ovalbumin and Rhinitis--Allergic--Perennial

In this study, we investigated the effects of Naju Jjok (Polygonum tinctorium Lour., NJJ) on interleukin (IL)-32 and thymic stromal lymphopoietin (TSLP) levels associated with allergic rhinitis (AR). Using female BALB/c mice, we created an animal model of ovalbumin (OVA)-induced AR. Prior to the callenge with OVA, the mice were administered, either nasally or orally with NJJ. In addition, we also used the eosinophilic cells line, Eol-1, stimulated with granulocyte‑macrophage colony-stimulation factor (GM-CSF). The mRNA and protein levels of inflammatory cytokines and markers [interleukin (IL)-32, IL-4, macrophage-inflammatory protein-2 (MIP-2), intercellular adhesion molecule-1 (ICAM-1), and cyclooxygenase-2 (COX-2)] were measured by RT-PCR and western blot analysis, respectively and serum levels were measured by ELISA. The increased levels of IL-32 in the mice with AR and in the stimulated eosinophilic cell line, Eol-1, were significantly reduced by NJJ. TSLP levels were also decreased following the oral administration of NJJ. Mice orally administered NJJ showed markedly alleviated clinical symptoms, such as a reduced number of nasal rubs, decreased spleen weight, decreased serum immunoglobulin E (IgE) levels and decreased serum histamine levels. The oral administration of NJJ significantly decreased the IL-4 levels, while increasing the interferon-γ levels in the spleen. The increased number of eosinophils and mast cells infiltrating the nasal mucosal tissue of the mice with AR were decreased following the oral administration of NJJ. NJJ effectively attenuated caspase-1 activity in the mice with AR and in the stimulated Eol-1 cells. The oral administration of NJJ significantly reduced the levels of inflammatory markers, such as MIP-2, ICAM-1 and COX-2. Furthermore, the intranasal administration of NJJ significantly reduced the early phase response to allergen exposure, such as nasal rubs, IgE production and histamine release, as well as the late phase responses, such as the expression of inflammatory markers. In conclusion, these data demonstrate that NJJ may play a regulatory role in nasal inflammation.

Topics: Administration, Oral; Animals; Caspase 1; Cell Line; Chemokine CXCL2; Cyclooxygenase 2; Cytokines; Disease Models, Animal; Eosinophils; Female; Histamine; Humans; Immunoglobulin E; Intercellular Adhesion Molecule-1; Interferon-gamma; Interleukins; Mast Cells; Mice; Mice, Inbred BALB C; Ovalbumin; Plant Extracts; Polygonum; Rhinitis, Allergic; Rhinitis, Allergic, Perennial; Spleen; Thymic Stromal Lymphopoietin

Almost a quarter of the world population suffers from IgE-mediated allergies. T cells and IgG-producing B cells can produce protection, but treatment for disease is laborious with unsatisfactory patient compliance.. We sought to identify whether paediatric allergy vaccines affected later allergen sensitization and onset of disease when used prophylactically.. A murine model of anaphylaxis was applied. Mice were first immunized with monovalent or multivalent allergy vaccines that also contained aluminium hydroxide and CpG oligodeoxynucleotide as adjuvants. Later, the mice were sensitized by multiple low-dose injections of aluminium-adsorbed allergen. After a dormant period, the mice were challenged systemically with high-dose allergen, and the clinical signs of anaphylaxis were recorded. Throughout the immunization and sensitization periods, blood was collected for serological testing.. Immunization with allergy vaccines produced antigen-specific protection against sensitization as measured by systemic anaphylaxis in mice. The long-term effect was observed both after juvenile (5-6 weeks) and neonatal (7 days) vaccination. Monovalent and pentavalent vaccines were protective to a similar level. Protection was associated with increased secretion of IgG2a and production of IFN-γ. Protection could also be transferred to sensitized mice via serum or via CD25-positive CD4 T cells.. Prophylactic and multivalent allergy vaccines in juvenile and neonatal mice protected against later sensitization and anaphylaxis. Such treatment may provide a rational measure for future management of allergen-related diseases and their strong socio-economic impact on daily life.

Topics: Adoptive Transfer; Allergens; Anaphylaxis; Animals; Cross Protection; Disease Models, Animal; Female; Humans; Immunization Schedule; Immunoglobulin E; Immunoglobulin G; Mice; Ovalbumin; Rhinitis, Allergic; Rhinitis, Allergic, Perennial; Vaccines

Anticholinergic drugs or vidian neurectomy can alleviate the symptoms of allergic rhinitis.. To show that inhibition of the cholinergic nerve influences the balance of T-helper type 1 and 2 cells in allergic rhinitis mice.. Twenty-four mice were randomly allocated to 1 of 4 groups: control, model, model with ipratropium bromide treatment, and model with 6-hydroxydopamine treatment. Allergic model-treated mice were sensitized with ovalbumin. Evaluation of allergic symptoms was recorded according to a symptom score. Ovalbumin serum IgE was measured by enzyme-linked immunosorbent assay. Expression of interleukin-4, interferon-γ, forkhead box P3, substance P, and vasoactive intestinal peptides was detected by immunohistochemistry and imaging analysis.. Symptoms in allergic mice were significantly alleviated by ipratropium bromide. Ovalbumin serum IgE and eosinophils of nasal mucosa were significantly decreased. Interleukin-4 expression level was significantly higher in the allergic model group than in the control group and significantly decreased by ipratropium bromide (P < .05). In contrast, the expression of forkhead box P3 was lower in the allergic model group than in the control group and increased with treatment by ipratropium bromide (P < .05). Conversely, interferon-γ expression was not changed by anticholinergic treatment in the nasal mucosa of allergic mice. Expression of substance P and vasoactive intestinal peptide was significantly increased in allergic mice and decreased by ipratropium bromide. Sympathetic denervation did not change the expression of interleukin-4, interferon-γ, forkhead box P3, substance P, and vasoactive intestinal peptide.. inhibition of the cholinergic nerve not only alleviated symptoms of allergic rhinitis by inhibiting the impulse of the parasympathetic nerve but also modulated the T-helper type 2-predominant immune reaction, expression of neuropeptides, and related inflammation factors.

Topics: Adrenergic Agents; Animals; Cholinergic Antagonists; Cholinergic Neurons; Disease Models, Animal; Eosinophils; Female; Forkhead Transcription Factors; Gene Expression; Immunoglobulin E; Interferon-gamma; Interleukin-4; Ipratropium; Mice; Mice, Inbred BALB C; Nasal Mucosa; Ovalbumin; Oxidopamine; Parasympathetic Nervous System; Rhinitis, Allergic; Rhinitis, Allergic, Perennial; Substance P; Th1 Cells; Th1-Th2 Balance; Th2 Cells; Vasoactive Intestinal Peptide

Diabetes is known to be regulated by cytokines secreted from Th1 cells, while allergic rhinitis (AR) is mainly regulated by Th2 cytokines. In recent past we have reported the development of diabetes in response to parthinium induced AR to rats. These results were contradictory to Th1/Th2 paradigm which suggests that Th1 and Th2 cells reciprocally counteract each other. Subsequently in silico interactome analysis further revealed that Th2 cytokines may signal to increase the level of Th1 along with the proteins involved in the development of diabetes. In present study we tried to understand the diabetogenic changes on the background of ovalbumin induced allergic rhinitis (OVA). Three groups of seven rats were considered; group I control (Ctrl); group II OVA and group III OVA+L-cetrizine (OVA+ D). The study continued for 48 days and the experiment was terminated on day 49, while L-cetrizine was administered for last 07 days (42-48 days). Group II showed increased levels of Th1 (IL-2) and Th2 cytokines, induction of allergic rhinitis and changes in the proteins involved in diabetes. In group III, most of the changes were reverted back towards normalcy. Induction of allergic rhinitis triggers Th2 cytokines that result increase IL-2 (Th1) and alterations in the metabolic parameters led to the condition of prediabetes.

Topics: Animals; Cells, Cultured; Cytokines; Humans; Inflammation Mediators; Male; Ovalbumin; Prediabetic State; Rats; Rats, Wistar; Rhinitis, Allergic, Perennial; Th1 Cells; Th1-Th2 Balance; Th2 Cells

KOB03 is a polyherbal medicine derived from an oriental prescription traditionally used to treat allergic diseases. In the present study, we compared the efficacy of KOB03 with modern drugs such as ketotifen and montelukast in an experimental mouse model of allergic rhinitis (AR). Ketotifen is a H1 receptor antagonist and montelukast is a leukotriene receptor antagonist. Mice were treated with KOB03, ketotifen or montelukast in an established AR mouse model using ovalbumin (OVA)-sensitized/challenged BALB/c mice. The treatment of KOB03 had inhibitory effects on symptom scores, serum levels of OVA-specific IgE, histamine, leukotriene C4, IL-4, TNF-α, and IL-1β in AR mice, and the histolopathological changes of nasal mucosa with mucin release and inflammation. AR mice treated with KOB03 had significantly lower serum levels of OVA-specific IgE, LTC4, IL-4, and IL-1β than mice treated with ketotifen, whereas they only had significantly lower serum levels of OVA-specific IgE and IL-4 than those treated with montelukast. In addition, the histolopathological changes of nasal mucosa with eosinophil infiltration were significantly lower in the KOB03-treated mice than those in the ketotifen and montelukast-treated group. These results suggest that KOB03 has therapeutic potential for treating AR like other modern medicines.

Topics: Acetates; Animals; Anti-Allergic Agents; Antigens; Cyclopropanes; Cytokines; Disease Models, Animal; Histamine H1 Antagonists; Immunoglobulin E; Ketotifen; Leukotriene Antagonists; Leukotriene C4; Male; Mice; Mice, Inbred BALB C; Nasal Mucosa; Ovalbumin; Plant Extracts; Quinolines; Rhinitis, Allergic; Rhinitis, Allergic, Perennial; Sulfides

In the present experiments, the possible role of curcumin in ovalbumin induced allergic rhinitis in guinea pig model was investigated. Various allergic rhinitis symptoms viz sneezing, rubbing frequencies, lacrimation and nasal congestion at various humidity conditions as well as on repeated sensitization were studied. The biochemical changes like serum IgE, IL-4 and nitric oxide (NO) in nasal lavage and eosinophil peroxidase activity in nasal homogenates were determined in allergic rhinitis. Curcumin treatment significantly reduced the symptoms (sneezing, rubbing frequencies, lacrimation and nasal congestion) and improved the histopathological alterations (reduction in inflammatory cells infiltration) of nasal mucosa in allergic rhinitis. Furthermore, curcumin treatment prevented significantly elevation of serum IgE, IL-4, NO in nasal lavage and eosinophil peroxidase in nasal homogenate. In the present experimental findings, we suggest that curcumin is a promising anti-allergic agent that may be useful in the clinical management of allergic rhinitis.

Topics: Acetates; Animals; Cromolyn Sodium; Curcumin; Cyclopropanes; Dose-Response Relationship, Drug; Eosinophil Peroxidase; Female; Gene Expression Regulation; Guinea Pigs; Humidity; Interleukin-4; Male; Nitric Oxide; Ovalbumin; Quinolines; Rhinitis, Allergic; Rhinitis, Allergic, Perennial; Sulfides

Recent epidemiological studies have suggested a positive link between atopy morbidity and exposure to phthalate esters, which are environmental chemicals mainly involved in house dust. Nevertheless, experimental studies applying several allergic in vivo models (in addition to epidemiological studies) are needed to prove the precise correlation between phthalates and facilitation of the allergic response/pathophysiology. Among the phthalate esters, di-(2-ethylhexyl) phthalate (DEHP) has been widely used in flexible polyvinyl chloride products, including vinyl flooring and wall covering, and has been widely suggested to have immunomodulating potential. In the present study, we examined the effects of airway exposure to DEHP on allergen (ovalbumin: OVA)-induced rhinitis in mice. The repeated administration of OVA via an intranasal route induced nasal inflammation characterized by the infiltration of granulocytes (neutrophils and eosinophils) into the nasal cavity. In this experimental setting, DEHP did not exaggerate OVA-related inflammatory pathology. However, local (nasal) IL-13 levels were significantly higher in mice treated with allergen plus DEHP than with allergen alone. Taken together, phthalate esters including DEHP have the potential to exacerbate the allergic milieu in the nasal system, as well as dermal and respiratory systems.

Topics: Air Pollutants; Animals; Cytokines; Diethylhexyl Phthalate; Female; Inhalation Exposure; Leukocyte Count; Mice; Mice, Inbred BALB C; Nasal Cavity; Nasal Lavage Fluid; Neutrophil Infiltration; Neutrophils; Ovalbumin; Rhinitis, Allergic; Rhinitis, Allergic, Perennial

Immunoglobulin E (IgE) is important for the development of allergic rhinitis (AR), though the contribution of IgE to the infiltration of eosinophils in the nasal mucosa has not been fully elucidated. In this study, antigen-induced sneezing and nasal eosinophil accumulation were comparatively investigated in anti-ovalbumin (OVA)-IgE transgenic (Tg) and wild-type (WT) mice.. Tg and OVA-immunized WT mice were intranasally challenged with OVA. Antigen-specific serum IgE level, sneezing and infiltration of eosinophil into the nasal cavity were then examined.. The level of serum OVA-specific IgE in Tg mice was significantly higher than that in antigen-immunized WT mice. Compared to saline challenge, intranasal challenge with OVA significantly induced sneezing in both Tg and immunized WT mice. However, antigen-induced nasal eosinophil infiltration was observed in immunized WT mice but not in Tg mice.. IgE-mediated responses might not play a crucial role in antigen-induced eosinophil infiltration in AR.

Topics: Animals; Antigens; Eosinophils; Female; Hypersensitivity; Immunoglobulin E; Mice; Mice, Transgenic; Nasal Mucosa; Ovalbumin; Rhinitis, Allergic, Perennial

Allergen-specific immunotherapy (ASIT) the only disease-modifying treatment for IgE-mediated allergies is characterized with long treatment duration and high risk of side effects. We investigated the safety, immunogenicity and efficacy of a novel ASIT, called DermAll, in an experimental allergic rhinitis model. We designed and characterized DermAll-OVA, a synthetic plasmid pDNA/PEIm nanomedicine expressing ovalbumin (OVA) as model allergen. DermAll-OVA was administered topically with DermaPrep device to target Langerhans cells. To detect the clinical efficacy of DermAll ASIT we quantified the nasal symptoms and characterized the immunomodulatory activity of DermAll ASIT by measuring cytokine secretion after OVA-stimulation of splenocytes and antibodies from the sera. In allergic mice DermAll ASIT was as safe as Placebo, balanced the allergen-induced pathogenic TH2-polarized immune responses, and decreased the clinical symptoms by 52% [32%, 70%] compared to Placebo. These studies suggest that DermAll ASIT is safe and should significantly improve the immunopathology and symptoms of allergic diseases.. A novel allergen-specific immunotherapy for IgE-mediated allergies is presented in this paper, using an experimental allergic rhinitis model and a synthetic plasmid pDNA/PEIm nanomedicine expressing ovalbumin as model allergen. Over 50% reduction of symptoms was found as the immune system's balance was favorably altered toward more TH2-polarized immune responses.

Topics: Administration, Topical; Allergens; Animals; Cytokines; Female; Immunization; Immunoglobulin E; Langerhans Cells; Mice; Mice, Inbred BALB C; Nanomedicine; Ovalbumin; Plasmids; Rhinitis, Allergic; Rhinitis, Allergic, Perennial; Th2 Cells; Vaccines, DNA

To investigate the method of development of allergic airway disease model in mice.. Ten BALB/c mice were devided into the model group and the control group. Each group contained 5 mice. Ovalbumin (OVA) was used as allergen. OVA was emulsified with aluminum hydroxide and injected intraperitoneally for sensitization. Afterwards the mice from model group were challenged with aerosolized 5% OVA and subsequently instilled with OVA intranasally. For the blank control group the mice were sensitized and challenged with phosphate buffer saline (PBS). After final challenge, the nasal symptoms were scored, and mice were sacrificed for evaluation of eosinophilia of nasal septum, peribronchial inflammation and goblet cell hyperplasia. Mice serum was collected for measurement of OVA-specific IgE concentration, and levels of IL-4 and IL-5 from bronchoalveolar fluids were also tested.. Compared with blank control mice, mice from model group displayed typical sneezing and nasal scratching symptoms. The histopathological changes, such as eosinophilia of nasal septum mucosa, infiltration of peribronchial inflammatory cells and hyperplasia of goblet cells were successfully induced by OVA sensitization and challenge. Moreover, mice in model group showed higher level of OVA-specific IgE in serum and IL-4 and IL-5 cytokines in bronchoalveolar fluids[mice from model group: IgE (1237.00 ± 153.20) pg/ml, IL-4 (46.50 ± 10.15) pg/ml, IL-5 (50.81 ± 11.41) pg/ml; mice from control group: IgE (191.90 ± 43.20) pg/ml, IL-4 (7.96 ± 1.80) pg/ml, IL-5 (7.53 ± 2.23) pg/ml;t value were 6.569, 3.738 and 3.724, respectively, all P < 0.05].. The method using OVA as allergen could effectively develop a mouse model of allergic airway disease which could be used for pathogenesis study and drug effect evaluation.

Topics: Allergens; Animals; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Eosinophilia; Immunoglobulin E; Interleukin-4; Interleukin-5; Mice; Mice, Inbred BALB C; Ovalbumin; Rhinitis, Allergic; Rhinitis, Allergic, Perennial

Interleukin-23 (IL-23) and IL-17 may be involved in the pathogenesis of allergic rhinitis (AR). However, a differentiation of the role of IL-23 and IL-17 has not been performed yet.. The aim of this study was therefore to investigate the immunomodulatory effects of IL-23 and IL-17, using a mouse model of AR.. Anti-IL-23p19 and anti-IL-17 Abs were administrated intranasally during rechallenge in ovalbumin (OVA)-induced AR in BALB/c mice. Immunomodulatory effects were evaluated by measuring nasal rubbing and sneezing occurrences, serum OVA-specific antibodies, Th2 responses (i.e. expression of IL-4, IL-5, IL-13 and IFN-γ genes in nasal mucosa, IL-4(+) CD4(+) T cells percentages in superficial cervical lymph nodes (LNs) and IL-4 production in LNs stimulated with OVA in vitro), and neutrophil, eosinophil and mast cell recruitment into the nasal mucosa.. The effect of IL-17 antagonism was limited to attenuating the Th2 responses and neutrophil and eosinophil infiltration. In contrast, treatment with anti-IL-23p19 Abs markedly reduced nasal rubbing and sneezing events, Th2 responses, serum OVA-specific IgE and IgG1 levels, as well as mucosal neutrophil, eosinophil and mast cell infiltration.. IL-17 and IL-23 may play a pathogenic role in an established AR mouse model; with a more pronounced contribution of IL-23 than IL-17.

Topics: Animals; Antibodies, Monoclonal; Disease Models, Animal; Immunoglobulin E; Immunoglobulin G; Immunologic Factors; Immunomodulation; Interleukin-17; Interleukin-23; Interleukin-23 Subunit p19; Male; Mast Cells; Mice; Neutrophil Infiltration; Neutrophils; Ovalbumin; Rhinitis, Allergic; Rhinitis, Allergic, Perennial; Th2 Cells

This study is aimed at exploring the role of neurokinin-1 receptor (NK-1R) in the development of allergic rhinitis (AR) in rats.. Sprague-Dawley rats were sensitized and challenged with ovalbumin to induce AR. The rats were treated intranasally with saline, control, or NK-1R-specific small interfering RNA (siRNA) before and during the challenge period. The numbers of sneezes and nose rubs and amount of nasal secretion in individual rats were measured. The levels of NK-1R expression in the nasal mucosal tissues after the last challenge were determined. The numbers of eosinophils in the collected nasal lavage fluid and the levels of serum interleukin (IL)-5 in individual rats were determined.. The levels of NK-1R expression in the nasal mucosal tissues of the AR rats that had been treated with saline or control siRNA were significantly higher than those in the healthy controls and the rats treated with NK-1R-specific siRNA, demonstrating NK-1R silencing. Furthermore, knockdown of NK-1R expression significantly reduced the amounts of sneezing, nose rubbing, and nasal secretions in AR rats. Knockdown of NK-1R expression also significantly eliminated eosinophil infiltration in the nasal tissues and reduced the levels of serum IL-5 in rats.. Knockdown of NK-1R expression decreased allergic inflammation in nasal mucosal tissues and alleviated the allergic rhinitis symptoms, suggesting that NK-1R may be a critical mediator of the development of AR.

Topics: Allergens; Animals; Eosinophils; Gene Knockdown Techniques; Interleukin-5; Leukocyte Count; Male; Nasal Lavage Fluid; Ovalbumin; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-1; Rhinitis, Allergic; Rhinitis, Allergic, Perennial; RNA, Small Interfering

We describe a method for allergic rhinitis (AR) induction in mice. Methodology involves nasal infusions of small volumes of ovalbumin for both initial sensitization and challenges. The latter are frequent and carried out over several weeks. This methodology more closely resembles natural AR induction than does the common use of systemic sensitization, often with adjuvants, followed by nasal challenges with relatively large allergen volumes. Also described are methodologies for collection of cardiac blood and perfusion for preparation of histological samples, both essential in verifying AR induction in individual animals.

Topics: Allergens; Animals; Disease Models, Animal; Mice; Nasal Mucosa; Ovalbumin; Rhinitis, Allergic; Rhinitis, Allergic, Perennial

Kaempferol (KP) is a major compound of Naju Jjok (Polygonum tinctorium Lour.). The effect of KP on allergic rhinitis (AR) has not been elucidated. Here, we report the effects and mechanisms of KP on new and predominant mediators of AR using an eosinophil cell line, Eol-1 and an ovalbumin (OVA)-induced AR mouse model. KP significantly inhibited the production of interleukin (IL)-32 and IL-8 and activation of caspase-1 in Eol-1 cells. Allergic symptoms and predominant mediators (IgE and histamine) in the KP-administered group were significantly lower than in the AR group. The levels of interferon-γ were enhanced while the levels of IL-4 were reduced in the KP group. KP significantly reduced the levels of IL-32 and thymic stromal lymphopoietin (TSLP) compared with the AR mice. KP reduced the levels of inflammation-related proteins. In the KP-administered groups, the infiltrations of eosinophils and mast cells increased by OVA were decreased. In addition, KP significantly reduced caspase-1 activity in nasal mucosa tissue of AR mice. Our findings indicate that KP has an anti-allergic effect through the regulation of the production of IL-32 and TSLP and caspase-1 activity in allergic diseases including AR.

