, Chemokine; Recombinant Proteins; Respiratory Hypersensitivity; Rhinitis; Th2 Cells

It has been suggested that airway bacterial infections exacerbate allergic disorders, and bacterial components in the air affect allergic inflammation via Toll-like receptors expressed on mast cells and dendritic cells in the airway mucosa.. Peptidoglycan (PGN) is a major component of the bacterial cell wall. We investigated the effect of PGN on the effector phase of allergic inflammation, in comparison with the effect of CpG-oligodeoxynucleotides (CpG), which is known to be a Th1 adjuvant.. Ovalbumin (OVA)-sensitized mice were challenged intranasally with OVA alone or OVA together with PGN or CpG. Nasal allergic symptoms and eosinophilia were scored, and the OVA-specific cytokine response was examined in the cells of cervical lymph nodes and nasal mucosa. Bone marrow-derived mast cells (BMMCs) and dendritic cells (BMDCs) were stimulated with PGN or CpG in vitro, and the expression level of cytokines and chemokines was examined by RT-PCR. In addition, the expression level of chemokines was examined by RT-PCR in mast cells of OVA-sensitized mice challenged with OVA alone or OVA together with PGN or CpG.. PGN exposure exacerbated the nasal allergic symptoms and eosinophilia, whereas CpG exposure suppressed them. In addition, PGN exposure increased the OVA-specific IL-4 response in the cells, whereas CpG exposure decreased it. On the other hand, there were no significant differences in the OVA-specific IFN-gamma response. PGN but not CpG induced the expression of thymus and activation-regulated chemokine (TARC) and macrophage/monocyte-derived chemokine (MDC) in both BMMCs and mast cells of mice sensitized and challenged with OVA. CpG but not PGN induced the expression of IFN-beta and interferon-inducible protein-10 (IP-10) in BMDCs, and histamine did not influence this effect.. These results demonstrate that PGN exposure exacerbates allergic inflammation mainly via mast cells, whereas CpG exposure suppresses allergic inflammation mainly via dendritic cells.

Topics: Animals; Antigens, Bacterial; Bone Marrow Cells; Dendritic Cells; Female; Interleukin-4; Lymphocyte Activation; Mast Cells; Mice; Mice, Inbred BALB C; Models, Animal; Ovalbumin; Peptidoglycan; Rhinitis; Th1 Cells; Th2 Cells; Toll-Like Receptor 2; Toll-Like Receptor 9

Jia Wei Cang Er Zi San, a traditional Chinese herbal formula, has been used to treat allergic rhinitis (AR) for several centuries. However, its effect on experimental animal models and its therapeutic mechanism remain unclear.. To study the effect of Shu-Bi-Lin, a modified Jia Wei Cang Er Zi San, on an animal model of AR.. Shu-Bi-Lin was administered to the guinea pig model of AR. Meanwhile, an antihistamine-treated group for the treatment control, an ovalbumin-sensitized and untreated group for the positive control, and a sham-sensitized, sham-challenged group for the sham control were studied in parallel. Symptomatic and some pathophysiologic variables were evaluated.. Sneezing and nasal scratching after challenges were significantly ameliorated in the Shu-Bi-Lin-treated group compared with the ovalbumin-sensitized and untreated group, but rhinorrhea volume was not reduced. Shu-Bi-Lin significantly suppressed the production of IgG1 in the passive cutaneous anaphylaxis test. The thromboxane B2 level in nasal lavage fluid was significantly deceased in the Shu-Bi-Lin-treated group; however, the reduction in histamine and peptide leukotriene levels did not reach statistical significance. In addition, eosinophil infiltration and endothelial nitric oxide synthase immunoreactivity in the nasal tissues were reduced in the Shu-Bi-Lin-treated group.. Shu-Bi-Lin could alleviate the nasal symptoms of AR, and its mechanism might be related to its inhibitory effect on type I anaphylaxis reactions and eosinophil infiltration in the nasal tissues, as well as the inhibition of some mediators related to AR.