Topics: Animals; Anti-Allergic Agents; Caspase 1; Cell Line; Cytokines; Disease Models, Animal; Enzyme Activation; Eosinophils; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Histamine; Humans; Immunoglobulin E; Interleukin-4; Interleukin-8; Interleukins; Kaempferols; Mast Cells; Mice; Mice, Inbred BALB C; Organ Size; Ovalbumin; Rhinitis, Allergic; Rhinitis, Allergic, Perennial; Spleen; Thymic Stromal Lymphopoietin

Lactoferrin (LF) can downregulate allergic airway inflammation in asthma. However, the in vivo effect of exogenous LF on allergic rhinitis (AR), a disease attributed to airway inflammation, has yet to be determined. We investigated the effect of intranasal administration recombinant human (rh) LF and its underlying mechanisms on AR in BALB/c mice. Multiple parameters of allergic responses were evaluated to determine the effect of rhLF. We found that the number of eosinophils and goblet cells, as well as mRNA and protein expression of type 2 helper T (Th2), Th17 and regulatory T (Treg) cells in the nasal cavity, was significantly upregulated in AR mice compared with the controls, Conversely, administration of rhLF prior to or after intranasal ovalbumin challenge markedly downregulated these same parameters. Th1-specific mRNA and protein expression in the nasal cavity of the controls was not different from that in AR mice, but expression significantly increased with rhLF treatment. The mRNA and protein expression of endogenous LF in the nasal cavity was significantly downregulated in AR mice compared with the controls. However, after rhLF treatment, endogenous LF mRNA and protein expression was significantly upregulated. Exogenous rhLF inhibited allergic inflammation in AR mice, most likely by promoting the endogenous LF expression and skewing T cells to a Th1, but not a Th2 and Th17 phenotype in the nasal mucosa. Our findings suggest that rhLF treatment may be a novel therapeutic approach for prevention and treatment AR.

Topics: Administration, Intranasal; Animals; Cytokines; Disease Models, Animal; Eosinophils; Goblet Cells; Inflammation; Lactoferrin; Lymphocyte Count; Mice; Mice, Inbred BALB C; Ovalbumin; Rhinitis, Allergic; Rhinitis, Allergic, Perennial; RNA, Messenger; T-Lymphocytes, Regulatory; Th1 Cells; Th17 Cells; Th2 Cells

Sphingosine-1-phosphate (S1P) plays a crucial role in homeostasis of the immune system by regulating lymphocyte recirculation and inflammatory cell recruitment. The levels of S1P are tightly controlled through regulated production and controlled breakdown by sphingosine-lyase (SL). The S1P analogue FTY720 has been developed as an immunosuppressant in transplantation and tested as a treatment for various inflammatory diseases. FTY720 exploits S1P biology by acting as a S1P1 and S1P 3 agonist and by inhibiting S1P breakdown by SL.. Here, we investigate interfering S1P in allergic rhinitis (AR) and its way of action.. Allergic rhinitis was induced by sensitizing mice to ovalbumin (OVA) and challenging the nose with OVA allergen. At the time of allergen challenge, mice received topical intranasal treatment with FTY720. To address the relative contribution of SL inhibition in mediating its effects, some mice were treated with the SL inhibitor 2-acetyl-4-tetrahydroxybutyl (THI).. FTY720 treatment resulted in significantly fewer eosinophils, mast cells and dendritic cells in the nasal mucosa of AR animals, compared with diluent treatment. Levels of IL-4, IL-5, IL-10 and IL-13 produced by lymph node cells fell significantly in FTY720-treated animals. Moreover, FTY720 proved potent enough to suppress inflammation in a model of persistent AR. In vitro and in vivo experiments indicate that FTY720 impaired Th2 differentiation and proliferation important in driving eosinophilia and induced apoptosis in mast cells.. Our results indicate that interfering with S1P metabolism is a powerful and feasible strategy to develop new topical agents that suppress AR.

Topics: Administration, Topical; Animals; Apoptosis; Disease Models, Animal; Drug Delivery Systems; Eosinophils; Fingolimod Hydrochloride; Immunosuppressive Agents; Lysophospholipids; Mast Cells; Mice; Mice, Inbred Strains; Ovalbumin; Propylene Glycols; Random Allocation; Rhinitis, Allergic; Rhinitis, Allergic, Perennial; Sensitivity and Specificity; Sphingosine; Th2 Cells

T(H)17 responses have recently been implicated to play a role in allergic airway diseases, but their local expression in the setting of allergic rhinitis (AR) and their regulation in allergic airway diseases remain unclear.. We sought to investigate the regulatory role of Clara cell 10-kDa protein (CC10), an endogenous regulator of airway inflammation, on T(H)17 responses in the setting of AR.. Wild-type and homozygous CC10-null mice were used to establish an ovalbumin (OVA)-induced AR model. Human recombinant CC10 was given during sensitization or challenge. T(H)17 responses in human subjects and mice were examined by using flow cytometry, quantitative RT-PCR assay, immunohistochemistry, and ELISA. The direct effect of CC10 on T(H)17 cells and CD11c(+) dendritic cells (DCs) was studied by means of cell culture. Adoptive transfer was used to examine the influence of CC10-conditioned DCs on airway inflammation. The regulatory effect of CC10 on the expression of the CCL20 gene was tested by using the BEAS-2B cell line.. Compared with those of control subjects, T(H)17 responses were enhanced in the nasal mucosa of patients with AR. CC10-null mice with AR showed enhanced T(H)17 responses, and CC10 treatment significantly decreased T(H)17 responses. CC10 had no direct effect on in vitro T(H)17 cell differentiation. CC10 could significantly decrease the expression of OX40 ligand, IL-23, and IL-6 but enhance CD86 and TGF-β expression in DCs. Importantly, CC10 was able to inhibit T(H)17 cell polarization in the presence of OVA-pulsed DCs. CC10 pretreatment inhibited T(H)17 responses elicited by adoptive transfer of OVA-pulsed DCs. Furthermore, CC10 decreased the expression of CCL20 in BEAS-2B cells induced by inflammatory cytokines.. T(H)17 responses are enhanced in patients with AR, and CC10 inhibits T(H)17 responses through modulation of the function of DCs.

Topics: Adoptive Transfer; Animals; B7-2 Antigen; Case-Control Studies; Cell Differentiation; Cell Line; Chemokine CCL20; Dendritic Cells; Eosinophils; Epithelial Cells; Humans; Interleukin-23; Interleukin-6; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Nasal Mucosa; Neutrophils; Ovalbumin; OX40 Ligand; Pneumonia; Receptors, Formyl Peptide; Recombinant Proteins; Rhinitis, Allergic; Rhinitis, Allergic, Perennial; Th17 Cells; Transforming Growth Factor beta; Uteroglobin

The pathophysiologic mechanism of allergy is dependent on the action of many redox-sensitive proinflammatory mediators. However, even though redox disturbances are believed to be a hallmark of inflammation, little is known of the effect of redox imbalance to the pathophysiology of allergic rhinitis. We thus opted to investigate the relation of oxidative stress and allergic rhinitis, through the utilization of a potent antioxidant substance (N-acetylcysteine [NAC]) in a rat model of allergic rhinitis and the evaluation of its action on specific markers of inflammation.. NAC (50 mg/kg and 250 mg/kg) was intraperitoneally administered to ovalbumin (OVA)-sensitized rats prior to intranasal challenge with OVA. Mucosal congregation of inflammatory cells (eosinophils and mast cells), mucosal expression of redox-sensitive enzymes (inducible nitric oxide synthase [iNOS] and cyclooxygenase 2 [COX-2]), and the blood levels of a key proinflammatory mediator (tumor necrosis factor-α [TNF-α]) were evaluated.. Intranasal OVA challenges lead to mucosal inflammation, induction of the mucosal expression of iNOS and COX-2 and elevation of TNF-α blood levels. NAC significantly inhibited accumulation of inflammatory cells and downregulated iNOS expression and TNF-α serum levels. The role of COX-2 appeared to be 2-fold and its expression was divergently modulated by NAC.. Our findings suggest that redox balance is involved in the pathophysiology of allergic rhinitis in rats and that NAC can potentially suppress the allergen-induced nasal inflammatory cascade. The investigation of the role of oxidative stress in atopy could help in the evaluation of the therapeutic potential of antioxidant substances in allergic diseases.

Topics: Acetylcysteine; Administration, Intranasal; Allergens; Animals; Anti-Inflammatory Agents; Antioxidants; Cyclooxygenase 2; Disease Models, Animal; Male; Nasal Mucosa; Nitric Oxide Synthase Type II; Ovalbumin; Rats; Rats, Sprague-Dawley; Rhinitis, Allergic; Rhinitis, Allergic, Perennial; Tumor Necrosis Factor-alpha

Although CD23-dependent transcytosis of IgE and IgE-derived immune complexes across respiratory epithelial cells is likely to play a pivotal role in the initiation and development of airway allergic inflammation, there is currently a lack of physiological support for this phenomena to suggest that the targeting of CD23 could be used as a means of therapeutic intervention. The present study was designed to detect the CD23 expression in the nasal mucosa of allergic rhinitis (AR) murine model by immunohistochemistry and western blotting, and to investigate whether intranasal anti-CD23 treatment could inhibit allergen-induced upper airway inflammation in the AR model. This is the first report to show that CD23 was constitutively expressed in murine nasal epithelial cells, and its expression was significantly up-regulated in the AR murine model. In vivo, the up-regulation of CD23 expression was correlated with increased serum IL-4 levels. Following intranasal anti-CD23 treatment, nasal symptoms were alleviated and histopathologic examination showed a significant decrease in eosinophilic infiltration. Meanwhile, ELISA analysis showed levels of serum leukotriene C4 (LTC4), eosinophil cation protein (ECP), ovalbumin (OVA)-specific IgE and IL-4 also significantly decreased, as were LTC4 and OVA-specific IgE in the nasal lavage fluid. Furthermore, Western blotting analysis showed that ECP expression in the nasal mucosa was down-regulated. Finally, flow cytometric analysis revealed anti-CD23 treatment inhibited Th2 cell responses. These results indicate that intranasal anti-CD23 treatment can reduce allergic responses in a murine model of allergic rhinitis.

Topics: Administration, Intranasal; Allergens; Animals; Budesonide; Disease Models, Animal; Down-Regulation; Eosinophil Cationic Protein; Eosinophils; Epithelial Cells; Female; Hypersensitivity; Immunoglobulin E; Inflammation; Interleukin-4; Leukotriene C4; Mice; Mice, Inbred BALB C; Nasal Mucosa; Ovalbumin; Random Allocation; Receptors, IgE; Rhinitis, Allergic; Rhinitis, Allergic, Perennial; Th2 Cells; Up-Regulation

Interleukin (IL)-33 is involved in the Th2 immune response and could play an essential role in nasal allergy. Therefore, we aimed to investigate the therapeutic potential of anti-IL-33 for allergic rhinitis (AR).. Twenty-four BALB/c mice were used. In group A (control group, n = 6), mice were sensitized and challenged with saline. Group B [ovalbumin (OVA) group, n = 6] mice received intraperitoneal and intranasal OVA challenge. In group C (control IgG group, n = 6), mice were injected intraperitoneally with rabbit control IgG before OVA challenge. In group D (anti-IL-33 group, n = 6), anti-IL-33 was injected before challenge. We evaluated the number of nose-scratching events and external morphology; serum total and OVA-specific IgE; number of eosinophils, neutrophils, and lymphocytes in bronchoalveolar lavage (BAL) fluid; histopathologic examination of nasal cavity; and IL-4, IL-5, and IL-13 in BAL fluid.. Anti-IL-33 treatment significantly reduced the nose-scratching events and ameliorated skin denudation. Serum total and OVA-specific IgE was significantly decreased in group D. The number of eosinophils in BAL fluid was also significantly decreased. Eosinophilic infiltration in the nasal cavity was significantly decreased in group D. IL-4, IL-5, and IL-13 in BAL fluid were also significantly decreased after treatment.. Anti-IL-33 antibody has a therapeutic potential for experimental AR.

Topics: Animals; Antibodies; Bronchoalveolar Lavage Fluid; Cytokines; Female; Immunoglobulin E; Injections, Intraperitoneal; Interleukin-13; Mice; Mice, Inbred BALB C; Ovalbumin; Rhinitis, Allergic, Perennial

Orai1 is the key subunit of the Ca(2+)-release-activated Ca(2+) channel. Our previous report has demonstrated that Orai1 expression in the airway was upregulated in the ovalbumin (OVA)-induced allergic rhinitis (AR) mouse models. To observe whether inhibition of Orai1 expression in the airway could suppress symptoms in a murine model of AR and to assess the impacts of this inhibition on the responses of local and systemic immunocytes, we administered recombinant lentivirus vectors that encoded shRNA against ORAI1 (lenti-ORAI1) into the nostrils of OVA-sensitized mice before the challenges, and analyzed its effect on allergic responses, as compared with the unsensitized mice and untreated AR mice. Administration of lenti-ORAI1 into the nasal cavity successfully infected cells in the epithelial layer of the nasal mucosa, and significantly decreased the frequencies of sneezing and nasal rubbing of the mice. Protein levels of leukotriene C4, OVA-specific IgE, and IL-4 in the nasal lavage fluid and serum and eosinophil cation protein in the serum were also significantly reduced by lenti-ORAI1, as were the mRNA levels of these factors in the nasal mucosa and spleen. These data suggested that administration of lenti-ORAI1 into the nasal cavity effectively decreased Orai1 expression in the nasal mucosa, alleviated AR symptoms, and partially inhibited the hyperresponsiveness of the local and systemic immune cells including T cells, B cells, mast cells and eosinophils that are involved in the pathogenesis of AR.

Topics: Animals; Calcium Channels; Down-Regulation; Eosinophil Cationic Protein; Glutathione Transferase; Immunoglobulin E; Interleukin-4; Lentivirus; Mice; Mice, Inbred BALB C; Nasal Mucosa; ORAI1 Protein; Ovalbumin; Rhinitis, Allergic, Perennial; RNA, Messenger; RNA, Small Interfering; Spleen; Transfection

In this study, we evaluated effect of glycyrrhizin on immunity function in allergic rhinitis (AR) mice. The AR mice model were induced by dripping ovalbumin in physiological saline (2 mg mL⁻¹, 10 μL) into the bilateral nasal cavities using a micropipette. After the AR model was induced, mice were randomly divided into six groups: the normal control, model, lycopene 20 mg kg⁻¹ (as positive control drug) group, and glycyrrhizin 10, 20, 30 mg kg⁻¹ groups. After the sensitization day 14, lycopene (20 mg/kg BW) and glycyrrhizin (10, 20 and 30 mg/kg BW) were given orally for 20 days once a day. Mice in the normal control and model groups were given saline orally once a day for 20 days. Results showed that glycyrrhizin treatment could dose-dependently significantly reduce blood immunoglobulin E (IgE), interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-6 (IL-6), nitrous oxide (NO), tumor necrosis factor-alpha (TNF-α) levels and nitrous oxide synthase (NOS) activity and enhance blood immunoglobulin A (IgA), immunoglobulin G (IgG), immunoglobulin M (IgM), interleukin-2 (IL-2) and interleukin-12 (IL-12) levels in AR mice. Furthermore, glycyrrhizin treatment could dose-dependently significantly enhance acetylcholinesterase (AchE) activity and reduce substance P (SP) level in peripheral blood and nasal mucosa of AR mice. We conclude that glycyrrhizin can improve immunity function in AR mice, suggesting a potential drug for the prevention and therapy of AR.

Topics: Acetylcholinesterase; Animals; Anti-Inflammatory Agents; Glycyrrhizic Acid; Immunoglobulins; Interleukins; Male; Mice; Nasal Mucosa; Nitric Oxide; Nitric Oxide Synthase; Ovalbumin; Random Allocation; Rats; Rhinitis, Allergic, Perennial; Substance P; Tumor Necrosis Factor-alpha

Recent studies have shown that transforming growth factor-β(1) (TGF-β(1)) plays an important role in the progression of allergic diseases.. Mouse models of allergic rhinitis were established by ovalbumin sensitization and challenge. Immunostaining was used to analyze the expression of TGF-β(1) in the mouse nasal mucosa. A chemotaxis assay was conducted to analyze the impact of TGF-β(1) stimulation on migration of mast cells differentiated from mouse bone marrow cells. Chemotaxis and Western blot analysis were further applied to investigate the pathways involved in mast cell migration induced by TGF-β(1) stimulation.. TGF-β(1) expression was induced in allergic rhinitis and phosphorylated Smad2 was expressed in mast cells present in the nasal mucosa. TGF-β(1) could induce migration of mast cells, but HTS466284, a TGF-β receptor 1 kinase inhibitor, inhibited this chemotactic activity. After TGF-β(1) stimulation, mast cell RhoA expression was significantly increased. TGF-β(1)-induced mast cell chemotaxis could be inhibited by the RhoA inhibitor Tat-C3 and myosin light chain kinase inhibitor ML-7.. TGF-β(1) plays a major role in inducing the accumulation of mast cells in allergic rhinitis.

Topics: ADP Ribose Transferases; Animals; Azepines; Botulinum Toxins; Chemotaxis; Disease Models, Animal; Disease Progression; Enzyme Inhibitors; Female; Mast Cells; Mice; Mice, Inbred BALB C; Naphthalenes; Nasal Mucosa; Ovalbumin; Rhinitis, Allergic, Perennial; rhoA GTP-Binding Protein; Smad2 Protein; Specific Pathogen-Free Organisms; Transforming Growth Factor beta1

Allergic rhinitis (AR) can cause significant olfactory loss, but few studies have specifically investigated AR effects on olfactory and nasal respiratory tissues per se. To address this, we used a murine AR protocol employing nasal allergen infusion for both sensitization and challenges. Seven- to 11-week BALB/c mice were bilaterally infused with 1% ovalbumin (OVA) in phosphate-buffered saline (PBS) or PBS alone for 6 or 11 weeks, given single bilateral PBS or OVA infusions 24 h before sacrifice, or left untreated. High OVA-specific IgE serum levels and eosinophil infiltration confirmed AR induction. Olfactory (OE) and respiratory (RE) epithelia showed distinctly different responses, most conspicuously, massive eosinophil infiltration of immediately RE-subjacent lamina propria. In OE, such infiltration was minimal. Significant RE hypertrophy and hyperplasia also occurred, although OE organization was generally maintained and extensive disruption localized despite a 20% reduction in sensory neurons and globose basal cells after 11 weeks OVA. Pronounced Bowman's gland hypertrophy crowded both OE and olfactory nerve bundles. Cellular proliferation was widely distributed in RE but in OE was localized to normally thinner OE and RE-proximal OE, suggesting possible indirect RE influences. Terminal deoxynucleotide transferase (TdT) nick end labeling was greater in OE than RE and, in contrast to other effects, occurred with acute infusions and chronic PBS alone, often unilaterally. Following chronic OVA, AR-related bilateral increases appeared superimposed on those. These findings indicate AR effects on olfactory function may be complex, reflecting various levels of RE/OE responses and interactions.

Topics: Animals; Cell Proliferation; Disease Models, Animal; Eosinophils; Immunoglobulin E; Mice; Mice, Inbred BALB C; Nasal Mucosa; Olfactory Mucosa; Ovalbumin; Respiratory Mucosa; Rhinitis, Allergic, Perennial

CCR4 is highly expressed on Th2 cells. These cells play an important role in acute inflammatory responses, including those involved in allergic rhinitis. We determined whether disrupting the CCR4 ligand interaction with CCR4 antagonist could alleviate allergic rhinitis in a mouse model.. BALB/c mice were sensitized with ovalbumin and alum by intraperitoneal injection and challenged with intranasally administered ovalbumin. Compound 22, which has been reported as a novel small-molecule antagonist of CCR4, was also administered intranasally. In addition, budesonide, an efficient glucocorticoid, was used as a positive control. The effects of compound 22 were quantified by multiple parameters of allergic responses in both nasal and pulmonary tissues.. Compound 22 significantly improved symptoms of allergic rhinitis and suppressed levels of total IgE of serum. It dramatically reduced the levels of IL-4 in bronchoalveolar lavage fluid and also decreased the number of inflammatory cells in the fluid. The infiltration of inflammatory cells, especially eosinophils, was markedly reduced in the nasal and pulmonary tissues. The number of IL-4+ cells was also significantly reduced in these tissues. Moreover, the numbers of Foxp3+ cells and IL-17+ cells were reduced, though not to a statistically significant degree.. In our research, CCR4 antagonists such as compound 22 were proven for the first time to alleviate murine allergic rhinitis when administered nasally. CCR4 antagonists may have therapeutic potential for the treatment of allergic rhinitis.

Topics: Administration, Intranasal; Alum Compounds; Animals; Bronchoalveolar Lavage Fluid; Budesonide; Chemotaxis; Disease Models, Animal; Female; Glucocorticoids; HEK293 Cells; Humans; Immunization; Immunoglobulin E; Immunologic Factors; Interleukin-4; Mice; Mice, Inbred BALB C; Neutrophils; Ovalbumin; Receptors, CCR4; Rhinitis, Allergic, Perennial; Th2 Cells

The association of allergic diseases and disease activity in systemic lupus erythematosus (SLE, lupus) is controversial. The study investigates lupus activity-related differences in the induction of late allergic rhinitis (LAR) in the female NZB×NZW(B/W)F(1) mouse model for lupus. The LAR, which is induced by ovalbumin, was examined during the preactive (before clinical onset) and active (after clinical onset) phases in mice. Induction of LAR was less severe in mice with active lupus in contrast to clinically healthy lupus mice that developed a more severe allergic rhinitis. Inhibition of the development of LAR may be due to reduced eosinophilia and local interleukin-4 secretion during active autoimmune disease. In addition, systemic interferon-γ, but not IL-4, production increased during the active phase, but not the preactive phase. This suggests that the predominating Th1 lineage commitment in mice with active lupus may be responsible for the inhibition of the allergic Th2 response. The present study may shed some light on the controversy of the prevalence of allergic diseases in SLE patients.

Topics: Animals; Antibodies, Antinuclear; Blood Urea Nitrogen; Creatinine; Eosinophilia; Eosinophils; Female; Inflammation; Interferon-gamma; Interleukin-4; Leukocytes; Lupus Erythematosus, Systemic; Lymphocyte Count; Mice; Mice, Inbred BALB C; Mice, Inbred NZB; Nasal Lavage Fluid; Neutrophils; Ovalbumin; Proteinuria; Rhinitis, Allergic; Rhinitis, Allergic, Perennial; Spleen; Th1 Cells; Th2 Cells

Bamboo salt (BS) is a specially processed salt according to the traditional recipe using sun-dried salt (SDS) and bamboo in Korea. The present study investigated the effects and mechanism of BS, SDS, NaCl, or mineral mixture (containing zinc, magnesium, and potassium) on ovalbumin (OVA)-induced allergic rhinitis (AR) animal model. The increased number of rubs was inhibited by the oral administration of BS, SDS, NaCl, mineral mixture, or nose inhalation of BS. The increased levels of IgE, histamine, and interleukin (IL)-1β in serum were reduced by BS. The level of interferon-γ was increased, whereas the level of IL-4 was reduced on the spleen tissue of BS-treated mice. In the BS-treated mice, the number of eosinophils and mast cells infiltration increased by OVA-sensitization were also decreased. Protein levels of inflammatory cytokines were reduced by BS or NaCl administration in the nasal mucosa of the AR mice. In addition, BS inhibited caspase-1 activity in the nasal mucosa tissue. In activated human mast cells, BS significantly inhibited the production of IL-1β and thymic stromal lymphopoietin and activation of caspase-1. Our data indicate that BS has anti-allergic and anti-inflammatory effects by regulating of caspase-1 activation in AR mice and in vitro models.

Topics: Animals; Bambusa; Caspase 1; Cell Line; Cytokines; Food Handling; Histamine; Humans; Immunoglobulin E; Mast Cells; Mice; Nasal Mucosa; Ovalbumin; Rhinitis, Allergic; Rhinitis, Allergic, Perennial; Sodium Chloride, Dietary

To elucidate the functions of nuclear factor kappa B (NF-κB) in mucin hypersecretion in allergic rhinitis (AR), we examined the in vivo effects of an NF-κB inhibitor, ammonium pyrrolidine dithiocarbamate (PDTC), on mucin 5 subtype AC (MUC5AC) expression in the nasal mucosa of ovalbumin-sensitized rats.. Randomized animal study.. Academic medical center.. Sprague Dawley rats were randomized into a control group (group A), an AR model group (group B), and an AR model treated with an NF-κB inhibitor (group C). Rats in groups B and C were sensitized systemically and locally by ovalbumin injection and inhalation, whereas group A was treated with normal saline in place of ovalbumin. Pyrrolidine dithiocarbamate (100 mg/kg/d) was given to group C by intraperitoneal injection for 5 days. NF-κBp65, MUC5AC, tumor necrosis factor (TNF)-α, and interleukin (IL)-6 were detected by immunohistochemistry, Western blotting, enzyme-linked immunosorbent assay, or real-time polymerase chain reaction.. NF-κB was activated in group B, and significant NF-κBp65 protein was expressed in the nucleus of cells from the nasal mucosa, resulting in upregulated transcription from TNF-α and IL-6 genes, as well as increased contents of TNF-α and IL-6 in the nasal lavage fluids. Pyrrolidine dithiocarbamate inhibited nuclear localization of NF-κBp65 and subsequent downregulation of the transcription and secretion of TNF-α and IL-6. MUC5AC was upregulated in group B but reduced in a time-dependent manner after inhibition of NF-κB activation.. NF-κB activation might induce MUC5AC hypersecretion in AR rats by inflammatory cytokines TNF-α and IL-6.

Topics: Animals; Interleukin-6; Mucin 5AC; Nasal Mucosa; NF-kappa B; Ovalbumin; Pyrrolidines; Random Allocation; Rats; Rats, Sprague-Dawley; Rhinitis, Allergic; Rhinitis, Allergic, Perennial; Thiocarbamates; Transcription Factor RelA; Tumor Necrosis Factor-alpha; Up-Regulation

The purpose of the present study was to investigate the effect of nucleotide-binding oligomerization domain 1 (NOD1), an innate immune sensor, on allergic inflammation and induction of regulatory T cells in a mouse model of allergic rhinitis. We also aimed to explore whether there were differences in the effect of NOD1 ligand according to the timing of administration. Study Design An in vivo study using an animal model.. Catholic Research Institutes of Medical Science.. Forty BALB/c mice were divided into 4 groups: control, OVA, pre-NOD1, and post-NOD1. Ovalbumin (OVA) was used for sensitization and challenge. The pre-NOD1 group received NOD1 ligand intranasally before sensitization, whereas the post-NOD1 group received it after sensitization. The effects of allergic inflammation and regulatory T cells were compared among the groups.. In the post-NOD1 group, serum OVA-specific IgE, eosinophil counts, interleukin (IL)-13 levels, and GATA-3 mRNA expression were significantly increased and Foxp3(+) mRNA expression and CD4(+) Foxp3(+) T cells were decreased compared with the OVA group. In the pre-NOD1 group, Foxp3 mRNA expression and CD4(+) Foxp3(+) T cells were significantly decreased compared with the OVA group. Although not significant, the pre-NOD1 group showed increases in serum OVA-specific IgE, eosinophil counts, IL-13 levels, and GATA-3 mRNA expression compared with the OVA group.. The innate immune response through NOD1 enhances allergen-specific Th2 response and suppresses induction of regulatory T cells in a mouse model of allergic rhinitis, and the effects are different depending on the timing of exposure to NOD1 ligand.

Topics: Animals; CD4-Positive T-Lymphocytes; Eosinophils; Female; Forkhead Transcription Factors; GATA3 Transcription Factor; Immunity, Innate; Immunoglobulin E; Interleukin-13; Ligands; Mice; Mice, Inbred BALB C; Nod1 Signaling Adaptor Protein; Ovalbumin; Rhinitis, Allergic; Rhinitis, Allergic, Perennial; RNA, Messenger; T-Lymphocytes, Regulatory

Hypoxia-inducible factor 1α (HIF-1α) is an important regulator of immune and inflammatory responses. We hypothesized that nasal allergic inflammation is attenuated by HIF-1α inhibition and strengthened by HIF-1α stabilization.. To elucidate the role of HIF-1α in a murine model of allergic rhinitis (AR).. Mice were pretreated with the HIF-1α inhibitor 2-methoxyestradiol (2ME2) or the HIF-1α inducer cobalt chloride (CoCl(2)) in an established AR murine model using ovalbumin (OVA)-sensitized BALB/c mice. HIF-1α and vascular endothelial growth factor (VEGF) expression in nasal mucosa was measured and multiple parameters of allergic responses were evaluated.. HIF-1α and VEGF levels were locally up-regulated in nasal mucosa during AR. Inflammatory responses to OVA challenge, including nasal symptoms, inflammatory cell infiltration, eosinophil recruitment, up-regulation of T-helper type 2 cytokines in nasal lavage fluid, and serum OVA-specific IgE levels were present in the OVA-challenged mice. 2ME2 effectively inhibited HIF-1α and VEGF expression and attenuated the inflammatory responses. Stabilization of HIF-1α by CoCl(2) facilitated nasal allergic inflammation. HIF-1α protein levels in nasal airways correlated with the severity of AR in mice.. HIF-1α is intimately involved in the pathogenesis of nasal allergies, and the inhibition of HIF-1α may be useful as a novel therapeutic approach for AR.

Topics: 2-Methoxyestradiol; Animals; Cobalt; Cytokines; Estradiol; Hypoxia-Inducible Factor 1, alpha Subunit; Immunoglobulin E; Immunohistochemistry; Inflammation; Male; Mice; Mice, Inbred BALB C; Nasal Mucosa; Ovalbumin; Rhinitis, Allergic; Rhinitis, Allergic, Perennial; Signal Transduction; Vascular Endothelial Growth Factor A

Nuclear factor kappa B (NF-κB) induces gene transcription by binding CREB-binding protein (CBP). The aim of the study was to detect the mechanisms by which NF-κB pathway regulated aquaporin 5 (AQP5) in the nasal mucosa of rats with allergic rhinitis (AR). Rats were divided into control (group C), model (group M), low-dose proline dithiocarbamate (PDTC) (group L) and high-dose PDTC (group H) groups. AR model was established by the sensitization with ovalbumin, then groups L and H were treated with PDTC (50 or 100 mg/kg/day) for 5 days. AQP5, interleukin-1β, NF-κBp65 and phosphorylated cAMP-response element binding protein (p-CREB) were detected by immunohistochemistry, Western blotting or real-time PCR. AQP5 expression in group M was lower than in group C, but in groups L and H it increased. NF-κBp65 expression in group M was higher than group C, but in groups L and H it reduced. p-CREB expression in group M was lower than group C, but in groups L and H it increased. Interleukin-1β gene level in group M was higher than group C, but in groups L and H it was lower. These data show that the NF-κB pathway could down-regulate AQP5 by interleukin-1β which inhibited CREB phosphorylation or by NF-κBp65 which competitively bound CBP.

Topics: Analysis of Variance; Animals; Aquaporin 5; Blotting, Western; CREB-Binding Protein; Down-Regulation; Immunoenzyme Techniques; Interleukin-1beta; Nasal Mucosa; NF-kappa B; Ovalbumin; Proline; Rats; Reverse Transcriptase Polymerase Chain Reaction; Rhinitis, Allergic, Perennial; Thiocarbamates

Chelidonic acid (CA) is known as an inhibitor of the rat brain glutamate decarboxylase. However, the pharmacological effects of CA in allergic reactions have not yet been defined. Here, we show the effects and the mechanism of CA in the ovalbumin (OVA)-sensitized allergic rhinitis (AR) model. CA significantly decreased the number of nasal/ear rubs and increment of IgE levels in the AR mice. The level of interferon-γ was enhanced while the level of IL-4 was reduced on the spleen tissue of the CA-administered AR mice. Expressions of IL-1β and cyclooxygenase-2 were inhibited by CA administration in the nasal mucosa tissues. Infiltration of eosinophils and mast cells was decreased in the CA-administered AR mice. Furthermore, CA decreased the caspase-1 activity in the same nasal mucosa tissue and human mast cell line, HMC-1. Our results indicate that CA may attenuate allergic reaction by inhibition of caspase-1 activity.

Topics: Animals; Anti-Allergic Agents; Caspase 1; Cyclooxygenase 2; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Eosinophils; Female; Histamine Release; Immunoglobulin E; Interleukin-1beta; Interleukin-4; Mast Cells; Mice; Mice, Inbred BALB C; Nasal Mucosa; Ovalbumin; Pyrans; Rhinitis, Allergic, Perennial; Spleen

The purpose of this pilot study was to investigate the effects of HR2 on allergen-specific immunotherapy in a mouse model of allergic rhinitis.. An in vivo study using an animal model.. Catholic Research Institutes of Medical Science.. Fifty mice were divided into 5 groups: control, allergic rhinitis (AR), immunotherapy (IT), immunotherapy with HR2 agonist (HI), and immunotherapy with HR2 antagonist (HB). All mice except for the control group were sensitized with ovalbumin (OVA). After 1 week, mice in the IT, HI, and HB groups underwent immunotherapy by intradermal injections of OVA. During immunotherapy, the HI group was injected with HR2 agonist, whereas the HB group was injected with HR2 antagonist. All sensitized mice were challenged with intranasal OVA. After the final challenge, allergic behavior was evaluated. Interleukin (IL)-13, interferon-γ, IL-10, and transforming growth factor (TGF)-β levels in nasal lavage fluid (NALF), as well as OVA-specific IgE levels in serum, were measured. The number of eosinophils in lamina propria was evaluated.. The levels of serum OVA-specific IgE and IL-13 in NALF were significantly increased in the HB group compared with the IT group (P < .05). Also, the tissue eosinophil counts were higher in the HB group than in the IT group (P < .05).. HR2 antagonist impaired OVA-specific immunotherapy in mice. Although confirmation of this preliminary result is needed, these findings suggest that HR2 receptors may have inhibitory effects on immune tolerance. The authors suggest that application of this property could enhance the efficiency of allergen-specific immunotherapy.

Topics: Animals; Cell Count; Desensitization, Immunologic; Eosinophils; Female; Histamine Agonists; Histamine H1 Antagonists; Immunoglobulin E; Interleukin-13; Mice; Mice, Inbred BALB C; Nasal Lavage Fluid; Nasal Mucosa; Ovalbumin; Receptors, Histamine H2; Rhinitis, Allergic, Perennial; Transforming Growth Factor beta

To evaluate the effects of peroxisome proliferator-activated receptor (PPAR)-γ agonist on the induction of regulatory T cells (Tregs) in a murine model of allergic rhinitis.. Randomized controlled trial.. Animal study.. BALB/c mice that received ovalbumin sensitization and challenge served as the ovalbumin group (n = 6). Two separate groups of 6 mice received intragastric administration with PPAR-γ agonist pioglitazone (30 mg/kg/d) or pioglitazone plus PPAR-γ antagonist GW9662 (0.5 mg/d) before each ovalbumin challenge. The control group (n = 6) was treated with drug vehicle alone. Various allergic responses were assessed. Real-time polymerase chain reaction was performed to investigate the mRNA expression of forkhead box P3 (Foxp3), T-bet, and GATA-3. Flow cytometry was used to determine the percentage of Tregs.. Mice developed typical pathophysiological allergic rhinitis features after the ovalbumin challenge. The frequencies of sneezing and scratching were significantly decreased by pioglitazone treatment (P < .0001). Eosinophils infiltration and the levels of interleukin-5 and interferon-γ in nasal cavity lavage fluid and sera immunoglobulin E were also markedly decreased by pioglitazone (P < .001). The expression of Foxp3 mRNA and the population of Tregs were significantly increased by pioglitazone (P < .05). Cotreatment with GW9662 reversed the anti-inflammatory effects of pioglitazone. The effects of PPAR-γ agonist on Foxp3 mRNA expression and Tregs induction were abrogated by administration of GW9662.. PPAR-γ agonist attenuates upper airway allergic inflammation in a PPAR-γ-dependent fashion, and the beneficial effects of pioglitazone in airway allergic inflammation may be mediated by induction of Tregs.

Topics: Anilides; Animals; Female; Forkhead Transcription Factors; GATA3 Transcription Factor; Immunoglobulin E; Interferon-gamma; Interleukin-5; Mice; Mice, Inbred BALB C; Nasal Lavage Fluid; Nasal Mucosa; Ovalbumin; Pioglitazone; PPAR gamma; Rhinitis, Allergic, Perennial; T-Box Domain Proteins; T-Lymphocytes, Regulatory; Thiazolidinediones

Because imperatorin (IPT), the furanocoumarins exhibits anti-inflammatory activity, we reasoned that IPT might modulate the allergic rhinitis (AR). The aim of this study was to analyze the regulation of AR by IPT. Here, we show the effect and mechanism of IPT in an ovalbumin (OVA)-induced AR model. The number of rubs after the OVA challenge in the OVA-sensitized mice was significantly higher than that in the OVA-unsensitized mice. The increased number of rubs was inhibited by the oral administration of IPT. The increased levels of IgE and histamine in the OVA-sensitized mice were reduced by IPT administration. The levels of interferon-γ were enhanced, whereas the levels of interleukin (IL)-4 were reduced on the spleen tissue of the IPT-administered AR mice. Protein levels of IL-1β, macrophage inflammatory protein-2, intercellular adhesion molecule-1, and cyclooxygenase-2 were reduced by IPT administration in the nasal mucosa of the OVA-sensitized mice. In the IPT-administered mice, the number of eosinophils and mast cells infiltration increased by OVA-sensitization were also decreased. In addition, IPT inhibited caspase-1 activity in the same nasal mucosa tissue. In activated human mast cells, the receptor-interacting protein 2 (RIP2), IκB kinase (IKK)-β, nuclear factor-κB (NF-κB)/RelA, and caspase-1 activation were increased, but increased RIP2, IKK-β, NF-κB/RelA, and caspase-1 activation were inhibited by the treatment of IPT. In addition, IPT inhibited caspase-1 activity and IL-1β production in IgE-stimulated bone marrow-derived mast cells. We can conclude that IPT exerts significant effects by regulating of caspase-1 activation in AR animal and in vitro models.

Topics: Animals; Blotting, Western; Bone Marrow Cells; Caspase 1; Caspase Inhibitors; Cell Line; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; Furocoumarins; Histamine; Histamine Release; Humans; I-kappa B Proteins; Inflammation; Mast Cells; Mice; Mice, Inbred BALB C; Nasal Mucosa; Ovalbumin; Peroxidase; Receptor-Interacting Protein Serine-Threonine Kinase 2; Receptor-Interacting Protein Serine-Threonine Kinases; Reverse Transcriptase Polymerase Chain Reaction; Rhinitis, Allergic, Perennial

CD30 ligand (CD30L) plays an important role in the amplification and/or activation of effector CD4(+) T cells, irrespective of Th cell subset. To examine the role of CD30L in allergic rhinitis, we evaluated an OVA model of allergic rhinitis in CD30L knock out (KO) mice on a BALB/c background sensitized with OVA. Symptoms of allergic rhinitis such as eosinophil infiltration into the nasal mucosa were drastically diminished in OVA-sensitized CD30L KO mice following intranasal challenge with OVA. The levels of OVA-specific IgE in the sera and the Th2 response in nasopharynx-associated lymphoid tissues and cervical LNs of CD30L KO mice were significantly lower than those of WT mice following intranasal challenge with OVA. Intranasal administration of CD30-Ig during the effector phase with OVA significantly prevented the development of allergic rhinitis in WT mice. These results suggest that CD30L plays an important role in allergic rhinitis and that the inhibition of CD30L/CD30 signaling might be useful as a novel biological therapy for allergic rhinitis.

Topics: Administration, Intranasal; Animals; CD30 Ligand; CD4-Positive T-Lymphocytes; Cell Movement; Eosinophils; Immunoglobulin E; Immunoglobulin G; Ki-1 Antigen; Lymph Nodes; Mice; Mice, Inbred BALB C; Mice, Knockout; Nasal Mucosa; Nasopharynx; Ovalbumin; Recombinant Fusion Proteins; Rhinitis, Allergic, Perennial; Th2 Cells

Epstein-Barr virus-induced gene 3 (EBI3) is a widely expressed interleukin-12-related protein that plays a critical role in the regulation of effector T cells and inflammatory responses.. Allergic rhinitis (AR) was induced in mice by both intraperitoneal injection and intranasal administration of ovalbumin. By using immunohistochemical techniques, we investigated EBI3 expression in mouse spleens. The expressions of EBI3 and forkhead transcription factor 3 (Foxp3) in CD4+CD25+ regulatory T (T(reg)) cells isolated from spleens were assessed by flow cytometry. RNA extraction and RT-PCR were used to measure EBI3 and Foxp3 mRNA expression.. EBI3 and Foxp3 were expressed mainly in the white pulp of the spleens. Flow cytometry analysis showed that EBI3 and Foxp3 coexpressed in mouse CD4+CD25+ T(reg) cells. Furthermore, RT-PCR and flow cytometry analysis showed that expression of both Foxp3 and EBI3 was reduced in CD4+CD25+ T(reg) cells in an AR mouse model compared with controls, but there was no difference in the frequency of CD4+CD25+ T(reg) cells.. The deficiency in CD4+CD25+ T(reg) cell suppressive activity in AR is associated with the molecular mediators EBI3 and Foxp3.

Topics: Animals; BALB 3T3 Cells; CD4 Antigens; Chronic Disease; Disease Models, Animal; Female; Flow Cytometry; Forkhead Transcription Factors; Gene Expression; Interleukin-2 Receptor alpha Subunit; Mice; Minor Histocompatibility Antigens; Ovalbumin; Receptors, Cytokine; Rhinitis, Allergic, Perennial; RNA, Messenger; Spleen; T-Lymphocytes, Regulatory

Human chemokine-like factor (CKLF1) is a human cytokine that exhibits chemotactic activities on a wide spectrum of leukocytes. One of CKLF1's C-terminal peptides, C19, exerts inhibitory effects on chemotaxis mediated by mouse Ccr3 and Ccr4 and human CCR3 and CCR4. Mouse models of asthma show that C19 can also inhibit the Th2 response. CCR3 and CCR4 are chemokine receptors important to allergic rhinitis, a condition whose pathogenesis is similar to that of asthma. Here, we established a mouse model of allergic rhinitis by repetitive sensitization and intranasal challenge with OVA and assessed whether C19 has therapeutic effects on this model. In this study, both intranasal and intraperitoneal administration of C19 reduced allergic symptoms such as sneezing and rubbing and serum concentration of IgE. C19 showed a strong ability to suppress eosinophil accumulation in nasal mucosa and lung tissues. C19 was able to suppress the Th2 cytokine IL-4 without augmenting the Th1 cytokine IFN-γ in BAL and IL-4(+) cells in the local nasal tissue. In terms of symptom amelioration, IgE reduction, and eosinophilia suppression, C19 was found to be as effective against allergic rhinitis as Budesonide. Moreover, intranasal treatment has a stronger therapeutic effect than other types of administration, and it may be more convenient and safe. For these reasons, C19 may have potential in the treatment of allergic rhinitis.

Topics: Administration, Intranasal; Animals; Anti-Inflammatory Agents; Bronchoalveolar Lavage Fluid; Budesonide; Disease Models, Animal; Eosinophils; Female; Immunoglobulin E; Interferon-gamma; Interleukin-4; Lung; MARVEL Domain-Containing Proteins; Membrane Proteins; Mice; Mice, Inbred BALB C; Nasal Mucosa; Ovalbumin; Peptides; Repressor Proteins; Rhinitis, Allergic, Perennial; Sneezing

Preclinical pharmacological characterization of GSK1004723, a novel, dual histamine H(1) and H(3) receptor antagonist.. GSK1004723 was characterized in vitro and in vivo using methods that included radioligand binding, intracellular calcium mobilization, cAMP production, GTPγS binding, superfused human bronchus and guinea pig whole body plethysmography.. In cell membranes over-expressing human recombinant H(1) and H(3) receptors, GSK1004723 displayed high affinity, competitive binding (H(1) pKi = 10.2; H(3) pKi = 10.6). In addition, GSK1004723 demonstrated slow dissociation from both receptors with a t(1/2) of 1.2 and 1.5 h for H(1) and H(3) respectively. GSK1004723 specifically antagonized H(1) receptor mediated increases in intracellular calcium and H(3) receptor mediated increases in GTPγS binding. The antagonism exerted was retained after cell washing, consistent with slow dissociation from H(1) and H(3) receptors. Duration of action was further evaluated using superfused human bronchus preparations. GSK1004723 (100 nmol·L(-1) ) reversed an established contractile response to histamine. When GSK1004723 was removed from the perfusate, only 20% recovery of the histamine response was observed over 10 h. Moreover, 21 h post-exposure to GSK1004723 there remained almost complete antagonism of responses to histamine. In vivo pharmacology was studied in conscious guinea pigs in which nasal congestion induced by intranasal histamine was measured indirectly (plethysmography). GSK1004723 (0.1 and 1 mg·mL(-1) intranasal) antagonized the histamine-induced response with a duration of up to 72 h.. GSK1004723 is a potent and selective histamine H(1) and H(3) receptor antagonist with a long duration of action and represents a potential novel therapy for allergic rhinitis.