Topics: Animals; Anti-Allergic Agents; Disease Models, Animal; Drugs, Chinese Herbal; Eosinophils; Guinea Pigs; Histamine; Histamine H1 Antagonists, Non-Sedating; Immunoglobulin E; Immunoglobulin G; Leukotrienes; Loratadine; Nasal Lavage Fluid; Nasal Mucosa; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Ovalbumin; Rhinitis; Sneezing; Thromboxane B2

This study was undertaken to investigate the involvement of cyclooxygenase-2 (COX-2) in allergic nasal inflammation in actively sensitized rats. An allergic rhinitis model was developed by the repeated topical application of antigen into the nasal cavities in the sensitized rats. The severity of allergic rhinitis was studied by measuring the nasal behavior, as well as electroencephalogram (EEG) activity by antigen challenge. The electrodes were implanted chronically into the bilateral olfactory bulb of the rats and the EEG was measured monopolarly with an electroencephalograph (EEG, Nohon Kohden, Japan). The intranasal application of antigen caused the increase of nasal allergic signs as well as an EEG spike in a dose-dependent fashion, and at a dose of 50 microg/site, it showed a significant effect. The responses induced by the antigen were evaluated with certain drugs, etodolac (a selective COX-2 inhibitor), indomethacin (a non-selective COX inhibitor), ramatroban (a thromboxane A2 receptor antagonist) and zafirlukast (a cys-leukotriene receptor antagonist). Etodolac showed the inhibition of nasal behavior and EEG spike in a dose-related fashion, and at doses of 3 and 10 mg/kg, it showed a significant effect. Moreover, ramatroban also caused the dose-related inhibition of nasal behavior and EEG spike induced by antigen. On the other hand, both indomethacin and zafirlukast had no effects on the responses induced by antigen, even at a higher dose. Therefore, it can be concluded that cyclooxygenase-2 actively participates in the allergic nasal inflammation in actively sensitized rats.

Topics: Animals; Carbazoles; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Disease Models, Animal; Electroencephalography; Etodolac; Hypersensitivity; Indoles; Indomethacin; Leukotriene Antagonists; Male; Olfactory Bulb; Ovalbumin; Phenylcarbamates; Rats; Rats, Wistar; Receptors, Thromboxane A2, Prostaglandin H2; Rhinitis; Sneezing; Sulfonamides; Tosyl Compounds

Eosinophil recruitment to the airways, including involvement of haemopoietic eosinophil-basophil progenitors (Eo/B-CFU), is primarily regulated by interleukin-5 (IL-5) and eotaxin. In this study, we investigated the haemopoietic mechanisms in upper and lower airway eosinophilic inflammation. Ovalbumin (OVA) sensitized and challenged BALB/c mice were used to establish isolated upper (UAC), isolated lower (LAC), or combined upper and lower airway (ULAC) inflammation. Airway, blood and bone marrow responses were evaluated in each model. Numbers of airway eosinophils and CD4(+) cells were increased significantly in the nasal mucosa in UAC and ULAC mice, and in the lung tissue in LAC and ULAC groups. Levels of IL-5 and eotaxin were increased significantly in the nasal lavage fluid (NL) in UAC and ULAC mice, and in the bronchoalveolar lavage fluid (BAL) in LAC and ULAC groups. The proportion of IL-5-responsive bone marrow Eo/B-CFU was significantly higher than the control in all treatment groups, but peaked much earlier in the ULAC group. Kinetic studies revealed that IL-5 and eotaxin in NL, BAL and serum peaked between 2 and 12 hr after OVA challenge in ULAC mice, and at 24 hr in UAC mice, related to the timing of maximal progenitor responses. These data support the concept that the systemic mechanisms linking rhinitis to asthma depend on the location and extent of airway allergen exposure.