Topics: Allergens; Animals; Benzazepines; Binding, Competitive; Bronchi; Bronchial Provocation Tests; Bronchoconstriction; Carbachol; Cell Line; CHO Cells; Cricetinae; Cricetulus; Female; Guinea Pigs; Histamine; Histamine H1 Antagonists; Histamine H3 Antagonists; Humans; In Vitro Techniques; Niacinamide; Ovalbumin; Phthalazines; Piperidines; Pyrilamine; Receptors, Histamine H1; Receptors, Histamine H3; Recombinant Proteins; Rhinitis, Allergic, Perennial; Transfection

To study the immunoregulatory effect of an optimal Chinese herbal monomer compound, which consists of three monomers, namely, icariin, baicalin and Astragalus saponin I, in a mouse model of allergic rhinitis.. A mouse model of allergic rhinitis was established by intraperitoneal injection of ovalbumin and aluminum hydroxide gel suspension. The splenic lymphocytes of the mice were separated, cultured in 96-well plates and divided into three groups: control group, concanavalin A group and compound group. Splenic lymphocyte proliferation was detected by cell counting kit-8 method at different time points. Cell cycle distribution was observed by flow cytometry (FCM) also at different time points. The changes of intracellular calcium concentration of splenic lymphocytes were measured by fluorescence microplate reader after the cells were incubated with fluorescence probe Fluo-3/AM.. The Chinese herbal monomer compound could inhibit cell proliferation induced by concanavalin A (P<0.01). And the inhibition presented a time-effect relationship. With extending of the action time, the inhibition rate gradually increased and reached peak at the 48th hour. FCM test revealed the fact that concanavalin A could promote cells to enter into the mitosis by reducing the percentage of cells in G0/G1 phases while increasing the percentage of cells in S and G(2)/M phases. Compared with the concanavalin A, the compound could increase the percentage of cells in G(0)/G(1) phases and at the same time reduce the percentage of cells in S and G(2)/M phases at different time points, with the effect most significant at the 24th hour (P<0.05 or P<0.01). The results of the test taken by the fluorescence microplate reader revealed that the fluorescence value of the concanavalin A group increased with time in the previous 24 h while the compound could reduce this trend obviously, thus reduce the intracellular calcium concentration (P<0.01).. The Chinese herbal monomer compound can inhibit the proliferation of cultured splenic lymphocytes of mice with allergic rhinitis. The effects of the compound of lowering intracellular calcium concentration and arresting cell cycle at G(0)/G(1) phases from entering into S and G(2)/M phases are responsible for its antiproliferation activity.

Topics: Animals; Cell Proliferation; Cells, Cultured; Drug Compounding; Drugs, Chinese Herbal; Flavonoids; Immunomodulation; Lymphocytes; Male; Mice; Mice, Inbred BALB C; Ovalbumin; Rhinitis, Allergic; Rhinitis, Allergic, Perennial; Saponins; Spleen; Triterpenes

In the present study, the anti-allergic effect of OR extract was evaluated on an ovalbumin (OVA)-induced allergic rhinitis in mice and rat peritoneal mast cells (RPMC).. Balb/c mice were systemically sensitized to OVA followed by intraperitoneal and nasal allergen challenges. We investigated the effect of OR extract on allergic symptoms, serological marker production and histological changes of the nasal mucosa in a mouse model of allergic rhinitis. We observed mast cell degranulation and detected the production of histamine and inflammatory cytokines by ELISA.. Compared to the OVA-control group, oral administration of OR extract at doses of 50 and 100 mg/kg significantly (p < 0.001) decreased the serum levels of histamine, OVA-specific IgE and Th2 cytokine,IIL-4 as well as increasing Th1 cytokine, IFN-gamma. Oral administration of OR extract also attenuated disease progression as determined by nasal symptoms and histological changes of the nasal mucosa in OVA-sensitized mice. Furthermore, treatment with OR extract at doses of 0.2, 0.5 ad 1 mg/mL in RPMC significantly (p <0.01, p <0.001 and p <0.001, respectively) decreased compound 48/80-induced histamine release and suppressed mast cell degranulation. Treatment with OR extract in RPMC also inhibited PMA/A23187-induced production of inflammatory cytokines such as TNF-alpha and IL-6. The mechanism of action underlying OR extract in allergic inflammation appears to be inhibition of the phosphorylation of ERK1/2 and p38 MAPK, in addition to blocking of the NFKB pathway.. These results indicate that OR extract has the potential to be a source of antiallergic agents for use in allergen and/or mast cell-mediated diseases including allergic rhinitis.

Topics: Animals; Anti-Allergic Agents; Apiaceae; Blotting, Western; Chromatography, High Pressure Liquid; Disease Models, Animal; Male; Mast Cells; Mice; Mice, Inbred BALB C; Ovalbumin; Phytotherapy; Plant Extracts; Plant Roots; Reverse Transcriptase Polymerase Chain Reaction; Rhinitis, Allergic, Perennial

Allergic rhinitis (AR) and asthma often coexist and are referred to as 'united airways' disease. However, the molecular and cellular pathways that are crucially involved in the interaction between upper and lower airways remain to be identified.. We sought to assess whether and how AR exacerbates lower airway inflammation upon allergen challenge in mice.. We previously developed an intranasal ovalbumin (OVA)-driven AR model, characterized by nasal eosinophilic inflammation, enhanced serum levels of OVA-specific IgE and Th2 cytokine production in cervical lymph nodes. In OVA-sensitized mice with or without AR, a lower airway challenge was given, and after 24 h, lower airway inflammation was analysed.. We found that AR mice were more susceptible to eosinophilic inflammation following a lower airway OVA challenge than OVA-sensitized controls. AR mice manifested increased numbers of eosinophils in bronchoalveolar lavage fluid and increased inter-cellular adhesion molecule-1 (ICAM-1) expression on lung endothelium, when compared with OVA-sensitized controls. Depletion of T cells in OVA-challenged AR mice completely abrogated all hallmarks of lower airway inflammation, including enhanced IL-5 and tissue eosinophilia. Conversely, adoptive transfer of Th2 effector cells in naïve animals induced lower airway eosinophilic inflammation after challenge with OVA. Blocking T cell recirculation during AR development by the spingosine-1 analogue FTY720 also prevented lower airway inflammation including ICAM-1 expression in AR mice upon a single lower airway challenge.. Our mouse model of 'united airways' disease supports epidemiological and clinical data that AR has a significant impact on lower airway inflammation. Circulating Th2 effector cells are responsible for lung priming in AR mice, most likely through up-regulation of ICAM-1.

Topics: Animals; Asthma; Disease Models, Animal; Female; Fingolimod Hydrochloride; Inflammation; Mice; Mice, Inbred BALB C; Ovalbumin; Propylene Glycols; Rhinitis, Allergic, Perennial; Sphingosine; Th2 Cells

Previous studies have shown that peroxisome proliferator-activated receptor gamma (PPARgamma) is involved in allergic rhinitis. It has been reported that 5-aminosalicylate (5-ASA) has an affinity for PPARgamma, but the effects of 5-ASA on the nasal symptoms of allergic rhinitis are unclear. This study aimed to clarify the effects of 5-ASA on nasal symptoms in an allergic rhinitis model in mice. Female BALB/c mice were sensitized by intraperitoneal injection of ovalbumin (OVA) and aluminium hydroxide hydrate gel (alum) on days 0, 5, 14 and 21. Seven days later, mice were sensitized by the intranasal application of OVA thrice a week. 5-ASA was also administered orally after instillation of the antigen from day 28. The severity of allergic rhinitis was assessed by determining the extent of 2 nasal allergic symptoms-sneezing and nasal rubbing. In addition, serum OVA-specific immunoglobulin E (IgE) antibody, interleukin (IL)-4, and IL-10 levels in nasal lavage fluid and histamine sensitivity were determined. Repeated oral administration of 5-ASA attenuated the progression of nasal symptoms in sensitized mice in a dose-dependent manner. Additionally, 5-ASA prevented an increase in histamine sensitivity. Finally, 5-ASA inhibited both OVA-specific IgE antibody and IL-4 production; however, it had no effect on IL-10 levels. These results indicate that 5-ASA has a prophylactic effect on allergic rhinitis.

Topics: Aluminum Hydroxide; Animals; Anti-Allergic Agents; Female; Histamine; Immunoglobulin E; Interleukin-10; Interleukin-4; Mesalamine; Mice; Mice, Inbred BALB C; Nasal Lavage Fluid; Ovalbumin; PPAR gamma; Rhinitis, Allergic, Perennial; Sneezing

It has been reported that olfactory function is impaired in patients with allergic rhinitis. However, the mechanism of olfactory dysfunction in allergic rhinitis remains poorly understood. Because of difficulties in obtaining and analyzing human olfactory mucosa due to both technical and ethical issues, an animal model needs to be established to clarify the mechanism of olfactory dysfunction in allergic rhinitis. The purpose of this study was to study olfactory function and changes in olfactory mucosa using allergic rhinitis mice.. A model of allergic rhinitis mice with olfactory dysfunction was developed by sensitizing with ovalbumin (OVA), and intranasally challenging with the same allergen. Olfactory function of mice with or without allergic rhinitis was assessed by odor detection ability test with cycloheximide and local field potential (LFP) with 1-octanal. We also evaluated histological changes in the olfactory mucosa of allergic rhinitis mice by both light and electron microscopy.. Both of odor detection ability test and LFP showed that olfactory function was impaired in mice with allergic rhinitis, but not in mice without allergic rhinitis. Histopathological findings showed prominent infiltration of eosinophils, plasma cells, neutrophils, mast cells, and macrophages in lamina propria of olfactory mucosa of mice with allergic rhinitis, although infiltration of these cells was not seen in control mice. Allergic rhinitis also increased the number and size of glands in olfactory mucosa, suggesting an elevated amount of mucin in olfactory mucosa.. This study showed for the first time that mice with allergic rhinitis have impaired olfactory function, increased size and number of olfactory glands, and infiltration of eosinophils, neutrophils, mast cells, plasma cells, and macrophages in the olfactory mucosa. This suggests that allergic reactions are seen in olfactory mucosa of mice with allergic rhinitis, and that greater olfactory gland activity is associated with olfactory dysfunction. Also, this mouse model could provide an expedient system for analyzing mechanisms of olfactory dysfunction.

Topics: Animals; Antibody Specificity; Eosinophils; Immunoenzyme Techniques; Immunoglobulin E; Macrophages; Male; Mice; Mice, Inbred C57BL; Microscopy, Electron, Transmission; Neutrophils; Olfactory Mucosa; Ovalbumin; Plasma Cells; Rhinitis, Allergic, Perennial; Sensory Thresholds; Smell

To investigate the effect of early allergen exposure on later development of allergic rhinitis in mouse.. Twenty-four BALB/c neonates were randomly divided into 4 groups (low-dose group, high-dose group, negative control group and positive control group), each group had 6 mice. The mice were administered ovalbumin (OVA) by subcutaneous injection on day 1, 5, 12 after birth (10 μg OVA in 0.05 ml saline for low-dose group, 1000 μg OVA in 0.05 ml saline for high-dose group, only saline for negative and positive control group). Then the mice were sensitized and intranasally challenged with OVA (saline without OVA was used in negative control group) after 6 weeks. Symptoms, histopathological changes of nasal mucosa were observed, OVA-IgE in serum was examined, cytokines IL-4, IL-5 and IFN-gamma were detected in the supernatant of cultured splenic mononuclear cells.. Compared to the positive control group, symptoms and nasal mucosa histological changes of high-dose group was indistinctive. The level of OVA-IgE and cytokines IL-4, IL-5 (x(-) +/- s) in high-dose group [(265.11 +/- 26.29), (446.39 +/- 72.83) and (171.24 +/- 15.66) pg/ml, respectively] were significantly lower than those in positive control group [(665.85 +/- 43.15), (1113.45 +/- 30.47), (255.36 +/- 30.96) pg/ml, respectively, t value were 0.000, 0.000 and 0.009, respectively, all P < 0.05]. The level of IFN-γ in high-dose group [(319.74 +/- 56.30) pg/ml] was significantly higher than those in positive control group [(170.02 +/- 14.50) pg/ml, t = 0.000, P < 0.05]. There was no significant difference of the results between the low-dose group and positive control group.. Neonatal immunization with high-dose OVA inhibited the future allergic rhinitis symptoms, nasal histological changes, serum OVA-IgE levels and Th1/Th2 cytokine imbalance, resulting in the protective effect.

Topics: Allergens; Animals; Animals, Newborn; Dose-Response Relationship, Immunologic; Immunoglobulin E; Interferon-gamma; Interleukin-4; Interleukin-5; Mice; Mice, Inbred BALB C; Nasal Mucosa; Nasal Provocation Tests; Ovalbumin; Rhinitis, Allergic, Perennial

Transforming growth factor-beta (TGF-beta) levels are elevated in the nasal mucosa in allergic rhinitis. However, because TGF-beta is secreted extracellulary in latent complexes, it remains unclear whether the local TGF-beta expression actually drives active signaling and affects the pathophysiology of allergic rhinitis. The objective of this study is to investigate whether TGF-beta signaling is activated in allergic rhinitis and plays a role in the pathophysiology of allergic rhinitis.. An ovabumin (OVA)-sensitized and -nasally challenged mouse model of allergic rhinitis was established and phosphorylation of Smad2 in the nasal mucosa was examined by immunohistochemistry. In addition, the effects of the pharmacological inhibition of endogenous TGF-beta signaling on the allergic rhinitis model were histologically examined. Furthermore, phosphorylation of Smad2 in the nasal mucosa samples obtained from patients with allergic rhinitis was also evaluated.. In the mouse model of allergic rhinitis, OVA challenge induced phosphorylation of Smad2 predominantly in epithelial cells in the nasal mucosa. In addition, the administration of an inhibitor of TGF-beta type I receptor kinase activity during OVA challenge suppressed goblet cell hyperplasia in the nasal mucosa. Furthermore, phosphorylated Smad2 expression increased in nasal epithelial cells in patients with allergic rhinitis.. These results suggest that TGF-beta signaling is activated in epithelial cells in the nasal mucosa in allergic rhinitis and may contribute to the development of goblet cell hyperplasia.

Topics: Animals; Cell Proliferation; Disease Models, Animal; Goblet Cells; Humans; Hyperplasia; Immunization; Mice; Nasal Mucosa; Ovalbumin; Phosphorylation; Protein Serine-Threonine Kinases; Pyrazoles; Quinolines; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal; Signal Transduction; Smad2 Protein; Transforming Growth Factor beta

Orai1 is an essential pore-forming subunit of the Ca(2+) release-activated Ca(2+) channels and plays a key role in the store-operated Ca(2+) entry. However, little is known about the function of this pathway in allergic airway diseases. In this study, we evaluated Orai1 expression in normal and allergic rhinitis (AR) mice airway and spleen. AR models were established by repetitive intraperitoneal sensitization followed by intranasal challenge with ovalbumin. Sneezing was counted, and eosinophils infiltration was analyzed through Luna stain. We performed the analysis of Orai1 protein in airway and spleen by immunohistochemical staining, Western blotting and enzyme-linked immunosorbent assay, and quantitatively examined Orai1 mRNA in the above tissues by real-time reverse transcription-polymerase chain reaction. Sneezes and eosinophil counts in the AR group were increased in comparison to those in the normal group. Orai1 protein was expressed in mucosal epithelium and submucosal glands epithelium of airway, and in immune cells of spleen. The immunostaining appeared stronger in AR mice than that in normal ones. Both the Orai1 protein and mRNA levels showed up-regulation in the AR group compared with those in the normal one. Our results indicate that Orai1 is up-regulated in the airway and spleen in allergic inflammation and may participate in the pathogenesis of allergic rhinitis.

Topics: Aluminum Hydroxide; Animals; Blotting, Western; Calcium Channels; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Immunohistochemistry; Inflammation; Mice; Mice, Inbred BALB C; ORAI1 Protein; Ovalbumin; Respiratory Mucosa; Reverse Transcriptase Polymerase Chain Reaction; Rhinitis, Allergic, Perennial; RNA, Messenger; Spleen; Trachea; Up-Regulation

Osteopontin (OPN) is a multifunctional protein that has recently been linked to allergic diseases. Clara cell 10 kDa protein (CC10) is another protein linked to allergy, and has been suggested to have an inhibitory role in inflammatory airway diseases. At this time, it is not known whether OPN is involved in allergic rhinitis (AR) or if there is any association between CC10 and OPN in AR.. To study the expression of OPN and its potential association with CC10 in AR.. The expression of CC10 and OPN in nasal mucosa of AR patients was investigated. AR animal models were established by using wild-type and CC10-knockout mice. In some experiments, human recombinant CC10 protein was given to AR mice during either sensitization or challenge. The phenotypic changes were examined by histology and real-time RT-PCR. The direct effect of CC10 on the OPN expression in spleen mononuclear cells and on the OPN-induced inflammatory cytokine expression in BEAS-2B cells was measured through in vitro cell culture.. OPN expression was up-regulated, with a concomitant down-regulation of CC10, in AR patients, showing a significant negative correlation between their expression. Compared with control mice sensitized with PBS, the OPN expression was significantly increased in AR mice; such an increase was more prominent in CC10-knockout mice, compared with wild-type. Administration of CC10 during both sensitization and challenge could markedly ameliorate Th2-skewed inflammation and OPN expression in nasal mucosa. CC10 administration at the sensitization phase could also reduce spleen OPN expression. The in vitro study showed that CC10 directly down-regulated the OPN expression in spleen mononuclear cells stimulated with OVA and suppressed the OPN-induced expression of Th2 cytokines and pro-inflammatory cytokines in BEAS-2B cells.. In the context of allergic airway responses, CC10 can inhibit OPN expression and suppress the Th2-promoting function of OPN, resulting in CC10's inhibitory biological effects.

Topics: Adult; Animals; Case-Control Studies; Cells, Cultured; Cytokines; Disease Models, Animal; Female; Humans; Inflammation Mediators; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Nasal Mucosa; Osteopontin; Ovalbumin; Pyroglyphidae; Recombinant Proteins; Respiratory Mucosa; Rhinitis, Allergic, Perennial; RNA, Messenger; Spleen; Th2 Cells; Uteroglobin

In this study, we investigated the effects of oral ingestion of Lactobacillus crispatus KT-11 strain (KT-11) on the immune response in an allergic rhinitis mouse model, ovalbumin (OVA)-sensitized BALB/c mice. Sneezing activity in mice that were administered a KT-11-supplemented diet was significantly lower than that in mice administered a KT-11-free diet (control diet) at age 11 weeks. We found that serum OVA-specific immunoglobulin E (IgE) levels and total number of interleukin (IL)-4(+) CD4(+) spleen cells in mice that were administered a KT-11-supplemented diet were significantly lower than in mice administered a control diet. The ratio of spleen interferon-γ(+) CD4(+) /IL-4(+) CD4(+) cells was higher in the mice administered the KT-11-supplemented diet compared to that in mice administered the control or L. rhamnosus GG-supplemented diet. In contrast, the number of CD11b(+) CD80(+) and FcεRIα(+) CD117(+) cells was significantly lower in mice administered the KT-11-supplemented diet. These results suggested that KT-11 reduced OVA-induced allergic symptoms in BALB/c mice via the adjustment of the T helper type 1/T helper type 2 balance, and a decrease in the number of antigen-presenting cells and high affinity IgE receptor-positive mast cells.

Topics: Administration, Oral; Animal Feed; Animals; Antigen-Presenting Cells; CD4 Antigens; Disease Models, Animal; Immunoglobulin E; Interleukin-4; Lactobacillus; Mast Cells; Mice; Mice, Inbred BALB C; Ovalbumin; Probiotics; Rhinitis, Allergic, Perennial; Spleen; Th1 Cells; Th2 Cells

Adipose tissue-derived stem cells (ASCs) exhibit immunosuppressive effects in allogeneic transplantation. However, there is no report that evaluates the in vivo immune-modulating effect of ASCs in an experimental allergic rhinitis (AR) model. We investigated whether ASCs migrate to the nasal mucosa in an AR mouse model and evaluated the immune-modulating effect of ASCs in the AR mouse model. Cultured ASCs (2 x 10(6)) were injected i.v. before the first allergen challenge in the AR mouse model. Migration of ASCs to the nasal mucosa was evaluated by immunofluorescence. The immunomodulatory effects of ASCs were evaluated by nasal symptoms, histology, serum ovalbumin (OVA)-specific antibody, and the cytokine profile of the spleen. ASCs migrated to the nasal mucosa in the AR mouse model. ASCs significantly reduced allergic symptoms and inhibited eosinophilic inflammation in the nasal mucosa. ASCs significantly decreased the serum allergen-specific IgE level and the IgG(1)/IgG(2a) ratio and significantly increased the IgG(2a) level in the AR mouse model. ASCs inhibited interleukin (IL)-4 and IL-5 production from OVA-incubated splenocytes, but enhanced interferon-gamma production. In conclusion, ASCs can migrate to the nasal mucosa in the AR mouse model and inhibit eosinophilic inflammation partly via shifting to a T-helper 1 (Th1) from a Th2 immune response to allergens.

Topics: Adipose Tissue; Animals; Antibody Formation; Cell Count; Cell Differentiation; Cytokines; Disease Models, Animal; Epitopes; Female; Immunoglobulin E; Immunoglobulin G; Immunologic Factors; Immunophenotyping; Mice; Mice, Inbred BALB C; Nasal Mucosa; Ovalbumin; Rhinitis, Allergic, Perennial; Spleen; Stem Cells

Interleukin-16 (IL-16) is a cytokine that induces selective migration of CD4+ cells and participates in inflammatory diseases including allergic rhinitis. Histamine and prostaglandin D(2) are important chemical mediators of allergic inflammation, and antiallergic drugs are commonly used for the treatment of allergic rhinitis. It remains unknown whether treatment with the drugs affects IL-16.. We evaluated the variability of IL-16 and the effects of the antiallergic drugs fexofenadine (40 mg/kg/day) and ramatroban (30 mg/kg/day) on IL-16 in an OVA-sensitized BALB/c murine experimental allergic rhinitis model.. We measured the expression level of IL-16 protein in the mouse nasal septal mucosa by immunohistochemistry, and the serum level of IL-16 by ELISA. Several other parameters associated with allergic rhinitis (nasal symptoms, OVA-specific IgE, eosinophil and T cell infiltration) were also measured.. Local and systemic expressions of IL-16 were significantly increased in OVA-sensitized mice when compared to the nonsensitized group. Fexofenadine and ramatroban significantly inhibited the following OVA-induced allergic features when compared to the nontreated sensitized group: sneezing, nasal rubbing, eosinophil infiltration, IL-16 expressions in nasal tissue, and serum IL-16 level. Serum OVA-specific IgE and local T cell infiltration were reduced, but they did not reach significant values.. These results suggest that IL-16 was both systemically and locally upregulated in the murine allergic rhinitis model and that IL-16 changed in parallel to allergic state by treatment with the drugs.

Topics: Animals; Anti-Allergic Agents; Carbazoles; Disease Models, Animal; Eosinophils; Female; Immunoglobulin E; Interleukin-16; Mice; Mice, Inbred BALB C; Nasal Mucosa; Ovalbumin; Platelet Aggregation Inhibitors; Rhinitis, Allergic, Perennial; Sulfonamides; Terfenadine

Peroxisome proliferator-activated receptor gamma(PPAR-gamma) has been shown to play an important role in the control of inflammatory responses acting on macrophages, mast cells, T cells, and eosinophils. The present study was aimed at investigating the effects of PPAR-gamma agonist on nasal symptoms and eosinophil accumulations in nasal mucosa by using a murine allergic rhinitis model. Furthermore, we examined the expression of PPAR-gamma in the nasal mucosa in mice.. BALB/c mice were sensitized and challenged intranasally with ovalbumin. Ciglitazone, a PPAR-gamma agonist, was administered orally 6 hours before each nasal challenge.. Administration of PPAR-gamma agonist significantly decreased the number of nasal rubs, nasal histamine responsiveness, serum IgE, IL-5 production from the spleen, and eosinophilic infiltration in the nasal mucosa. Furthermore, PPAR-gamma was expressed in eosinophils and epithelial cells in the nasal mucosa by immunohistochemistry.. PPAR-gamma was expressed in eosinophils and epithelial cells in the nasal mucosa. Also, the oral administration of ciglitazone is effective in upper airway allergic inflammation in mice.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Behavior, Animal; Eosinophils; Epithelial Cells; Female; Histamine; Immunoglobulin E; Interferon-gamma; Interleukin-13; Interleukin-5; Mice; Mice, Inbred BALB C; Nasal Mucosa; Ovalbumin; PPAR gamma; Rhinitis, Allergic, Perennial; Sneezing; Spleen; Thiazolidinediones

Allergic rhinitis is 1 of the most common atopic diseases with strong similarity to asthma. Interleukin (IL) 27 is an immunosuppressive cytokine, and lack of the IL-27 receptor (WSX-1) resulted in exacerbation of allergic airway hyperresponsiveness.. To address the role of IL-27/WSX-1 in the rhinitis model compared with the asthma model.. Wild-type or WSX-1(-l-) female mice were immunized intraperitoneally 4 times with ovalbumin adsorbed to aluminum potassium sulfate at a 1-week interval. The sensitized mice were then challenged for 14 days with ovalbumin intranasally from days 22 to 35. Clinical scores, serum antigen specific IgE levels, and cytokine production in the nasal lavage fluid were examined. Cytokine and chemokine expression in the cervical lymph nodes, nasopharynx-associated lymphoid tissues, and nasal mucosa was also examined.. WSX-1(-l-) mice developed augmented immune responses in the serum (IgE production), cervical lymph nodes (cytokine and chemokine expression), and nasopharynx-associated lymphoid tissues (cytokine and chemokine expression), whereas local responses, such as clinical scores and nasal lavage fluid cytokine production, were reduced in WSX-1(-l-) mice. Expression of some chemokines was also reduced in the nasal mucosal tissues of WSX-1(-l-) mice.. In contrast to the immunosuppressive role observed in the asthma model, IL-27/WSX-1 topically plays an exacerbating role in the pathogenesis of allergic rhinitis, presumably through differential expression of chemokines.

Topics: Animals; CD4-Positive T-Lymphocytes; Cervix Uteri; Chemokines; Cytokines; Disease Models, Animal; Female; Gene Expression; Immunization; Immunoglobulin E; Interleukins; Lymphocyte Activation; Lymphoid Tissue; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nasal Lavage Fluid; Nasal Mucosa; Nasopharynx; Ovalbumin; Receptors, Cytokine; Receptors, Interleukin; Rhinitis, Allergic, Perennial; Signal Transduction

Compared to healthy subjects, individuals with allergic airway disease (e.g., asthma, allergic rhinitis) have enhanced inflammatory responses to inhaled ozone. We created a rodent model of ozone-enhanced allergic nasal responses in Brown Norway rats to test the therapeutic effects of the dietary supplement gamma-tocopherol (gammaT). Ovalbumin (OVA)-sensitized rats were intranasally challenged with 0% or 0.5% OVA (in saline) on Days 1 and 2, and then exposed to 0 or 1 ppm ozone (eight hours/day) on Days 4 and 5. Rats were also given 0 or 100 mg/kg gammaT (p.o., in corn oil) on days 2 through 5, beginning twelve hours after the last OVA challenge. On Day 6, nasal tissues were collected for histological evaluation and morphometric analyses of intraepithelial mucosubstances (IM) and eosinophilic inflammation. Nasal septal tissue was microdissected and analyzed by reverse transcriptase polymerase chain reaction (RT-PCR) for mucin glycoprotein 5AC (MUC5AC) expression levels. Histological analysis revealed mild to moderate eosinophil influx in the mucosa lining the nasal airways and maxillary sinus of OVA-challenged rats (eosinophilic rhinosinusitis). Ozone exposure of allergic rats further increased eosinophils in the maxillary sinus (400%), nasolacrimal duct (250%), and proximal midseptum (150%). Storage of intraepithelial mucosubstances (IM) was not significantly affected by OVA challenge in filtered air-exposed rats, but it was increased by ozone in the septum (45%) and maxillary sinus (55%) of allergic compared to control rats. Treatment with gammaT attenuated the ozone/ OVA-induced synergistic increases in IM and mucosal eosinophils in both nasal and paranasal airways. gamma-Tocopherol also blocked OVA and ozone-induced MUC5AC gene expression. Together, these data describe a unique model of ozone enhancement of allergic rhinosinusitis and the novel therapeutic efficacy of a common supplement, gammaT, to inhibit ozone exacerbation of allergic airway responses.

Topics: Analysis of Variance; Animals; Asthma; Eosinophils; gamma-Tocopherol; Male; Mucin 5AC; Nasal Cavity; Nasal Mucosa; Ovalbumin; Ozone; Rats; Rhinitis, Allergic, Perennial

Recent studies have shown that by acting as strong TH1 response-inducing adjuvants, DNA immunostimulatory sequence oligdeoxynucleotides (ISS-ODNs) can be used in the treatment of allergic diseases, and efforts are being made to enhance these TH1 adjuvant actions.. To determine whether intranasally delivered ISS-ODN/cholera toxin B (CTB) conjugate has enhanced antiallergic effects in an allergic rhinitis mouse model.. BALB-c mice were sensitized with ovalbumin. Chemical conjugation of ISS-ODN and CTB was performed. After a single local intranasal administration of 50 microg of ISS-ODN or high- and low-dose (50- and 5-microg) ISS-ODN/CTB conjugate, we measured the allergic response in terms of sneezing events, eosinophil infiltration in the nasal mucosa, serum ovalbumin specific IgE and IgG2a levels, and TH1 and TH2 cytokine levels in nasal lavage fluid and spleen cell cultures.. A single local administration of 50 microg of ISS-ODN did not suppress the allergic phenotype. However, 50 and 5 microg of ISS-ODN/CTB conjugate significantly attenuated allergic symptoms, eosinophil infiltration in the nasal mucosa, and interleukin 4 production from nasal lavage fluid and cultured splenocyte supernatant compared with the allergic control. Serum specific IgG2a and interleukin 12 production in nasal lavage fluid and spleen cell cultures was significantly increased.. In a mouse model of allergic rhinitis, a single intranasal delivery of low-dose ISS-ODN/CTB conjugate effectively protects previously sensitized mice from allergic hypersensitivity responses. With further research, ISS-ODN/CTB conjugate may serve as a new allergen-independent intranasal vaccine for the treatment of allergic rhinitis.

Topics: Adjuvants, Immunologic; Administration, Intranasal; Animals; Cholera Toxin; DNA; Eosinophils; Female; Immunoglobulin G; Immunotoxins; Interleukin-12; Interleukin-4; Mice; Mice, Inbred BALB C; Nasal Lavage Fluid; Nasal Mucosa; Oligodeoxyribonucleotides; Ovalbumin; Rhinitis, Allergic, Perennial; Vaccines, Conjugate

To investigate the expression of thymic stromal lymphopoietin (TSLP) in the nasal mucosa of mouse with allergic rhinitis.. Twenty wide type BALB/c mouse were divided into 2 groups randomly. Two groups were included, allergic rhinitis group (group A) and control group (group B). The mouse model of allergic rhinitis was established by ovalbumin (OVA) sensitization and challenge. The expressions of TSLP in the nasal mucosa was determined by realtime quantitative PCR and immunohistochemical method.. The expression of TSLP in the nasal mucosa of group A was significantly higher than that in group B (P<0.01).. TSLP plays a role in the mouse model of allergic rhinitis.

Topics: Animals; Cytokines; Disease Models, Animal; Female; Mice; Mice, Inbred BALB C; Nasal Mucosa; Ovalbumin; Rhinitis, Allergic, Perennial; Thymic Stromal Lymphopoietin

KP-496 is a novel dual antagonist for leukotriene (LT) D(4) and thromboxane (TX) A(2) receptors. We investigated effects of KP-496 on antigeninduced nasal blockage in 2 guinea pig models of allergic rhinitis.. Male Hartley guinea pigs were used.. Animals were actively sensitized with ovalbumin (OVA) or Japanese cedar pollen, and were then repeatedly challenged with OVA or pollen, respectively. KP-496 (0.003 %-0.05 %) was intranasally administered 0.5 or 1 h before and 2 h after an antigen challenge.. As an indicator of nasal blockage, specific airway resistance was measured using a double-flow plethysmograph system. Statistical analyses were performed with Dunnett's test (OVA model) or t-test (pollen model).. Although early phase response was not affected by even a high dose (0.03 %) of KP-496, late phase nasal blockage (1.68 +/- 0.26) was inhibited by 0.01 % (0.87 +/- 0.19; p <0.05) and 0.03 % (0.44 +/- 0.12; p <0.01) of KP-496 in the OVA model. On the other hand, both early (5.60 +/- 0.77) and late phase responses (7.90 +/- 1.70) were inhibited by 0.05 % KP-496 to 2.68 +/- 0.84 (p <0.05) and 2.71 +/- 0.83 (p <0.05), respectively, in the pollen model, in which nasal hyperresponsiveness had been acquired by multiple challenges.. KP-496 may be clinically effective for nasal blockage in allergic rhinitis.

Topics: Airway Resistance; Animals; Area Under Curve; Benzoates; Disease Models, Animal; Guinea Pigs; Humans; Leukotriene Antagonists; Male; Nasal Mucosa; Nasal Obstruction; Ovalbumin; Pollen; Receptors, Leukotriene; Receptors, Thromboxane A2, Prostaglandin H2; Rhinitis, Allergic, Perennial; Sneezing; Thiazoles

The aim of this study was to clarify the mechanisms of the inhibitory effect of a histamine H3 receptor agonist, Sch 50971, on nasal signs in an allergic rhinitis model in mice. The severity of allergic rhinitis was assessed by determining the extent of two markers of allergic symptoms (sneezing and nasal rubbing). The topical application of a histamine H3 receptor antagonist, clobenpropit, into the nasal cavities resulted in a dose-dependent increase in sneezing and nasal rubbing, and both Sch 50971 and a tachykinin NK1 receptor antagonist, L-733,060, inhibited these reactions in non-sensitized mice. Sch 50971 caused no inhibition of histamine- and substance P-induced nasal symptoms; however, the reactions induced by capsaicin were significantly decreased by Sch 50971 in non-sensitized mice. Sch 50971 and cetirizine inhibited antigen-induced sneezing and nasal rubbing in sensitized mice. On the other hand, cetirizine inhibited nasal symptoms induced by antigen in capsaicin-pretreated mice, whereas no effect was observed in Sch 50971. From these results, we concluded that Sch 50971 blocked nasal symptoms by the inhibition of substance P release via histamine H3 receptors located on peri]pheral sensory nerve endings.

Topics: Animals; Capsaicin; Cetirizine; Disease Models, Animal; Female; Histamine; Histamine Agonists; Histamine H1 Antagonists, Non-Sedating; Imidazoles; Mice; Mice, Inbred BALB C; Ovalbumin; Piperidines; Pyrrolidines; Receptors, Histamine H3; Rhinitis, Allergic, Perennial; Substance P; Thiourea

To investigate the effect of rosiglitazone, a synthetic selective peroxisome proliferator-activated receptor (PPAR)-gamma agonist, for cytokine production and PPAR-gamma expression in nasal mucosa.. Mice in allergic rhinitis group received ovalbumin sensitization followed by ovalbumin intranasal challenge. Mice in the rosiglitazone group received rosiglitazone treatment additionally. Various allergic responses were then assessed.. The frequency of nasal rubs and ovalbumin-specific immunoglobulin E decreased significantly in the rosiglitazone group compared with the allergic rhinitis group. The rosiglitazone group also showed that inflammation was markedly reduced by rosiglitazone administration. Immunohistochemistry showed that PPAR-gamma protein expression in nasal mucosa was enhanced in the allergic rhinitis group and the rosiglitazone group compared with control mice.. PPAR-gamma activation with rosiglitazone effectively inhibited allergic symptom development, nasal mucosal inflammation, and production of ovoalbumin-specific immunoglobulin E and Th2-type cytokine. Our results provide evidence of the therapeutic potential of PPAR-gamma agonist for the treatment of allergic rhinitis.

Topics: Animals; Disease Models, Animal; Female; Immunoglobulin E; Immunohistochemistry; Mice; Mice, Inbred BALB C; Ovalbumin; PPAR gamma; Rhinitis, Allergic, Perennial; Rosiglitazone; Thiazolidinediones

Ovalbumin-induced guinea pig model of rhinitis was assessed for its utility in the studies of rhinitis. Systemic sensitization and challenge with ovalbumin-induced rhinitis symptoms and an increase in anti-OVA-IgE and IgG titers, positive skin reactions and nasal lavage IL-4 concentration. Histopathology of nasal mucosa showed infiltration of eosinophils and other inflammatory cells consistent with the symptoms. Topical sensitization of ovalbumin yielded inconsistent symptoms of rhinitis. In systemic sensitization model, repeated challenge of ovalbumin caused similar response for at least 3 consecutive challenges. The symptoms were affected by relative humidity in the air and dosing volume of topical drugs. Sneezing and lacrimation were reduced by acute oral administration of the H1 receptor antagonists and steroids or the prophylactic oral administration of cysteinyl leukotriene (CysLT1) receptor antagonist montelukast or acute topical antihistamines, mast cell stabilizer sodium cromoglycate and anticholinergic agent ipratropium bromide, but not by a topical steroid. Nose rubbing was reduced significantly by some oral and topical antihistamines. Oral steroids offered excellent protection against all symptoms. Dexamethasone and montelukast also inhibited nasal lavage IL-4 concentration and inflammatory cell infiltration. Treatment with topical steroid fluticasone for 2 weeks had no effect on sneezing or rubbing. However, it caused complete inhibition of congestion. The cyclooxygenase inhibitor indomethacin had no effect on symptoms of rhinitis. The adrenergic alpha receptor agonist-decongestant oxymetazoline caused reduction in congestion. These results suggest that differential responsiveness to symptoms of rhinitis by a new agent can be very well profiled in the model in congruence with the mediation pathways and mechanism of action of drugs. The model provides complete symptomatic characterization of rhinitis and is a good tool for its study.

Topics: Administration, Oral; Administration, Topical; Animals; Anti-Allergic Agents; Disease Models, Animal; Female; Guinea Pigs; Humidity; Immunoglobulin E; Immunoglobulin G; Interleukin-4; Male; Ovalbumin; Passive Cutaneous Anaphylaxis; Rhinitis, Allergic, Perennial; Sneezing

The present study was performed to study the participation of histamine H(3) receptors in nasal symptoms using Sch 50971, a potent and selective agonist of the H(3) receptor. Repeated topical application of antigen caused an increase in sneezing and nasal rubbing in sensitized mice. Oral administration of Sch 50971 and imetit, specific H(3)-receptor agonists, resulted in an inhibition of nasal symptoms induced by an antigen similar to an H(1)-receptor antagonist, cetirizine. Furthermore, simultaneous use of H(3)-receptor agonists, Sch 50971 or imetit, and an H(1)-receptor antagonist, cetirizine, caused a significant inhibitory effect on nasal symptoms at doses that showed no effect when used separately. The number of eosinophils in the nasal mucosa of mice sensitized with antigen was significantly decreased by cetirizine; however, Sch 50971 and imetit had no effect on eosinophil infiltration. These results clearly indicate that H(3) receptors are involved in the etiology of nasal allergy, and the stimulation of H(3) receptors may be useful as a novel therapeutic approach in nasal allergy.

Topics: Animals; Anti-Allergic Agents; Cetirizine; Chemotaxis, Leukocyte; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Eosinophils; Female; Histamine Agonists; Histamine H1 Antagonists, Non-Sedating; Imidazoles; Mice; Mice, Inbred BALB C; Nasal Mucosa; Ovalbumin; Pruritus; Pyrrolidines; Receptors, Histamine H3; Rhinitis, Allergic, Perennial; Sneezing; Thiourea; Time Factors

We examined the role of prostanoid DP receptor in nasal blockage in an experimental allergic rhinitis model in guinea pigs. Local inhalation of prostaglandin D(2) (PGD(2)) to the nasal cavity resulted in an increase in intranasal pressure in guinea pigs actively sensitized by repeated antigen exposure but not in non-sensitized guinea pigs. Nasal hyperresponsiveness was observed when the guinea pigs were exposed to histamine and U-46619 (11alpha, 9alpha-epoxymethano-PGH(2); a thromboxane (TX) A(2) mimetic) after repeated antigen exposure. S-5751 ((Z)-7-[(1R,2R,3S,5S)-2-(5-hydroxybenzo[b]thiophen-3-ylcarbonylamino)-10-norpinan-3-yl]hept-5-enoic acid), a prostanoid DP receptor antagonist, inhibited not only PGD(2)-induced nasal blockage but also nasal hyperresponsiveness to histamine and U-46619 in sensitized guinea pigs. Combined exposure of the nasal cavity of guinea pigs to an aerosol of PGD(2) with histamine or U-46619 at sub-threshold concentrations synergistically caused a marked increase in intranasal pressure. These responses were significantly suppressed by S-5751. These results suggest that PGD(2) plays a critical role in the increase in intranasal pressure via prostanoid DP receptor, probably through synergistically enhancing the nasal response with other chemical mediators released from mast cells and other inflammatory cells activated by allergens.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Administration, Intranasal; Allergens; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Guinea Pigs; Histamine; Male; Nasal Mucosa; Nasal Obstruction; Nose; Ovalbumin; Pressure; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin; Rhinitis, Allergic, Perennial; Thiophenes; Time Factors

The mechanisms of distant manifestation after a local allergic reaction are largely unknown. This study examined the development of cutaneous lesions in a mouse model of late allergic rhinitis (LAR). BALB/c mice were sensitized by ovalbumin (OVA) intraperitoneally two times (on days 0 and 10) and challenged by OVA intranasally on day 14. Four days after OVA challenge, nasal and cutaneous lesions including helper T (Th) responses, expression of adhesion molecules and presence of OVA and IgE were examined, and compared with unsensitized and unchallenged (control) mice. Compared with the control group, the LAR group developed LAR characterized by infiltration of lymphocytes and eosinophils, increased IgE values and increased productions of IL-4 and IL-5, but not IFN-gamma. A dominant infiltration of eosinophils and increase in mast cells, attachment of eosinophils to endothelium, intense expression of VCAM-1 on endothelium in venules and VLA-4 expression on eosinophils and mast cells were recognized in the cutaneous tissues. There were no differences in the expression of ICAM-1 on vascular endothelium and LFA-1 on infiltrated leucocytes between the two groups. CLA expression on lymphocytes was not detected, and the binding of OVA and IgE on mast cells and eosinophils was found in the cutaneous lesions in the LAR group, but not in the control group. This study suggests that acute urticaria[corrected]-like lesions in OVA-unexposed cutaneous tissues may be induced by immediate allergic reaction due to the systemic development of Th2-type response in a mouse model of LAR.

Topics: Acute Disease; Allergens; Animals; Cell Adhesion Molecules; Cells, Cultured; Cytokines; Disease Models, Animal; Eosinophils; Female; Immunoglobulin E; Leukocyte Count; Mice; Mice, Inbred BALB C; Nasal Septum; Ovalbumin; Rhinitis, Allergic, Perennial; Spleen; Th2 Cells; Urticaria

The cysteinyl leukotrienes (cysLTs) are potent lipid mediators in allergic disease, acting through the receptors, cysLT1R and cysLTR2, and are produced by eosinophils derived from eosinophil/basophil (Eo/B) bone marrow (BM) progenitors. We have demonstrated the suppressive effects of either interleukin-5 (IL-5) deficiency or montelukast on eosinophil recruitment in murine allergic rhinitis, but neither of them fully abrogated the symptoms caused by residual inflammation and cytokine redundancy in eliciting BM Eo/B responses. We hypothesized that IL-5 deficiency and montelukast act synergistically to suppress tissue inflammatory and BM responses. Our objective was to investigate the effects of the cysLT1R antagonist, montelukast, on in vivo tissue inflammatory and BM responses in murine experimental allergic rhinitis with or without IL-5 deficiency. Three groups of age-matched BALB/c mice with or without IL-5 deficiency were tested: controls (ovalbumin sensitization and challenge, placebo treatment) and two montelukast-treated groups (2.5 mg/kg or 5 mg/kg). Nasal symptoms, BM and nasal mucosal eosinophils, basophils, and BM Eo/B colony-forming units (CFU) were evaluated. Montelukast decreased nasal symptoms in a dose-dependent manner, and significantly decreased the number of eosinophils in both BM and nasal tissue in IL-5-replete mice compared to controls. In IL-5-deficient mice, in which eosinophilia was absent, montelukast significantly decreased both nasal symptoms and basophils in BM and nasal mucosal tissue, and lowered IL-5-responsive Eo/B-CFU ex vivo, compared to controls. The addition of cysLT1R blockade to IL-5 deficiency more fully attenuates symptoms and upper airway inflammation than either factor alone, providing evidence of systemic, BM mechanisms in allergic rhinitis.