Topics: Animals; Antigens, CD34; Asthma; Bronchoalveolar Lavage Fluid; Chemokine CCL11; Chemokines, CC; Disease Models, Animal; Eosinophils; Female; Hematopoiesis; Hematopoietic Stem Cells; Immunity, Mucosal; Interleukin-5; Leukocyte Count; Mice; Mice, Inbred BALB C; Nasal Lavage Fluid; Ovalbumin; Rhinitis

Allergic rhinitis is an inflammatory disease of the nasal mucosa, induced by histamine, leukotrienes, and other substances released from mast cells. Fexofenadine hydrochloride, the active metabolite of terfenadine, is a novel, nonsedating antiallergic drug having H1 receptor antagonistic activity. Fexofenadine is effective for the treatment of allergic rhinitis. However, its mechanism of action in attenuating nasal congestion has not yet been elucidated. Therefore, we first examined the effects of fexofenadine on a guinea pig model of antigen-induced rhinitis. We also evaluated the effects of mepyramine, zafirlukast and ramatroban in this model; these drugs are an H1 receptor antagonist, a selective leukotriene antagonist and a selective thromboxane antagonist, respectively. Rhinitis was induced by ovalbumin (OVA) instillation into the nasal cavity of animals that had been sensitized by two earlier OVA injections (s.c. and i.p.). The nasal airway resistance was measured for 45 min after the challenge. Fexofenadine hydrochloride (20 mg/kg) and terfenadine (20 mg/kg) administered orally 70 min prior to the challenge significantly inhibited (fexofenadine, p < 0.001, terfenadine, p < 0.05) the increase in nasal airway resistance. Ramatroban (30 mg/kg) administered orally 60 min prior to the challenge also significantly inhibited (p < 0.05) the increase in nasal airway resistance. In contrast, mepyramine (3 mg/kg i.v.) and zafirlukast (3 mg/kg p.o.) failed to reduce the increase in nasal airway resistance. These results suggest that thromboxane may be involved in the increase in the nasal airway resistance in this model. Accordingly, fexofenadine may reduce the increase in nasal airway resistance by inhibiting the release of chemical mediators, including thromboxane, that are involved in the increase in nasal airway resistance in this model.

Topics: Airway Resistance; Animals; Anti-Allergic Agents; Area Under Curve; Carbazoles; Disease Models, Animal; Guinea Pigs; Indoles; Leukotrienes; Male; Ovalbumin; Phenylcarbamates; Pyrilamine; Rhinitis; Sulfonamides; Terfenadine; Thromboxanes; Tosyl Compounds

To develop a physiologic test of nasal responsiveness in mice and to evaluate whether mice with acute bacterial sinusitis develop nasal hyperresponsiveness.. Several experimental studies will be described. The first was a titration pilot study. The second was a randomized, placebo-controlled study. The remainder were before-and-after trials. SPECIES: BALB/c or C57BL/6 mice.. For these experiments, we exposed mice to histamine intranasally, then counted the number of sneezes and nose rubs as the primary outcome measure of nasal responsiveness. First, we constructed a dose-response curve. Second, we treated the mice with desloratadine, a histamine 1 receptor antagonist, prior to histamine exposure. Third, we challenged, with intranasal histamine, mice made allergic using 2 techniques. Fourth, we infected mice with Streptococcus pneumoniae to determine whether acute sinusitis causes nasal hyperresponsiveness to histamine exposure.. Nasal histamine challenge led to a reproducible, dose-dependent increase in sneezing and nose rubs. The response to histamine exposure was blocked by desloratadine (P < or = .05). Allergic mice had a significant increase in responsiveness (P < or = .05) over baseline after exposure to antigen. Mice with acute sinusitis had a sustained increase in responsiveness, although less severe than after allergy, compared with baseline values that lasted 12 days after infection (P < or = .05).. Nasal challenge with histamine is a physiologic test of nasal responsiveness. The hyperresponsiveness of allergic mice to histamine exposure parallels the response to nonspecific stimuli during the human allergic reaction. In addition, we showed that acute bacterial sinusitis causes nasal hyperresponsiveness in mice.