Topics: Acetates; Animals; Basophils; Bone Marrow; Colony-Forming Units Assay; Cyclopropanes; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Eosinophils; Hematopoietic Stem Cells; Interleukin-5; Leukotriene Antagonists; Mice; Mice, Inbred BALB C; Nasal Mucosa; Ovalbumin; Quinolines; Rhinitis, Allergic, Perennial; Sulfides

Allergic airways disease is initiated and perpetuated by an aberrant Th2 inflammatory response regulated in part by the cytokines IL-4 and IL-13, each of which induces activation of the STAT-6 transcription factor. Data from murine models indicate that the clinical manifestations of acute asthma are STAT-6 dependent, and thus, STAT-6 is a target for drug development in allergic airways disease. We designed a novel chimeric peptide (STAT-6 inhibitory peptide (STAT-6-IP)) comprised of a sequence predicted to bind to and inhibit STAT-6, fused to a protein transduction domain, to facilitate cellular uptake of the STAT-6-binding peptide. Our data demonstrate that the STAT-6-IP inhibited OVA-induced production of Th2 cytokines IL-4 and IL-13 in vitro. In contrast, the STAT-6-IP did not affect production of IFN-gamma, demonstrating specificity for Th2 cytokine inhibition. Following intranasal administration, the STAT-6-IP was localized to epithelial cells in the airways. Finally, in in vivo murine models of allergic rhinitis and asthma, intranasal delivery of the STAT-6-IP inhibited OVA-induced lung inflammation and mucus production as well as accumulation of eosinophils and IL-13 in bronchoalveolar lavage fluid and OVA-dependent airway hyperresponsiveness. Together these data show that local application of cell-penetrating peptide inhibitors of STAT-6 has significant potential for the treatment of allergic rhinitis and asthma.

Topics: Acute Disease; Administration, Intranasal; Animals; Asthma; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Eosinophils; Interleukin-13; Interleukin-4; Mice; Mucus; Ovalbumin; Peptides; Pneumonia; Protein Binding; Recombinant Fusion Proteins; Respiratory Mucosa; Rhinitis, Allergic, Perennial; STAT6 Transcription Factor; Th2 Cells

To investigate the effect and mechanism of Biminne, a Chinese herbal compound preparation, for treatment of allergic rhinitis (AR).. AR model of mouse was induced by intraperitoneal injection of ovalbumin (OVA), and the changes in behavior, proliferative activity of splenic lymphocyte, serum levels of total IgE and OVA specific IgE were observed.. Biminne showed effects in reducing the frequency of sneezing and nasal rubbing, inhibiting the proliferation of splenic lymphocyte stimulated by phyto-hemagglutinin (PHA) and OVA, and lowering the levels of serum total IgE and OVA specific IgE.. Biminne could inhibit the proliferation of splenic lymphocyte and reduce serum level of IgE in mice with AR.

Topics: Animals; Cell Proliferation; Drugs, Chinese Herbal; Immunoglobulin E; Lymphocytes; Male; Mice; Mice, Inbred BALB C; Ovalbumin; Phytotherapy; Random Allocation; Rhinitis, Allergic, Perennial

Allergic rhinitis is one of the most common chronic diseases. There are a number of effective therapeutic options for allergic rhinitis patients, such as intranasal corticosteroids. How to avoid the adverse effects of these traditional medicines has come to public attention and started the search for effective and safe medicine. We used BALB/c mice with experimental allergic rhinitis, and determined that levamisole delivered locally (intranasal, i.n.) could attenuate early-phase inflammatory response, decrease histamine, suppress edema and eosinophil infiltration, and diminish the ovalbumin-specific serum IgE level. Detailed analysis of cytokine gene expression showed that levamisole can decrease IL-4, IL-5 and IL-13 mRNA and increase IL-12, IL-18 and IFN-gamma mRNA. Levamisole showed analogous effects of down-regulating Th2 cytokines with budesonide and distinct up-regulating effects on Th1 cytokines gene expression. Our findings offer potential options for allergic rhinitis therapy.

Topics: Administration, Intranasal; Aluminum Hydroxide; Animals; Anti-Allergic Agents; Bordetella pertussis; Coloring Agents; Cytokines; Enzyme-Linked Immunosorbent Assay; Eosinophils; Histamine; Histamine Release; Immunoglobulin E; Immunohistochemistry; Indicators and Reagents; Interleukin-12; Levamisole; Male; Mice; Mice, Inbred BALB C; Naphthalenesulfonates; Nasal Mucosa; Ovalbumin; Reverse Transcriptase Polymerase Chain Reaction; Rhinitis, Allergic, Perennial

The present study was conducted to determine whether lactate dehydrogenase-elevating virus (LDV) infection at the sensitization and challenge phases affect the development of delayed allergic eosinophilic rhinitis induced by ovalbumin (OVA) in BALB/c mice (DAR group). Compared to the DAR group, LDV infection at the priming (DAR/LDVs group) and immunizing (DAR/LDVc group) phases reduced the induction of eosinophils in the bone marrow (BM) and/or blood. However, the number of eosinophils in the BM was not affected in the DAR/LDVc group. In addition, total blood IgE values were reduced in the DAR/LDVs but not the DAR/LDVc groups. Compared to the production of cytokines from splenic cells and blood IgE values in the DAR group, OVA-specific IL-4 and IFN-gamma productions and IgE values were reduced in the DAR/LDVs, whereas OVA-specific IFN-gamma and IL-4 productions were increased and decreased, respectively in the DAR/LDVc,but not the DAR/LDVs groups. Both DAR/LDVs and DAR/LDVc groups reduced the development of eosinophilic rhinitis associated with reduced VCAM-1 expression on endothelium in blood vessels and ICAM-1 expression on nasal respiratory epithelium at inflamed areas. The present study suggests that LDV infection at the sensitization phase may reduce the development of T helper (Th) 1 and Th2 responses, whereas LDV infection at the challenge phase may inhibit the development of Th2 response by shifting to Th1 response. These may be responsible for the reduction of the development of DAR by LDV infection.

Topics: Animals; Arterivirus Infections; Bronchial Provocation Tests; Disease Models, Animal; Eosinophilia; Female; Immunization; Immunoglobulin E; Immunologic Factors; Interferon-gamma; Lactate dehydrogenase-elevating virus; Mice; Mice, Inbred BALB C; Nasal Mucosa; Ovalbumin; Rhinitis, Allergic, Perennial; Species Specificity; Specific Pathogen-Free Organisms; Th1 Cells; Th2 Cells

We investigated the effect of Lactobacillus acidophilus strain L-55 isolated from infant feces on experimental allergic rhinitis in BALB/c mice. The heat-treated cells of strain L-55 were orally administrated for 4 consecutive weeks to mice sensitized by ovalbumin (OVA), and nasal symptoms (sneezing and nasal rubbing) induced by OVA challenge were evaluated. Strain L-55 at doses of 1 and 10 mg cells/mouse significantly inhibited nasal symptoms by repeated administration over a period of 2 weeks. Furthermore, we measured the level of OVA-specific IgE titers in the serum by passive cutaneous anaphylaxis (PCA) reaction. PCA titers in the sera from mice administrated strain L-55 were significantly lowered compared with the control. These results suggest that oral administration of strain L-55 may be useful for alleviating the nasal symptoms of allergic rhinitis.

Topics: Administration, Oral; Animals; Behavior, Animal; Disease Models, Animal; Feces; Female; Humans; Immunoglobulin E; Infant; Lactobacillus acidophilus; Mice; Mice, Inbred BALB C; Ovalbumin; Passive Cutaneous Anaphylaxis; Rhinitis, Allergic, Perennial; Sneezing

Allergic rhinitis is one of the most common causes of chronic cough. The characteristic feature of allergic rhinitis is eosinophilic nasal inflammation. This study was determined to find the relation between airway eosinophils and chemically-induced cough in guinea pigs with antigen-induced rhinitis at the early and late allergic phases. Forty animals were sensitized with ovalbumin (OVA) and divided into four separated groups. Four weeks later, the sensitized animals were either once or repeatedly (6 times at 7-day intervals) intranasally challenged with OVA to develop experimental allergic rhinitis. The control group was given saline. Cough was elicited by inhalation of citric acid aerosols and evaluated at 30 min (early phase) or 24 h (late phase) after the 1st or 6th nasal challenge (NC) in the sensitized animals. The citric acid-induced cough was significantly increased in the sensitized animals in the early allergic phase after the first and repeated NC compared with the control values [14(9-19) vs. 16(10-17) vs. 8(6-10); P=0.049], whereas there was no significant increase in the cough response tested in the late allergic phase. A correlation between the cough intensity and the number of eosinophils from nasal mucosa only (P=0.008) was found.

Topics: Aerosols; Animals; Bronchi; Citric Acid; Cough; Disease Models, Animal; Eosinophilia; Guinea Pigs; Larynx; Lung; Mice; Nasal Mucosa; Ovalbumin; Pulmonary Eosinophilia; Rhinitis, Allergic, Perennial; Severity of Illness Index; Time Factors; Trachea

Cough is a common and important symptom of asthma and allergic rhinitis. Previous experimental evidence has shown enhanced cough sensitivity during early phase of experimental allergic rhinitis in guinea pigs. We hypothesized that airway inflammation during the late phase response after repeated nasal antigen challenge may affect the afferent sensory nerve endings in the larynx and tracheobronchial tree and may also modulate cough response. In the present study we evaluated the cough sensitivity during a period of early and late allergic response in sensitized guinea pigs after repeated nasal antigen challenges. Forty-five guinea pigs were sensitized with ovalbumin (OVA). Four weeks later 0.015 ml of 0.5 % OVA was intranasally instilled to develop a model of allergic rhinitis that was evaluated from the occurrence of typical clinical symptoms. Animals were repeatedly intranasally challenged either by OVA (experimental group) or by saline (controls) in 7-day intervals for nine weeks. Cough was elicited by inhalation of citric acid aerosols. Cough was evaluated at 1 or 3 h after the 6th nasal challenge and 17 or 24 h after the 9th nasal challenge. The cough reflex was significantly increased at 1 and 3 h after repeated nasal challenge in contrast to cough responses evoked at 17 and 24 h after repeated nasal challenge. In conclusion, enhanced cough sensitivity only corresponds to an early allergic response after repeated nasal challenges.

Topics: Allergens; Animals; Citric Acid; Cough; Disease Models, Animal; Guinea Pigs; Immunization; Male; Nasal Provocation Tests; Ovalbumin; Respiratory System; Rhinitis, Allergic, Perennial; Sneezing; Time Factors

Allergic rhinitis is one of the most common allergic inflammatory diseases characterized by a predominant TH2 response with antigen-specific IgE synthesis. IL-15 plays important roles in activation and maintenance of memory CD8+T cells capable of producing IFN-gamma, which regulates TH2 responses.. To investigate the roles of endogenous IL-15 in allergic inflammation, we examined allergic rhinitis in IL-15 knockout (KO) mice sensitized with ovalbumin followed by intranasal rechallenge with ovalbumin.. IL-15KO mice were sensitized intraperitoneally with ovalbumin/complete Freund's adjuvant on day 0 and ovalbumin/IFA on day 7, and then were intranasally challenged with ovalbumin on days 21, 22, 23, 24, and 25. Nasal symptoms and histologic changes were examined. IgE production and TH2 responses were measured by ELISA. Purified CD8+T cells or recombinant IL-15 were administered into ovalbumin-sensitized mice.. The levels of IgE production and TH2 responses in IL-15KO mice were comparable to those in control mice after ovalbumin sensitization. However, sneezing, infiltration of eosinophils into the nasal mucosa, and TH2 cytokine production were aggravated in ovalbumin-sensitized IL-15KO mice after intranasal challenge with ovalbumin. Adoptive transfer of CD8+6 T cells from ovalbumin-sensitized mice suppressed the TH2 responses in mice but not in IL-15KO mice. Administration of IL-15 with ovalbumin significantly prevented the development of allergic rhinitis in ovalbumin-sensitized mice.. We demonstrate with IL-15KO mice that endogenous IL-15 plays an important role in suppression of allergic rhinitis at effector phase. Intranasal administration of IL-15 is useful as a therapeutic approach to control allergic rhinitis.. Intranasal administration of recombinant IL-15 might become new immunotherapy for allergic rhinitis.

Topics: Administration, Intranasal; Animals; CD8-Positive T-Lymphocytes; Disease Models, Animal; Epitopes, T-Lymphocyte; Interleukin-15; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Mice, Knockout; Ovalbumin; Rhinitis, Allergic, Perennial

Studies show that children in rural environments develop less asthma and allergic rhinitis than their urban counterparts. This may be a result, in part, of neonatal exposure to environmental antigens such as LPS and/or early exposure to allergens.. This study examined the effects of neonatal allergen and/or LPS exposure on subsequent immune responses to allergen.. Newborn mice were exposed to LPS and/or ovalbumin. At age 6 weeks, these animals were sensitized and challenged with ovalbumin, and airway inflammation, hyperresponsiveness, and cytokine expression were assessed.. Animals exposed to LPS in the neonatal period developed T cells expressing CD25 and IL-10 on sensitization and challenge. They demonstrated abrogation of airway hyperresponsiveness and significant decreases in IL-13 from bronchoalveolar lavage fluid and in specific IgE. IL-4-expressing spleen cells were also significantly decreased. Mice exposed in the neonatal period to ovalbumin demonstrated airway hyporesponsiveness after subsequent ovalbumin sensitization and challenge and did not produce specific IgE. In contrast, these animals showed increases in IFN-gamma. Animals exposed to both LPS and ovalbumin developed a response characterized by IL-10 and IFN-gamma-expressing T cells.. This suggests that mucosal antigen exposure in the neonatal period results in inhibition of allergic responses to environmental allergens. Early LPS exposure directs mucosal responses toward tolerance, whereas ovalbumin exposure follows the T(H)1-type response on subsequent sensitization.. This study suggests that prevention of airways allergy may be best achieved by appropriate exposure of the airway mucosa early in life to environmental antigens.

Topics: Allergens; Animals; Animals, Newborn; Asthma; Cytokines; Environment; Female; Immune Tolerance; Interleukin-10; Lipopolysaccharides; Mice; Mice, Inbred BALB C; Ovalbumin; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal; T-Lymphocytes, Regulatory

Until now there has been no method for physiologically evaluating nasal hypersensitivity in mice. Enhanced pause (Penh) has been used as an indicator that reflects changes in the lower airway. Recently, however, there is disagreement regarding the significance of the Penh system; this is because Penh is not essentially a physiological parameter, and it might not necessarily represent a change in the lower respiratory tract. The purpose of the present study is to investigate whether Penh could be applicable for analyzing nasal hypersensitivity in mice. BALB/c mice were sensitized with ovalbumin (OVA) through a combination of intraperitoneal injection and daily intranasal challenge in an awake condition. Penh was measured at each time point during sensitization, or a serial change in Penh value was followed after the final nasal challenge and the effect of treatment was assessed. Following sensitization and nasal challenge, the Penh value gradually increased and showed a significant difference on day 14. Changes in IgE, eosinophil infiltration into nasal mucosa, and OVA-induced symptoms all strongly correlated with the increase in Penh. On day 19, after OVA nasal provocation, Penh gradually increased and reached maximal values 25 min after the challenge. Pretreatment with dexamethasone or a histamine H1 blocker significantly suppressed this increase in Penh. We confirmed that intranasal OVA challenge did not induce bronchoconstriction by measuring airway resistance and bronchoalveolar lavage fluid, and through histological examination. These results clearly demonstrate that Penh could be a useful noninvasive indicator for studying nasal hypersensitivity.

Topics: Airway Resistance; Animals; Bronchoalveolar Lavage Fluid; Eosinophils; Epinephrine; Histamine; Hypersensitivity, Immediate; Immunization; Immunoglobulin E; Lung; Male; Mice; Mice, Inbred BALB C; Nasal Cavity; Nasal Mucosa; Ovalbumin; Rhinitis, Allergic, Perennial

The pathophysiology of the early- and late-phase nasal response to allergen challenge is not completely defined. Recent technical advances enable direct monitoring of these responses in mice.. IL-13 is detected in the nasal membranes of both human beings and mice with allergic rhinitis, but its role in disease pathogenesis is unclear. We measured early and late nasal allergic responses after treatment with soluble IL-13Ralpha2-IgG fusion protein (sIL-13Ralpha2-Fc), and in IL-13-deficient mice (IL-13(-/-)).. IL-13(-/-) mice (BALB/c background) and wild-type mice were sensitized to ovalbumin by intraperitoneal injection and then challenged intranasally with ovalbumin without sedation. The sIL-13Ralpha2-Fc or control human IgG was administered by intraperitoneal (i.p.) injection 24 hours and 1 hour before each ovalbumin challenge. Early nasal responses after the 4th ovalbumin challenge and late nasal responses 24 hours after the 6th ovalbumin challenge were assessed.. Sensitized/challenged wild-type mice treated with sIL-13Ralpha2-Fc or IL-13(-/-) mice demonstrated significantly reduced late nasal responses in face of persistent nasal tissue eosinophilia; the early nasal response was little affected by targeting IL-13. Goblet cell hyperplasia was not detected in nasal membranes.. The data indicate that IL-13 is a major contributor to the development of a late nasal response with little influence on the early response, and without affecting nasal eosinophilic inflammation. Inhibition of IL-13 may have an important therapeutic application in preventing the persistent nasal blockage in allergic rhinitis.. Current therapies for allergic rhinitis may not take into account the important differences in the pathophysiology of the early and late responses and the important role of IL-13 in sustaining chronic nasal congestion and obstruction.

Topics: Animals; Eosinophils; Injections, Intraperitoneal; Interleukin-13; Interleukin-13 Receptor alpha2 Subunit; Mice; Mice, Inbred BALB C; Mice, Knockout; Ovalbumin; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal; Time Factors

To investigate whether the effect of Biminne on allergic rhinitis (AR) was through improving vascular permeability of nasal mucosa.. Rat's model in Biminne-treated group and model group was induced by intraperitoneal injection of ovalbumin (OVA) and aluminum hydroxide gel suspension Biminne-treated rats were orally given Biminne suspension from the 8th day to the 17th day. On the 18th day, Evan's blue dye (EBD) in the nasal perfusate was detected to assess the vascular permeability.. EBD concentration was higher in the model rats than that in the normal rats, and lower in the Biminne-treated rats than that in the model rats (both P < 0.01).. Biminne could improve vascular permeability of nasal mucosa in sensitized rats, which may be the mechanism of its clinical effect on AR.

Topics: Animals; Anti-Allergic Agents; Capillary Permeability; Drugs, Chinese Herbal; Injections, Intraperitoneal; Male; Nasal Mucosa; Ovalbumin; Rats; Rats, Inbred BN; Rhinitis, Allergic, Perennial

To determine the therapeutic effect of spirulina platensis in allergic rhinitis (AR).. Ovalbumin sensitized white rats used as AR animals were treated with spirulina platensis (SPP). At the end of the treatment, the differences in the behavior science were observed; the changes in the nasal mucosa and mast cell degranulation were studied pathologically; and the levels of serum histamine and total immunoglobulin (Ig) E were determined by enzyme-linked immune sorbent assay.. The behavior science score of the SPP treatment group was lower than that of the negative control group (P < 0.01 ) ; inflammatory reaction of nasal mucosa in the SPP treatment group were remarkably relieved; the number of nasal mucosa mastocyte and mast cell degranulation in the SPP treatment group were lower than that of the negative control group (P <0.01 ). The levels of serum histamine and total IgE in the SPP treatment group were lower than that of the negative control group (P <0.01 ). It had no significant difference in the positive control group and the SPP treatment group and the blank control group (P > 0.05 ).. Spirulina platensis can prevent and treat AR in rats, which implies the possibility of using spirulina platensis for AR patients in the future.

Topics: Animals; Eukaryota; Male; Ovalbumin; Phytotherapy; Random Allocation; Rats; Rats, Sprague-Dawley; Rhinitis, Allergic, Perennial

To observe the early and late symptomatic, pathological and immunological changes in an intranasal ovalbumin-induced animal model of allergic rhinitis in guinea pigs.. Guinea pigs were intranasally sensitized with ovalbumin absorbed on aluminum hydroxide and after 5 days' interval, they were challenged with 1% ovalbumin solution once every 3 days for total 11 times. Two control groups were studied in parallel, the positive treatment control group was treated with antihistamine and the negative control group was sham-sensitized and sham-challenged. Typical symptoms of allergic rhinitis, such as sneezing, nasal scratching, nasal blockage and rhinorrhea were evaluated. Passive cutaneous anaphylaxis reaction (PCA) was performed to measure the levels of IgG1 and IgE. Eosinophils infiltration and goblet cells in nasal mucosa were observed. In addition, the level of histamine and the number of total leukocytes and eosinophils in the nasal lavage fluid were also measured.. In the model group, symptoms of sneezing, nasal scratching, nasal blockage and rhinorrhea were induced after ovalbumin challenge. The respiratory rate (RR), which reflected the resistance of upper airway, showed a biphasic change. In the PCA test, IgG1 and IgE levels increased after challenges. Eosinophil infiltration in nasal mucosa was more obvious in active groups in comparison to with the negative control group (P < 0.05 or < 0.01). The histamine, total leucocytes and eosinophils levels in nasal lavage fluid also showed higher in the model group (P < 0.05 or < 0.01). The antihistamine treated animals were also induced out above changes but modest compared with the model group (P < 0.05 or < 0.01). The negative control showed few of above changes with significant difference (P < 0.05 or < 0.01).. Our results implied that the modified animal model of allergic rhinitis was capable of showing satisfactory symptomatic and pathophysiological changes in allergic rhinitis. It showed a biphasic nasal blockage with shorter establishment duration. The model also had good treatment reaction to antihistamine. The animal model we introduced may be useful in the study of allergic rhinitis.

Topics: Administration, Intranasal; Animals; Disease Models, Animal; Guinea Pigs; Nasal Lavage Fluid; Ovalbumin; Rhinitis, Allergic, Perennial

Experimental allergic rhinitis produces enhanced cough response in awake guinea pigs. Leukotriene receptor antagonists, as anti-inflammatory agents, have been effective in treatment of asthma and allergic rhinitis to inhibit the early and late allergic response. In the present study, we evaluated the effect of montelukast (Singulair, Merck, USA) on the cough reflex in an experimental model of allergen-induced rhinitis in guinea pigs. Guinea pigs (n=16) were sensitized with intraperitoneal ovalbumin (OVA). The animals were then used to develop a model of allergic rhinitis by repeated intranasal instillation of 0.5% OVA at weekly intervals for 8 weeks. Allergic rhinitis was evaluated from the occurrence of typical clinical symptoms including sneezing, conjunctival and nasal secretion, or nasal acoustic phenomenon. Between the 6(th) and 8(th) nasal challenge (NCh) the animals (n=8) were treated daily for 14 days with oral montelukast (10mg/kg). Cough was induced by citric acid aerosol inhalation in gradually increasing concentration (0.05-1.6 M) and was evaluated before sensitization and then after the 1(st), 6(th), and 8(th) nasal challenge when rhinitis symptoms were most conspicuous. The intensity of cough was significantly increased after the first and repeated nasal OVA challenges, and reduced after the 8(th) NCh that was preceded with montelukast treatment [9(6-14) vs. 16.5(14-22) vs. 25.5(23-42) vs. 8.5(8-13); P=0.0003]. We conclude that antileukotriene therapy suppresses the stimulating effect of experimental allergic rhinitis on the chemically-induced cough in awake guinea pigs.