Topics: Acute Disease; Animals; Dose-Response Relationship, Drug; Histamine; Histamine H1 Antagonists, Non-Sedating; Loratadine; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Nasal Mucosa; Ovalbumin; Rhinitis; Sinusitis; Stem Cells; Streptococcus pneumoniae

Listeriolysin O (LLO), a cholesterol-dependent cytolysin derived from Listeria monocytogenes, is a potent inducer of interleukin (IL)-12, IL-18 and interferon (IFN)-gamma. We have shown that LLO facilitates development of T cells mediating protective immunity against L. monocytogenes through the induction of IFN-gamma production at an early stage. Based on this finding, it is postulated that LLO inhibits differentiation of Th2 cells and the Th2 immune response. By using a murine model of ovalbumin (OVA)-induced allergic rhinitis, we investigated whether LLO has an ability to modulate the Th2-type immune disorder. In mice sensitized intraperitoneally with ovalbumin (OVA)/alum and challenged intranasally with OVA, a large number of eosinophils migrated into the nasal tissue, and high titres of anti-OVA IgE and IgG(1) antibodies were detected in sera. However, LLO treatment during sensitization markedly inhibited the eosinophil infiltration and production of these anti-OVA antibodies. A large number of T cells from mice sensitized and challenged with OVA produced high level of IL-4 and IL-5 but not IFN-gamma after stimulation with OVA. In contrast, OVA-specific IFN-gamma-producing T cells were preferentially induced in mice treated with LLO at the time of sensitization. In the absence of LLO administration, the expression level of GATA-3 and SOCS-3 in CD4(+) T cells was enhanced after sensitization with OVA. LLO treatment resulted in a reduction of GATA-3 and SOCS-3 expressions but induced the transcription of T-bet instead. Taken together, these data show clearly that LLO is capable of inhibiting Th2 immune response by skewing differentiation of antigen-specific T cells into Th1 cells.

Topics: Animals; Bacterial Toxins; Cell Differentiation; Epitopes, T-Lymphocyte; Female; GATA3 Transcription Factor; Gene Expression; Heat-Shock Proteins; Hemolysin Proteins; Interferon-gamma; Mice; Mice, Inbred BALB C; Ovalbumin; Recombinant Proteins; Rhinitis; RNA, Messenger; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; T-Box Domain Proteins; Th1 Cells; Th2 Cells; Transcription Factors

While effective for the prevention and treatment of allergic rhinitis (AR) symptoms, currently available medications do not reverse allergen specific hypersensitivities. Therefore, pharmacotherapeutics are not curative and their daily use is often required for years. These investigations were conducted to determine whether immunostimulatory sequence oligodeoxynucleotide (ISS-ODN) delivery protects previously sensitized mice from AR hypersensitivity responses and modulates their allergen specific immune profiles. Mice were first sensitized with ovalbumin (OVA) and alum, twenty-four hr before beginning a series of seven daily intranasal (i.n.) allergen challenges, subsets of mice received a single i.n. or intradermal (i.d.) dose of ISS-ODN or control oligodeoxynucleotide (C-ODN), a single intraperitoneal (i.p.) injection of dexamethasone (DXM), or no intervention. Mice receiving i.d. or i.n. ISS-ODN were found to have attenuated immediate and late phase effector cell responses to i.n. OVA challenge. Specifically, ISS-ODN treated mice had less histamine and cysteinyl leukotriene release and eosinophilic inflammation in their nasal passages than mice treated with C-ODN. In addition, splenocytes from ISS-ODN but not C-ODN treated mice displayed attenuated OVA-specific interleukin (IL)-4, IL-5, and IL-13 but increased interferon-gamma responses. Finally, ISS-ODN was generally a more effective treatment than DXM, both in blunting AR hypersensitivity responses and in shifting T helper 2 Th2-biased immune parameters towards Th1 dominance. As ISS-ODN delivery rapidly attenuated effector cell responses in this AR model in an allergen independent manner, the present results suggest that therapy with ISS-ODN alone may be an effective alternative to corticosteroid medications for the clinical management of AR.

Topics: Administration, Intranasal; Allergens; Animals; Bone Marrow Cells; Cytokines; Female; Macrophages; Mice; Mice, Inbred BALB C; Oligodeoxyribonucleotides; Ovalbumin; Respiratory Hypersensitivity; Rhinitis; Th2 Cells; Vaccines, DNA

Allergic rhinitis is a common cause of chronic cough. Topical corticosteroids are regarded as the most effective first-time treatment in allergic rhinitis. In this study we evaluated the cough sensitivity during the early and late allergic responses in guinea pigs with experimental allergic rhinitis. Another aim of the study was to follow up the effect of inhaled beclomethasone dipropionate on the cough in guinea pigs with allergic rhinitis. 31 guinea pigs were sensitized with ovalbumin (OA). Animals were intranasally challenged with OA (experiment) or saline (control) in 7-day intervals for 9 weeks. Cough was induced by inhalation of citric acid aerosols in gradually increasing concentrations for 30 s and was evaluated 1 h after the 8(th) nasal challenge (NCH) and 17 h after the 9(th) NCH. Cough was significantly increased only during an early allergic response, 1 h after repeated NCH [18 (14-23) vs. 8 (3-10); P<0.001]. Five experimental animals were inhaling aerosol of beclomethasone dipropionate seven days between the 8(th) and the 9(th) NCH and cough was evaluated 1 h after the 9(th) NCH. Inhaled corticosteroids significantly inhibited the enhanced allergic rhinitis related cough [4 (1-9) vs.19 (9-37) vs. 6 (3-9); P<0.05].

Topics: Administration, Inhalation; Aerosols; Animals; Anti-Inflammatory Agents; Beclomethasone; Bronchial Provocation Tests; Citric Acid; Cough; Guinea Pigs; Male; Ovalbumin; Rhinitis

Allergic rhinitis is a risk factor for the development of asthma. About 80% of asthmatic patients also have rhinitis. However, the pattern of induction of allergic rhinitis and asthma remains unclear.. The purpose of this study was to investigate the development of upper airway inflammation in mice during the development of an asthma-like disease and after an acute allergen provocation.. BALB-c mice were sensitized intraperitoneally (i.p) to ovalbumin (OA, days 1-13) and were challenged with aerosols of either OA or saline on 8 consecutive days (days 33-40). In a second experiment, chronic exposure for 8 days was followed by 10 days of rest and then an acute nebulized allergen provocation was performed (day 50). Inflammatory parameters were investigated at different time-points.. Upper and lower eosinophilic airway inflammation were simultaneously induced in the course of repeated inhalations of nebulized OA, as shown by analyses of nasal and broncho-alveolar lavage fluids and histological sections of the nose and bronchi. Mice that developed bronchial hyper-responsiveness also had increased thickness of the nasal mucosa on magnetic resonance image (MRI) scans. When chronic exposure was followed by acute allergen provocation, the latter caused a systemic increase in IL-5 levels, with a concomitant rise in blood and airway eosinophils, primarily in the nose.. Simultaneous induction of eosinophilic inflammation in the nose and lungs was found in a mouse model of respiratory allergy. These findings support the viewpoint that upper and lower airway disease represent a continuum of inflammation involving one common airway and provide evidence for the concept of global airway inflammation after inhalation of allergen.

Topics: Aerosols; Allergens; Animals; Antibody Specificity; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Eosinophilia; Eosinophils; Follow-Up Studies; Immunization; Immunoglobulin E; Inhalation Exposure; Interleukin-5; Leukocyte Count; Lymphocyte Count; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred BALB C; Nasal Lavage Fluid; Nasal Mucosa; Ovalbumin; Pilot Projects; Pneumonia; Radiography; Rhinitis