Topics: Acetates; Administration, Oral; Animals; Citric Acid; Cough; Cyclopropanes; Disease Models, Animal; Guinea Pigs; Laryngeal Mucosa; Leukotriene Antagonists; Male; Membrane Proteins; Ovalbumin; Quinolines; Receptors, Leukotriene; Rhinitis, Allergic, Perennial; Sulfides; Time Factors

Histamine is one of the most important chemical mediators causing nasal allergic symptoms, and H1 receptor antagonist have been used as the treatment first choice in nasal allergy. The presence of H3 receptors has also been determined in the human nasal mucosa, but few studies have investigated the involvement of H3 receptors in nasal allergy.. We used a murine allergic model to investigate the presence of nasal mucosa H3 receptor mRNA and any H3 receptor agonist or antagonist influences on clinical nasal allergic symptoms.. H3 receptor mRNA in nasal mucosa was investigated by reverse-transcription polymerase chain reaction. OVA-sensitized mice were given an intraperitoneal injection of H3 receptor agonist or antagonist, and clinical nasal allergic symptoms were scored over 10 minutes after nasal provocation of OVA. Inhibition of nasal allergic symptoms was also examined using an H1 receptor antagonist alone and using a both an H3 receptor agonist and an H1 receptor antagonist.. H3 receptor mRNA was identified in the murine nasal mucosa. The H3 receptor agonist (R)-alpha-metylhistamine significantly inhibited clinical nasal allergic symptoms of OVA-sensitized mice. The H3 receptor agonist and H1 receptor antagonist inhibited clinical nasal allergic symptoms in the murine allergic model more strongly than the single drug.. The foregoing results indicate that H3 receptors are involved in modulation of nasal allergy. H3 receptor agonists can also be useful as a novel therapeutic approach in nasal allergy. Both H3 receptor agonist and H1 receptor antagonist may be more effective than a single drug.

Topics: Allergens; Animals; Histamine Agonists; Histamine Antagonists; Histamine H1 Antagonists; Male; Mice; Mice, Inbred BALB C; Models, Animal; Nasal Mucosa; Ovalbumin; Receptors, Histamine H3; Rhinitis, Allergic, Perennial

There have been few reports using animal models to study the development of allergic rhinitis. Characterization of such a model in mice would be advantageous given the availability of reagents and gene-manipulated strains.. We sought to develop a murine model of allergic rhinitis in the absence of lower airway changes.. After sensitization and challenge, both wild-type and FcepsilonRI-deficient mice were studied for their ability to develop early- and late-phase nasal responses. In the invasive approach, direct measurements of nasal airway resistance (R(NA)) were obtained; in the noninvasive approach using whole-body plethysmography, respiratory frequency and expiratory and inspiratory times were monitored. In both approaches, nasal responses were determined either acutely after challenge (early phase) or 24 hours after challenge (late phase).. After challenge of sensitized mice, R(NA) significantly increased. In parallel, respiratory frequency significantly decreased and was highly correlated with the increases in R(NA). Sensitized wild-type mice had an early-phase nasal response and persistent nasal blockage (late-phase response) after allergen challenge. In contrast, sensitized and challenged FcepsilonRI alpha-chain-deficient mice did not have an early-phase nasal reaction and exhibited reduced nasal blockage and lower IL-13 levels in nasal tissue homogenates.. These data indicate that FcepsilonRI is essential to development of an early-phase nasal response and contributes to the development of the late-phase nasal response. These invasive and noninvasive approaches provide new opportunities to evaluate the mechanisms underlying the development of nasal responses to allergen and to assess various therapeutic interventions.

Topics: Administration, Intranasal; Airway Resistance; Animals; Binding, Competitive; Drug Administration Schedule; Eosinophils; Immunization; Immunoglobulin E; Immunoglobulin G; Injections, Intraperitoneal; Interleukin-13; Kinetics; Mice; Mice, Knockout; Nasal Cavity; Ovalbumin; Receptors, IgE; Respiratory Mechanics; Rhinitis, Allergic, Perennial

To explore a new immunotherapy against allergic rhinitis.. The recombinant protein of CTLA4 extracellular domain was obtained through construction of CTLA4-yeast expression system. The allergic rhinitis in mice was induced by sensitizing and challenging with ovalbumin (OVA). The allergic rhinitis related symptoms and the morphological changes in nasal mucosa were compared between the allergic rhinitis group and the CTLA4 extracellular domain group treated with CTLA4 extracellular domain before each challenge by ways of intraperitoneal injection.. CTLA4 extracellular domain with a molecular weight of 28 000, which was confirmed by Western blot, could be generated through CTLA4-yeast expression system. The purified CTLA4 extracellular domain could inhibit T cells proliferation in mixed lymphocyte reaction with a inhibitory rate of 95.4%. The mice in allergic rhinitis group appeared typical allergic rhinitis symptoms after OVA challenge, such as rhinorrhea and sneeze. Meanwhile the nasal pathological studies showed edema and congestion in mucosa tissue and local influx of inflammatory cells. Whereas in CTLA4 extracellular domain group, the nasal symptoms were rarely observed, and the pathological change in nasal mucosa was significantly abated.. The protein of CTLA4 extracellular domain could prevent the allergic rhinitis in mice. The underlying mechanism of which might be the inhibition of the T cell activation.

Topics: Animals; Antigens, CD; Cells, Cultured; CTLA-4 Antigen; Humans; Mice; Mice, Inbred BALB C; Nasal Mucosa; Ovalbumin; Recombinant Proteins; Rhinitis, Allergic, Perennial

Our previous study revealed that exposure to 0.4 ppm ozone (O(3)) enhanced nasal allergy-like reactions in guinea pigs. In the present study, we investigated the concentration-dependency of the effects of exposure to O(3) on the aggravation of nasal allergy-like reactions induced by repeated nasal administration of antigen. Guinea pigs were exposed to filtered air or 0.1-0.6 ppm O(3) for 5 weeks. After each weekly administration of ovalbumin (OVA), sneezes and nasal secretions were measured. The number of eosinophils infiltrating the nasal septum and the titers of OVA-specific antibody were measured 24h after the last administration. Ozone increased sneezing and nasal secretion induced by OVA, nasal responsiveness to physical stimuli, and the number of infiltrating eosinophils in a concentration-dependent manner. The titer of anti-OVA-IgG was increased in animals exposed to 0.6 ppm O(3). Thus, exposure to O(3) aggravated nasal allergy-like symptoms concentration dependently. The aggravation was caused by induction of nasal hyperresponsiveness, the infiltration of eosinophils, and the increase in the production of anti-OVA-IgG. The estimated maximum likelihood estimation concentrations (MLECs) and bench mark concentrations (BMCs) of O(3) for these indices were in the range of 0.09-0.18 and 0.02-0.06 ppm, respectively.

Topics: Administration, Inhalation; Animals; Benchmarking; Dose-Response Relationship, Drug; Eosinophils; Guinea Pigs; Immunoglobulin G; Male; Nasal Mucosa; Ovalbumin; Oxidants, Photochemical; Ozone; Rhinitis, Allergic, Perennial; Sneezing

To study the effect of botulinum toxin-A on inhibiting rhinorrhea, on expression of VIP at nasal mucosa, on morphometrical change with an immunohistochemical and histological methods in rats allergic rhinitis.. Ovalbumin sensitized the rat as animal model of allergic rhinitis. Animals were divided into control group (n = 8), allergic group (n = 12), allergic animal treated by BTX-A group (n = 6). VIP immunoreactivity at nasal mucosa in the rat allergic rhinitis was studied by immunohistochemical. The morphometrical changes at nasal mucosa were observed by histological staining methods.. The results showed that the symptoms of allergic rhinitis, nasal rhinorrhea and sneezing, were remarkably relieved after ovalbumin application in the rat. The nasal rhinorrhea symptom diminished after BTX-A treated. The quantity of nasal secretion were significantly reduced(P < 0.05) in allergic one treated by BTX-A group as compared with allergic group. Hematoxylin and eosin staining demonstrated that no edema, small vessels were found in the nasal mucosa and after BTX-A treatment, but edema, vasodilational and inflammational cell infiltration were observed in the allergic group. Immunohistochemical study revealed that VIP immunoreactive fibers in the nasal mucosa showed a marked decrease after BTX-A application, but the density and a large number of VIP fibers were significantly found in the allergic group.. The results suggested that local BTX-A treatment was a selective and non-traumatic method to reduce a long lasting desensitization of the nasal mucosa, to alleviate nasal congestion, rhinorrhea and sneezing, and to reduce the sensory neuron sensitivity of the mucosa.

Topics: Animals; Botulinum Toxins, Type A; Female; Nasal Mucosa; Ovalbumin; Random Allocation; Rats; Rats, Wistar; Rhinitis, Allergic, Perennial; Vasoactive Intestinal Peptide

A collaborative research study was conducted in order to improve our understanding of the source-to-receptor pathway for ambient fine particulate matter (aerodynamic diameter < or = 2.5 mu m; PM2.5) and subsequently to investigate the identity and sources of toxic components in PM2.5 responsible for adverse health effects in allergic humans. This research used a Harvard fine particle concentrator to expose Brown Norway rats, with and without ovalbumin-induced allergic airway disease, to concentrated air particles (CAPs) generated from ambient air in an urban Detroit community where the pediatric asthma rate was three times higher than the national average. Rats were exposed to CAPs during the exposure periods in July (mean = 676 microg/m3) and September (313 microg/m3) of 2000. Twenty-four hours after exposures lung lobes were either lavaged with saline to determine cellularity and protein in bronchoalveolar lavage fluid (BALF), or removed for analysis by inductively coupled plasma-mass spectrometry (ICP-MS) to detect ambient PM2.5-derived trace element retention. PM2.5 trace elements of anthropogenic origin, lanthanum (La), vanadium (V), manganese (Mn), and sulfur (S), were recovered from the lung tissues of CAPs-exposed rats. Recovery of those pulmonary anthropogenic particles was further increased in rats with allergic airways. In addition, eosinophils and protein in BALF were increased only in allergic animals exposed to CAPs. These results demonstrate preferential retention in allergic airways of air particulates derived from identified local combustion sources after a short-term exposure. Our findings suggest that the enhancement of allergic airway responses by exposure to PM2.5 is mediated in part by increased pulmonary deposition and localization of potentially toxic elements in urban air.

Topics: Air Pollutants; Allergens; Animals; Bronchoalveolar Lavage Fluid; Eosinophils; Inhalation Exposure; Lung; Mass Spectrometry; Michigan; Ovalbumin; Particle Size; Proteins; Rats; Rats, Inbred BN; Rhinitis, Allergic, Perennial; Specific Pathogen-Free Organisms; Trace Elements; Urban Health

The involvement of chemical mediators other than histamine in eosinophil infiltration in the nasal mucosa was studied using histamine H(1) receptor-deficient mice. Histamine H(1) receptor-deficient mice and wild-type controls were immunized with ovalbumin and consecutive topical antigen instillation was performed. Histological alterations and eosinophil infiltration into the nasal mucosa of mice were examined. Diffuse infiltration of inflammatory cells and edema after sensitization with antigen were observed in the nasal mucosa in both wild-type and histamine H(1) receptor-deficient mice. The number of eosinophils in the nasal mucosa in mice sensitized with antigen was significantly increased as compared with controls. The number of eosinophils in the nasal mucosa was significantly decreased by cetirizine and epinastine, ramatroban and zafirlukast in wild-type mice. Not only histamine but also thromboxane A(2) and leukotrienes play important roles in allergic rhinitis, especially in the late phase participating in nasal eosinophilia.

Topics: Adjuvants, Immunologic; Animals; Disease Models, Animal; Eosinophilia; Eosinophils; Histamine H1 Antagonists; Leukocyte Count; Leukotriene Antagonists; Mice; Mice, Inbred C57BL; Mice, Knockout; Nasal Mucosa; Ovalbumin; Receptors, Histamine H1; Receptors, Thromboxane; Rhinitis, Allergic, Perennial

Allergic rhinitis is an inflammation involving T(H)2-type cytokine production, with pathologic eosinophil infiltration in the nasal mucosa. Although TNF-alpha is thought to be a pro-inflammatory cytokine, the relationship between TNF-alpha and allergic rhinitis has not been clarified.. The role of TNF-alpha in a murine model of ovalbumin (OVA)-sensitized allergic rhinitis was investigated by using mice deficient in the gene encoding TNF-alpha (TNF-alpha(-/-) mice).. Both wild-type (TNF-alpha(+/+)) and TNF-alpha(-/-) mice were sensitized with OVA by means of intraperitoneal injection. They were then challenged with intranasal OVA, and various allergic responses were assessed.. The production of OVA-specific IgE in the serum (P <.05) and the frequency of sneezes (P <.05) and nasal rubs (P <.05) decreased significantly in TNF-alpha(-/-) mice after OVA sensitization compared with that in TNF-alpha(+/+) mice (P <.05). The mRNA expression of IL-4, IL-10, and eotaxin in nasal mucosa in TNF-alpha(-/-) mice was also significantly suppressed compared with that in TNF-alpha(+/+) mice after OVA sensitization (P <.05). Furthermore, the expression of both endothelial-leukocyte adhesion molecule 1 and vascular cell adhesion molecule 1 mRNA in the nasal mucosa was significantly suppressed (P <.05), although intercellular adhesion molecule 1 mRNA expression did not decrease significantly in TNF-alpha(-/-) mice compared with that in TNF-alpha(+/+) mice after OVA sensitization. In addition, the effect of TNF-alpha on endothelial-leukocyte adhesion molecule 1 and vascular cell adhesion molecule 1 expression by means of Western blot analysis was compatible with the mRNA results. Pathologically, eosinophil infiltration in nasal mucosa was significantly restricted in TNF-alpha(-/-) mice compared with in TNF-alpha(+/+) mice after OVA sensitization (P <.05).. TNF-alpha is necessary for antigen-specific IgE production and for the induction of T(H)2-type cytokines and chemokines. Furthermore, TNF-alpha might be important for the expression of adhesion molecules to recruit eosinophils to the allergic inflammatory site. We conclude that the lack of TNF-alpha inhibited the development of allergic rhinitis.

Topics: Animals; Cell Adhesion Molecules; Chemokines; Cytokines; Eosinophilia; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Ovalbumin; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal; RNA, Messenger; Th2 Cells; Tumor Necrosis Factor-alpha

TAK-427 (2-[6-[[3-[4-(diphenylmethoxy)piperidino]propyl]amino]imidazo[1,2-b]pyridazin-2-yl]-2-methylpropionic acid dihydrate) is a novel anti-allergic agent that has both histamine H1-receptor antagonist and anti-inflammatory activities. In this study, we evaluated the efficacy of TAK-427 on acute nasal responses and nasal obstruction using various guinea pig models of allergic rhinitis. TAK-427 inhibited the histamine-induced nasal reactions with an ID50 value of 0.633 mg/kg, p.o. TAK-427 (0.1-10 mg/kg, p.o.) and most histamine H1-receptor antagonists tested inhibited the increase in intranasal pressure, nasal hypersecretion, sneezing and nasal itching caused by a single antigen challenge in sensitized guinea pigs. In addition, TAK-427 (0.3, 30 mg/kg, p.o.) significantly inhibited the development of nasal obstruction when sensitized guinea pigs were repeatedly challenged via inhalation with Japanese cedar pollen, whereas the histamine H1-receptor antagonist, azelastine (1 mg/kg, p.o.), and ketotifen (1 mg/kg, p.o.) were without effect. These results suggest that TAK-427 might not only suppress acute nasal symptoms but also ameliorate nasal obstruction via the effects other than those as a histamine H1-receptor antagonist.

Topics: Acute Disease; Animals; Anti-Inflammatory Agents; Disease Models, Animal; Guinea Pigs; Histamine; Histamine H1 Antagonists; Imidazoles; Male; Nasal Obstruction; Ovalbumin; Pollen; Pyridazines; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal; Sneezing

There is renewed interest in antihistamines for the treatment of allergic asthma. A growing body of literature has shown that the newer compounds can affect inflammatory cell accumulation and cytokine/chemokine production. In a murine model of allergen-induced airway inflammation and hyperresponsiveness, the ability of fexofenadine to affect these outcomes was tested in a primary sensitization and challenge model and after treatment of donor mice before the adoptive transfer of T cells into recipients receiving limited allergen exposure. Mice were sensitized and challenged with allergen (ovalbumin). Airway function after inhaled methacholine was monitored in parallel to the assessment of tissue and airway inflammation and cytokine production. In further experiments, lung T lymphocytes from sensitized/challenged donor mice were transferred into naive recipients before limited airway challenge with the allergen. Administration of fexofenadine before challenge but after sensitization was effective in preventing tissue eosinophilia and airway hyperresponsiveness. Moreover, the treatment of donor mice with fexofenadine before transfer of lung T cells effectively prevented airway hyperresponsiveness and eosinophilia in naive mice exposed to limited airway challenge. These data therefore support the potential for fexofenadine in the treatment of allergen-induced airway hyperresponsiveness and inflammation.

Topics: Administration, Inhalation; Adoptive Transfer; Allergens; Animals; Anti-Allergic Agents; Antibody Specificity; Bronchoalveolar Lavage Fluid; Bronchoconstrictor Agents; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Eosinophils; Female; Histamine H1 Antagonists; Immunoglobulin E; Injections, Intraperitoneal; Leukocyte Count; Methacholine Chloride; Mice; Mice, Inbred BALB C; Ovalbumin; Respiratory Hypersensitivity; Rhinitis, Allergic, Perennial; T-Lymphocytes; Terfenadine; Time Factors; Treatment Outcome

To elucidate the mechanism of bone marrow response regulated by interleukin-5 (IL-5) in the model of allergic rhinitis.. Twenty SD rats were randomly divided into allergic rhinitis (AR) group and control group. The leucocytes in the smears of bone marrow and peripheral blood were counted, and the expression of IL-5 was detected by immunohistochemistry.. The ratio of eosinophils to white cells in bone marrow smears of AR group was significantly higher than that of control group(P < 0.01). The ratio of basophils to white cells in bone marrow smears of AR group was significantly higher than that of control group(P < 0.01). The ratio of eosinophils to white cells in peripheral blood smears of AR group was significantly higher than that of control group(P < 0.01). The ratio of IL-5 positive cells to white cells in bone marrow smears of AR group was significantly higher than that of control group (P < 0.05). The ratio of IL-5 positive cells to white cells was significantly positively correlated with the ratio of eosinophils to white cells in bone marrow smears of AR group (R = 0.85, P < 0.01).. IL-5 regulates the proliferation and differentiation of eosinophils in bone marrow.

Topics: Animals; Basophils; Bone Marrow Cells; Cell Count; Eosinophils; Interleukin-5; Male; Ovalbumin; Random Allocation; Rats; Rats, Sprague-Dawley; Rhinitis, Allergic, Perennial

Allergic rhinosinusitis is characterized by eosinophilic inflammation of the upper airway, which is induced by TH-2 cytokines. CpG oligodeoxynucleotides (ODN) are known to induce TH-1 and to suppress TH-2 cytokines in a variety of settings, including murine models of asthma.. To examine the effect of CpG ODN in a murine model of upper airway allergic inflammation and to correlate with reduction of its manifestations of sneezing and nasal scratching.. BALB/c mice were sensitized using Ovalbumin (Ova) intraperitoneally and challenged with aerosolized Ova. CpG ODN were administered at the time of Ova sensitization. Outcomes measured included nasal symptoms, submucosal eosinophilia in the areas lined by respiratory or olfactory epithelium, and bone marrow eosinophilia. To delineate the mechanism of CpG ODN-induced suppression of eosinophilic inflammation, in vitro experiments were carried out to examine the effect of stimulation with Ova on splenocytes obtained from mice that were treated with CpG or control ODN (or no ODN) in vivo. Supernatant was collected after 72 hours of incubation and cytokines were measured by enzyme linked immunosorbent assay.. CpG ODN administered at the time of Ova sensitization effectively abrogated nasal symptoms and eosinophilic upper airway inflammation compared with mice treated with control ODN or with no ODN. Cytokine data revealed that Ova sensitization suppressed IFN-gamma and induced IL-4 and IL-5 compared with non-sensitized mice. CpG ODN treatment reversed these effects.. CpG ODN prevents the development of TH-2-mediated eosinophilic inflammation and symptoms in a murine model of allergic rhinosinusitis.

Topics: Adjuvants, Immunologic; Animals; Bone Marrow; Bronchoalveolar Lavage Fluid; Cells, Cultured; Chronic Disease; CpG Islands; Cytokines; Eosinophils; Female; Immunization; Inflammation; Lung; Mice; Mice, Inbred BALB C; Oligodeoxyribonucleotides; Ovalbumin; Respiratory Hypersensitivity; Respiratory Mucosa; Rhinitis, Allergic, Perennial; Sinusitis; Spleen

Allergic rhinitis (AR) is the most common atopic disease with strong links to asthma. We have developed a murine model of AR to study nasal, bronchial, and systemic immune response to local allergen stimulation.. The purpose of this study was to develop and characterize a murine model of AR.. Six- to 8-week-old BALB/c mice were sensitized by means of intranasal (local) application of ovalbumin (OVA) or systemic intraperitoneal injection. They were then challenged with intranasal OVA, and allergic response was assessed.. Intranasal particle deposition was found to be exclusively in the nares. All sensitized animals showed increased levels of OVA-specific serum IgE and IgG after challenge, although the timing to maximal response varied with the route and dose of allergen used. Histology of the upper and lower airways showed marked eosinophilic infiltration, and analysis of bronchoalveolar lavage fluid showed increased IL-5 and PMN infiltrates after challenge.. Using exclusive local sensitization and challenge of mouse nares, we were able to demonstrate inflammatory changes in both the upper and lower airways, even though distribution of allergen particles appeared to be only in the nares of these animals. This provides further evidence for the importance of the upper airway in lower airways disease. We have shown that the route of administration greatly affects the characteristics of the subsequent immune responses.