The role of inflammatory effector cells in the pathogenesis of airway allergy has been the subject of much investigation. However, whether systemic factors are involved in the development of local responses in both upper and lower airways has not been fully clarified. The present study was performed to investigate aspects of the pathogenesis of isolated allergic rhinitis in a murine model sensitized to ovalbumin (OVA). Both upper- and lower-airway physiological responsiveness and inflammatory changes were assessed, as well as bone marrow progenitor responses, by culture and immunohistological methods. Significant nasal symptoms and hyper-responsiveness appeared after intranasal OVA challenge (P < 0.0001 and P < 0.01, respectively), accompanied with significant nasal mucosal changes in CD4+ cells (P < 0.001), interleukin (IL)-4+ cells (P < 0.01), IL-5+ cells (P < 0.01), basophilic cells (P < 0.02) and eosinophils (P < 0.001), in the complete absence of hyper-responsiveness or inflammatory changes in the lower airway. In the bone marrow, there were significant increases in CD34+ cells, as well as in eosinophils and basophilic cells. In the presence in vitro of mouse recombinant IL-5, IL-3 or granulocyte-macrophage colony-stimulating factor (GM-CSF), the level of bone marrow eosinophil/basophil (Eo/Baso) colony-forming cells increased significantly in the OVA-sensitized group. We conclude that, in this murine model of allergic rhinitis, haemopoietic progenitors are upregulated, which is consistent with the involvement of bone marrow in the pathogenesis of nasal mucosal inflammation. Both local and systemic events, initiated in response to allergen provocation, may be required for the pathogenesis of allergic rhinitis. Understanding these events and their regulation could provide new therapeutic targets for rhinitis and asthma.

Topics: Allergens; Animals; Basophils; Bone Marrow Cells; Cell Culture Techniques; Eosinophils; Female; Hematopoietic Stem Cells; Immunoglobulin E; Leukocyte Count; Male; Mice; Mice, Inbred BALB C; Nasal Mucosa; Ovalbumin; Rhinitis; Trypan Blue

The production of immunoglobulin E (IgE) antibody is largely dependent on the ratio between interleukin-4 (IL-4) (a T helper 2 (Th2)-type cytokine) and interferon-gamma (IFN-gamma) (a T helper 1 (Th1)-type cytokine). Interleukin-5 (IL-5) (also a Th2-type cytokine) is an important eosinophil differentiation factor and also co-stimulates B-cell growth and differentiation. The present study was designed to evaluate and compare the expression of IFN-gamma, IL-4 and IL-5 mRNA in the nasal mucosal membrane of sensitized Brown-Norway (BN) rats. Fourteen BN rats were divided into two groups: non-sensitized (control) and sensitized. The sensitized group was injected with ovalbumin (OA) intraperitoneally on three consecutive days. Twenty-one days later, rats were exposed to 1% OA aerosol. Twenty-four hours after exposure to aerosol, nasal mucosa was extracted from both groups and reverse transcriptase-polymerase chain reaction (RT-PCR) was performed. The densities of the bands of IL-4, IL-5 and IFN-gamma mRNA were expressed as percentages against beta-actin mRNA. Our results showed that the mean values for IL-4 and IL-5 mRNA were increased significantly in sensitized rats compared with control rats. In contrast, the mean value for IFN-gamma mRNA was significantly lower in sensitized rats compared with those of the control group. Our data therefore suggest that sensitization of rat nasal mucous membranes results in the predominant expression of Th2-type cytokines.

Topics: Airway Resistance; Animals; Azo Compounds; Blotting, Southern; Coloring Agents; Enzyme-Linked Immunosorbent Assay; Gene Expression; Histamine; Immunoglobulin E; Interferon-gamma; Interleukin-4; Interleukin-5; Male; Nasal Mucosa; Nasal Obstruction; Ovalbumin; Polymerase Chain Reaction; Rats; Rats, Inbred BN; Rhinitis; RNA, Messenger; Trypan Blue

To elucidate the mechanism of immunotherapy, we tested the effect of ovalbumin and ovalbumin-pullulan conjugate immunotherapy on the expression of interleukin (IL)-4, IL-5 and interferon-gamma (IFN-gamma) mRNA in the nasal mucosa of sensitized rats. Forty-five rats were injected with ovalbumin intraperitoneally on three consecutive days and later were exposed to ovalbumin aerosol. The rats were injected intradermally, on six consecutive days, with saline, ovalbumin or ovalbumin-pullulan conjugate. Later, nasal mucosa was obtained and reverse transcription-polymerase chain reaction (RT-PCR) was performed. Nasal responses and specific immunoglobulin E (IgE) were measured. Although the immunotherapy significantly decreased nasal airway resistance, dye leakage and histamine content in nasal irrigation after allergen challenge, no significant difference was found in IL-4 and IL-5 mRNA expression or in specific IgE level among the three groups. We conclude that in this allergic model, the improvement of nasal responses after immunotherapy was the result of a mechanism other than decrease of T-helper 2 (Th2) cytokines.

Topics: Airway Resistance; Allergens; Animals; Blotting, Southern; Enzyme-Linked Immunosorbent Assay; Gene Expression; Histamine; Immunoglobulin E; Immunotherapy; Interferon-gamma; Interleukin-4; Interleukin-5; Male; Nasal Mucosa; Ovalbumin; Polymerase Chain Reaction; Rats; Rats, Inbred BN; Rhinitis; RNA, Messenger

The aim of this study was to examine the pathophysiological role of capsaicin-sensitive sensory nerves in an animal model of nasal allergy. In ovalbumin (OA)-sensitized guinea pigs, a significant increase in nasal total airway resistance (TAR) was noted for at least 180 min after topical antigen challenge. The TAR response to antigen challenge was significantly inhibited for 120 min by general capsaicin pretreatment (167 +/- 12.1 vs. 113 +/- 5.0%, p < 0.001, and 186 +/- 14.9 vs. 119 +/- 6.6%, p < 0.001, control vs. capsaicin pretreatment group at 20 and 90 min after challenge, respectively). However, TAR was significantly though slightly affected even after general capsaicin pretreatment. Following nasal capsaicin challenge, TAR increased for 90 min, and nasal secretion for 30 min. Both the TAR and secretory responses to nasal capsaicin challenge were significantly greater in OA-sensitized guinea pigs than in nonsensitized animals (171 +/- 12.1 vs. 137 +/- 7.4% at 30 min, p < 0.05, and 82.3 +/- 8.6 vs. 13.4 +/- 1.7 mg/10 min, p < 0.05, TAR and secretory response to 300 microM nasal capsaicin challenge, respectively). These results suggest that capsaicin-sensitive sensory nerve reflexes play an important role in the occurrence of early-phase nasal symptoms following topical antigen exposure and are accelerated in OA-sensitized guinea pigs.

Topics: Airway Resistance; Animals; Capsaicin; Disease Models, Animal; Guinea Pigs; Immunization; Male; Nasal Mucosa; Neurons, Afferent; Nose; Ovalbumin; Reflex; Rhinitis

Dermatophagoides farinae-, ovalbumin- and lactalbumin-specific IgG, IgG1, IgG4, IgA and IgM were evaluated in 161 healthy children [Group 1], 84 children with bronchial asthma and/or allergic rhinitis but without atopic dermatitis [Group 2], and 54 children with atopic dermatitis but without bronchial asthma and allergic rhinitis [Group 3]. We also studied D. farinae-, egg-white-, and milk-specific IgE of children with allergic diseases. D. farinae-specific IgG, IgG1, IgG4 and IgA in Groups 2 and 3 increased until 5 years of age and thereafter they remained constant. After 2 years of age, D. farinae-specific IgG, IgG1, IgG4 and IgA in Group 2 were higher than those in Groups 1 and 3. Ovalbumin- and lactalbumin-specific IgG, IgG1, IgG4 and IgA in Groups 2 and 3 increased until 1 year of age and thereafter decreased. Until 1 year of age, ovalbumin- and lactalbumin-specific IgG, IgG1 and IgG4 in Groups 3 were higher than those in Groups 1 and 2. D. farinae-, ovalbumin- and lactalbumin-specific IgM were constant in all ages of all groups. These results suggest that atopic dermatitis in young children is related to food-specific immunoglobulins and that respiratory allergic diseases in older children is related to D. farinae-specific immunoglobulins.

Topics: Adolescent; Age Factors; Allergens; Antigens, Dermatophagoides; Asthma; Child; Child, Preschool; Dermatitis, Atopic; Enzyme-Linked Immunosorbent Assay; Humans; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Immunoglobulins; Infant; Lactalbumin; Ovalbumin; Rhinitis