Topics: Animals; Asthma; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Immunoglobulin E; Immunoglobulin G; Interferon-gamma; Interleukin-4; Interleukin-5; Lung; Male; Mice; Mice, Inbred BALB C; Nasal Mucosa; Ovalbumin; Rhinitis, Allergic, Perennial

Recent studies have demonstrated an important role for IL-5-dependent bone marrow eosinophil progenitors in allergic inflammation. However, studies using anti-IL-5 mAbs in human asthmatics have failed to suppress lower airway hyperresponsiveness despite suppression of eosinophilia; therefore, it is critical to examine the role of IL-5 and bone marrow responses in the pathogenesis of allergic airway disease. To do this, we studied the effects of IL-5 deficiency (IL-5(-/-)) on bone marrow function as well as clinical and local events, using an established experimental murine model of allergic rhinitis. Age-matched IL-5(+/+) and IL-5(-/-) BALB/c mice were sensitized to OVA followed by 2 wk of daily OVA intranasal challenge. IL-5(-/-) OVA-sensitized mice had significantly higher nasal mucosal CD4(+) cells and basophilic cell counts as well as nasal symptoms and histamine hyperresponsiveness than the nonsensitized group; however, there was no eosinophilia in either nasal mucosa or bone marrow; significantly lower numbers of eosinophil/basophil CFU and maturing CFU eosinophils in the presence of recombinant mouse IL-5 in vitro; and significantly lower expression of IL-5Ralpha on bone marrow CD34(+)CD45(+) progenitor cells in IL-5(-/-) mice. These findings suggest that IL-5 is required for normal bone marrow eosinophilopoiesis, in response to specific Ag sensitization, during the development of experimental allergic rhinitis. However, the results also suggest that suppression of the IL-5-eosinophil pathway in this model of allergic rhinitis may not completely suppress clinical symptoms or nasal histamine hyperresponsiveness, because of the existence of other cytokine-progenitor pathways that may induce and maintain the presence of other inflammatory cell populations.

Topics: Animals; Antigens, CD34; Basophils; Bone Marrow; Cell Differentiation; Cells, Cultured; Colony-Forming Units Assay; Eosinophils; Female; Hematopoietic Stem Cells; Histamine; Interleukin-5; Leukocyte Common Antigens; Male; Methylcellulose; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Nasal Mucosa; Ovalbumin; Receptors, Interleukin; Receptors, Interleukin-5; Rhinitis, Allergic, Perennial

Repeated exposures to ozone cause inflammation and mucous cell metaplasia (MCM) in the nasal mucosa of laboratory animals. Similar cellular responses occur in humans during allergic rhinitis. We tested the hypothesis that exposure to ozone will enhance the inflammatory and epithelial responses associated with allergic rhinitis. Ovalbumin (OVA)-sensitized Brown Norway rats were exposed to ozone (0.5 ppm, 8 h/day) for 1 day or 3 consecutive days. Immediately after each ozone exposure, animals were challenged intranasally (IN) with either sterile saline or OVA dissolved in saline (1%, 50 microg/nasal passage). Twenty-four h after the last IN challenge rats were sacrificed; nasal tissues were removed and processed for light microscopic examination and morphometric analysis of numeric densities of inflammatory and epithelial cell populations and volume densities of intraepithelial mucosubstances. A single OVA challenge caused a significant influx of neutrophils and eosinophils into the submucosa of all nasal tissues. Ozone exposure further enhanced the appearance of eosinophils in the maxilloturbinates of OVA-challenged rats but did not increase inflammation in other nasal tissues. After 3 days of ozone/OVA coexposures, the nasal transitional epithelium lining the maxilloturbinates had increased numbers of epithelial cells as well as the appearance of mucus-containing cells in areas normally absent of these secretory cells (i.e., MCM). Multiple challenges with OVA caused increased epithelial mucosubstances in the respiratory epithelium lining the septum without increasing the number of epithelial cells. Multiple exposures to both ozone and OVA caused greater increases in intraepithelial mucosubstances in the septum than those elicited by OVA alone. These results demonstrate that exposure to ozone exacerbates epithelial and inflammatory responses associated with allergen challenge. In addition, coexposure of these agents enhanced the induced production of nasal mucosubstances caused by either agent alone.

Topics: Administration, Inhalation; Animals; Bromodeoxyuridine; Cell Nucleus; Disease Models, Animal; DNA; Eosinophils; Image Processing, Computer-Assisted; Immunoenzyme Techniques; Male; Mucoproteins; Nasal Mucosa; Neutrophils; Ovalbumin; Ozone; Rats; Rats, Inbred BN; Rhinitis, Allergic, Perennial; Turbinates

Increased antigen-specific IgE expression is a hallmark of the allergic response in mice. IgG1 may also be involved. Co-injection of mice with diesel exhaust particles (DEP) and ovalbumin three times over a 2 week period lead to a rapid and marked elevation of ovalbumin-specific IgE, IgG1 and also IgG2a, compared with ovalbumin alone. When DEP were injected 1 day before or after ovalbumin on each occasion, their adjuvant effect was considerably muted, suggesting that the adjuvant effect of DEP is short-lived, or that a physical interaction between ovalbumin and DEP is required. DEP were extracted with methylene chloride. Both the resulting core carbon particles and the organic extract enhanced ovalbumin specific IgE and IgG1 levels. Thus the adjuvant effect of DEP in this model is due both to the physical and the chemical attributes of the particles. The tricyclic hydrocarbons phenanthene (the most prevalent polycyclic aromatic hydrocarbon in DEP) and anthracene were both capable of enhancing antigen-specific IgE and IgG1 production. The phenolic antioxidant, butylated hydroxyanisole, which can affect gene expression via the antioxidant responsive element (ARE), had a lesser effect. Two agonists for the aryl hydrocarbon receptor, 3-methychloranthrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin, either were without effect or suppressed the response, suggesting that DEP adjuvancy may not be mediated by this receptor.

Topics: Adjuvants, Immunologic; Allergens; Animals; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Immunoglobulin E; Immunoglobulin G; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Ovalbumin; Particle Size; Polychlorinated Dibenzodioxins; Polycyclic Aromatic Hydrocarbons; Rhinitis, Allergic, Perennial; Vehicle Emissions

The ability of O3 exposure to aggravate ovalbumin (OVA)-induced nasal allergy-like symptoms was studied in guinea pigs. Guinea pigs were exposed to filtered air or to 0.4 ppm O3 for 5 weeks. During the exposure, 1% OVA or saline was administered into the nasal cavities once a week. Sneezes and nasal secretions were measured for a 20-min period following OVA administration. The number of eosinophils infiltrating both nasal epithelium and subepithelium and titers of specific anti-OVA-IgG were measured 24 h after the last administration. Ozone increased OVA-induced sneezing and nasal secretion, as well as induced nasal hyper-responsiveness to physical stimuli. The number of eosinophils infiltrating the nasal subepithelium was increased by O3, and the titer of anti-OVA-IgG tended to increase in the O3-exposed animals. Thus, exposure to O3 aggravated nasal allergy-like symptoms by inducing nasal hyper-responsiveness, the infiltration of eosinophils, and by tending to increase the production of anti-OVA-IgG.

Topics: Administration, Intranasal; Animals; Antibody Specificity; Eosinophils; Guinea Pigs; Immunoglobulin E; Immunoglobulin G; Male; Nasal Mucosa; Ovalbumin; Ozone; Rhinitis, Allergic, Perennial; Sneezing

The presence of nitric oxide (NO) in the nose is well documented; however, the role of this molecule in nasal physiology is still poorly understood. Our laboratory has previously demonstrated that NO is a mediator of the immediate secretory response to an intranasal histamine challenge in a rat model of nasal allergy. Histamine challenge, however, does not elicit a late-phase response (LPR). To study the role of NO in the LPR, we developed a model of nasal allergy in which brown Norway rats are actively sensitized to the allergen ovalbumin and later challenged intranasally with either phosphate-buffered saline solution (vehicle), ovalbumin in vehicle, or ovalbumin and the NO synthase inhibitor N -nitro-l -arginine methyl ester. In each experiment, nasal lavage samples were collected 30, 120, 240, and 360 minutes after challenge. Lavage samples were analyzed for albumin content by ELISA, inflammatory cell concentration with a hemocytometer, and evidence of inflammation by light microscopy. Blocking NO synthesis with N -nitro-l -arginine methyl ester significantly inhibited both albumin exudation and inflammatory cell influx into the nasal cavity during the LPR. These data suggest that NO plays a role in the LPR of nasal allergy.

Topics: Albumins; Allergens; Animals; Enzyme Inhibitors; Histamine; Inflammation Mediators; Nasal Lavage Fluid; Nasal Mucosa; Nasal Provocation Tests; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Ovalbumin; Passive Cutaneous Anaphylaxis; Rats; Rats, Inbred BN; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal

We produced ovalbumin (OVA)-sensitized rats as an animal model of nasal allergy. Intranasal instillation of OVA induced hypertrophic and metaplastic changes of goblet cells in nasal epithelium of OVA- sensitized rats. Intraepithelial mucosubstance in nasal mucosa increased significantly at 24 h after 3 or 7 d of OVA instillation, accompanied by mucosal infiltration of eosinophils. The effects of H1-antagonist (d-chlorpheniramine malate), H2-antagonist (cimetidine), dexamethasone, indomethacin, cysteinyl leukotrienes (cysLTs)-antagonist (ONO1078), and antirat neutrophil antiserum on OVA-induced changes were examined. Mucus production was significantly inhibited by dexamethasone, and ONO1078, whereas eosinophil infiltration was significantly inhibited by H1-antagonist, dexamethasone, and anti-rat neutrophil antiserum. These results indicate that cysLTs (LTs C4, D4, and E4) may play an important role in antigen-induced mucus production, and that eosinophil infiltration does not relate to mucus production. Intranasal instillation of lipopolysaccharide (LPS) also induced intraepithelial mucus production, and it was significantly inhibited by dexamethasone, indomethacin, and antirat neutrophil antiserum; however, cysLTs antagonist had no effect on LPS-induced change. These results indicate that neutrophil and cyclooxygenase products are important in LPS-induced mucus production, and there are different mechanisms of mucus production between allergic inflammation and LPS stimulation.

Topics: Animals; Antigens; Chlorpheniramine; Chromones; Cimetidine; Dexamethasone; Eosinophils; Histamine H1 Antagonists; Histamine H2 Antagonists; Humans; Immune Sera; Immunization; Leukotriene Antagonists; Lipopolysaccharides; Male; Mucus; Nasal Mucosa; Neutrophils; Ovalbumin; Rats; Rats, Inbred F344; Rhinitis, Allergic, Perennial

An animal model of chronic allergic rhinitis was developed by repeated local booster sensitization into the nasal cavity in sensitized rats. The severity of allergic rhinitis was assessed by determining the extent of two markers of nasal allergic symptoms (sneezing and nasal rubbing) after antigen challenge. The number of incidents of sneezing and nasal rubbing was markedly increased during intranasal instillation of antigen in sensitized rats. The PCA titers were also markedly elevated by intranasal sensitization. Some histamine H(1)-receptor antagonists such as chlorpheniramine, ketotifen, astemizole and epinastine inhibited the increase in antigen-induced nasal symptoms in a dose-related manner. Nasal rubbing was more potently inhibited by H(1)-receptor antagonists than sneezing. In conclusion, we developed a chronic allergic rhinitis model showing nasal symptoms in rats, and this model may be useful for evaluating the effects of drugs on allergic rhinitis.

Topics: Allergens; Animals; Anti-Allergic Agents; Astemizole; Chlorpheniramine; Dibenzazepines; Disease Models, Animal; Dose-Response Relationship, Drug; Histamine H1 Antagonists; Imidazoles; Immunization; Ketotifen; Nasal Cavity; Ovalbumin; Passive Cutaneous Anaphylaxis; Rats; Rats, Wistar; Rhinitis, Allergic, Perennial; Sneezing; Time Factors

Ag-specific T cell activation requires the engagement of T cell receptor (TCR) with antigen in the context of MHC, and the engagement of appropriate costimulatory molecules. It is well established that B7/CD28-CTLA4 costimulatory pathway plays an important role in the induction of T helper (Th) cells in T-cell dependent immune reactions. In this study, we evaluated the effects of blocking the costimulatory pathway by systemic administration of CTLA4-Ig during repeated nasal antigen challenges in systemically presensitized mouse. The antigen-induced early phase nasal symptoms, nasal hyperresponsiveness to histamine and nasal eosinophilia were significantly suppressed by CTLA4-Ig treatment. Elevation of serum level of antigen-specific IgE, but not IgG1 or IgG2a was inhibited by the treatment. In relation to cytokine levels in the tissue extracts of the nasal mucosa, an up-regulation of IL-4 was significantly inhibited, however, the levels of IL-5 and IFN-gamma were not affected by the treatment. These results suggest that B7/CD28-CTLA4 costimulatory pathway plays an important role in on-going Th2-related allergic reactions in the nose.

Topics: Abatacept; Animals; Antigens, CD; Antigens, Differentiation; CTLA-4 Antigen; Cytokines; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Eosinophils; Histamine; Immunoconjugates; Immunoglobulins; Immunosuppressive Agents; Male; Mice; Mice, Inbred BALB C; Nasal Lavage Fluid; Nasal Mucosa; Ovalbumin; Recombinant Fusion Proteins; Rhinitis, Allergic, Perennial; Sneezing; Specific Pathogen-Free Organisms

We examined the effect of a specific cysteinyl leukotriene (LT) receptor antagonist, 4-oxo-8-[4-(4-phenylbutoxy)benzoylamino]-2-(tetrazol-5-yl)-4 H-1-benzopyran hemihydrate (pranlukast), on a novel model of allergic rhinitis induced by repeated intranasal ovalbumin challenge in actively sensitized guinea pigs. Repeated intranasal ovalbumin challenge caused a biphasic increase of nasal airway resistance, peaking 0.5 and 4 h after the final challenge. The early-phase response was accompanied by an increase in sneezing and nasal secretion, while that in the late phase was associated with edema and eosinophil infiltration of the nasal mucosa. Analysis of nasal lavage fluid showed that cysteinyl LTs increased in both phases. Pranlukast, when administered 1 h before every ovalbumin challenge, dose-dependently suppressed the increase of nasal airway resistance in the early- and late phase with evidence of histopathological improvements in the late phase. Pranlukast, however, failed to suppress sneezing and nasal secretion. We suggest that cysteinyl LTs play an important role in allergic rhinitis especially in the nasal obstruction due to edema of the nasal mucosa membrane.

Topics: Airway Resistance; Animals; Chromones; Cysteine; Disease Models, Animal; Guinea Pigs; Leukotriene Antagonists; Leukotrienes; Male; Nasal Mucosa; Ovalbumin; Rhinitis, Allergic, Perennial; Serine Proteinase Inhibitors

In an attempt to study the pathogenesis of mucosal hypersensitivity in allergic rhinitis, we investigated the suppressive effects of cyclosporin A (CyA) and glucocorticosteroids on ovalbumin (OA)-induced hypersensitivity to topical histamine challenge.. Actively sensitized Dunkin-Hartley guinea pigs.. OA and alum were applied to guinea pigs intraperitoneally 3 times at two-week intervals. After general sensitization, OA inhalation was performed every day for 6 days as topical sensitization. Before inhalation, treatment with CyA (50 mg/kg, p.o.), glucocorticosteroids (beclomethasone propionate (1.0 mg/kg, i.p.), fluticasone propionate (FP, 0.5 mg/kg, i.p.)) or vehicle were performed, and the sensitivity to histamine was measured before and after the inhalation. Moreover, in actively (general and topical) sensitized guinea pigs, FP (0.5 mg/kg, i.p.) was applied every day for 5 days and histamine sensitivity was evaluated before and after the application.. We found that histamine sensitivity was significantly increased by nasal antigen challenge in this guinea pig model, and that the occurrence of histamine hypersensitivity was inhibited by the pretreatment with CyA and glucocorticosteroids. Although multiple administration of FP gradually reduced the histamine hypersensitivity according to the period of administration, it did not significantly alter the histamine hypersensitivity after the occurrence of hypersensitivity.. It is concluded that CyA and glucocorticosteroids suppress antigen-induced histamine hypersensitivity in a guinea pig model of allergic rhinitis.

Topics: Administration, Inhalation; Androstadienes; Animals; Anti-Allergic Agents; Anti-Inflammatory Agents; Beclomethasone; Cyclosporine; Disease Models, Animal; Drug Hypersensitivity; Fluticasone; Glucocorticoids; Guinea Pigs; Histamine; Immunosuppressive Agents; Injections, Intraperitoneal; Male; Ovalbumin; Rhinitis, Allergic, Perennial

The in vivo model of nasal microvascular leakage was used for the nasal allergic challenge in ovalbumin (OA)-sensitized guinea pigs, or nasal stimulation with leukotriene D4 (LTD4) in non-sensitized animals. An intravenous injection of Evans blue dye was given as an index of nasal microvascular leakage. Following the nasal stimulation with LTD4, the concentration of dye in the nasal lavage fluid rapidly increased. Oral administration of ONO-1078 (pranlukast) (3-30 mg/kg) significantly inhibited the LTD4-induced nasal microvascular leakage. In OA-sensitized guinea pigs, the excretions of dye into nasal lavage fluid were recognized soon after the topical antigenic stimulation and continued for over 60 minutes. Oral administration of ONO-1078 (30 mg/kg) significantly inhibited the antigen-induced microvascular leakage. These results suggest that ONO-1078 may be of therapeutic use for nasal allergy.

Topics: Animals; Anti-Asthmatic Agents; Chromones; Disease Models, Animal; Guinea Pigs; Leukotriene Antagonists; Leukotriene D4; Male; Membrane Proteins; Ovalbumin; Receptors, Leukotriene; Rhinitis, Allergic, Perennial

To observe the changes of epithelial apical membrane short-circuit current (Isc) of antigen-sensitized rat nasal mucosa with the stimulation of Substances P (SP).. The epithelial apical membrane Isc were measured with Ussing chamber technique, and and we observed the blockage to the effect of SP by neurokinin receptor antagonist Cp96345, histamine H1 receptor antagonist pyrilamine, H2 antagonist ranitidine and neurotoxin respectively.. The Isc increased significantly with the stimulation of SP. The effect of SP on Isc could be blocked significantly by pretreatment with four substances.. SP releasing from nervous endings plays the role on elicit a series of pathological changes like enhanced Isc, epithelial permeabilities, etc.

Topics: Animals; Biphenyl Compounds; Electrophysiology; Epithelium; Histamine H1 Antagonists; Histamine H2 Antagonists; Male; Nasal Mucosa; Ovalbumin; Pyrilamine; Ranitidine; Rats; Rats, Sprague-Dawley; Rhinitis, Allergic, Perennial; Substance P; Tetrodotoxin

To explore the potential role of substance P receptor (SPR) in the initiation and development of allergic rhinitis (AR).. Twenty healthy rats were randomly divided into two groups. A model of allergic rhinitis in rat was established by using ovalbumin intraperitoneal immunization and nasal antigen challenge. The nasal mucosa obtained from seven out of ten AR models as well as ten normal controls were studied routinely by HE and immunohistochemical staining to observe the distribution and changes of SPR.. The study showed that immunoreactivity to SPR was present both on the surface and in the cytoplasm of epithelial cells, eosinophils, glandular cells and its ducts, mast cells, plasmocyte and other monocytes. During nasal hypersensitiveness, the staining density and the positive staining cells increased significantly as compared with those in normal controls.. The increase of SPR in nasal mucosa in rat AR model indicates that SPR might play a critical role in the development of AR.

Topics: Animals; Female; Male; Nasal Mucosa; Ovalbumin; Random Allocation; Rats; Rats, Wistar; Receptors, Neurokinin-1; Rhinitis, Allergic, Perennial

To define the role of leukotriene (LT) in allergic rhinitis, we examined the effects of a cysteinyl (Cys) LT antagonist (ONO-1078, pranlukast).. Actively sensitized Dunkin-Hartley guinea pigs.. ONO-1078 (pranlukast), 3-100 mg/kg p.o. 1 h before antigen challenge.. Nasal symptoms (sneezing, nasal scratches), changes of total airway resistance (TAR by plethysmography) and eosinophil infiltration into the nasal mucosa were determined following topical antigen (OA) challenge. Dunnet's test (TAR and symptoms) and the Mann-Whitney U-test (eosinophils) were applied.. Control animals showed bi-phasic nasal responses, peaking 10 min and 240 min after the topical antigen challenge, respectively. While the early-phase response was characterized by nasal symptoms of sneezing and scratching accompanied by the increase in TAR, the late-phase was characterized by an increase in TAR accompanied by eosinophil infiltration into nasal mucosa. The nasal symptoms (sneezing and scratching) were not inhibited by pretreatment with ONO-1078 at doses up to 100 mg/kg (p.o., n = 15). Although early peak responses of TAR were not affected with even the highest dose (30 mg/kg, p.o., n = 6), late-phase TAR peak response (control: 174.8 +/- 8.2%, n = 6) were significantly inhibited by 10 mg/ kg (142.7 +/- 15.8%; p < 0.05, n = 6) and 30 mg/kg (118.0 +/- 6.6%; p < 0.01, n = 6) of ONO-1078 (p.o.). In addition, the eosinophil infiltration induced by the antigen was not inhibited by ONO-1078 (30 and 100 mg/kg, p.o., n = 6).. Our results suggest that Cys LT may play an important role in the late-phase increase in TAR in the guinea pig model of allergic rhinitis.

Topics: Administration, Topical; Airway Resistance; Animals; Anti-Asthmatic Agents; Chromones; Cysteine; Disease Models, Animal; Eosinophils; Guinea Pigs; Leukotriene Antagonists; Nasal Mucosa; Ovalbumin; Plethysmography; Rhinitis, Allergic, Perennial; Serine Proteinase Inhibitors

To examine the effects of a specific cysteinyl leukotriene (cysLT) antagonist, pranlukast, on allergic rhinitis, antigen-induced rhinitis in guinea pigs was modified by pretreatment with an cyclooxygenase inhibitor (indomethacin) followed by an H1-blocker (pyrilamine). Intranasal ovalbumin (OVA) administration in actively sensitized guinea pigs resulted in concentration-dependent increases in nasal permeability and nasal airway resistance (NAR). Although pyrilamine (1 mg/kg, i.v.) abolished these antigen-induced changes, pretreatment with indomethacin (5 mg/kg, i.v.) followed by pyrilamine enhanced these responses to a degree similar to that observed with OVA challenge alone. Analyses of nasal perfusate in indomethacin/pyrilamine-pretreated animals showed that cysLTs increased by 270.8%, whereas thromboxane B2 decreased by 88.3% as compared with those on challenged with OVA alone. Oral administration of pranlukast (1-10 mg/kg) dose-dependently prevented increases in nasal permeability and NAR of indomethacin/pyrilamine-pretreated animals. However, an anti-allergic agent, azelastine, did not affect these responses. These results indicate that pranlukast suppresses antigen-induced cysLT-mediated responses of allergic rhinitis in actively sensitized guinea pigs. A cysLT antagonist, pranlukast, may thus prevent cysLT-mediated symptoms of allergic rhinitis.

Topics: Airway Resistance; Animals; Anti-Allergic Agents; Anti-Asthmatic Agents; Chromones; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Drug Interactions; Guinea Pigs; Histamine H1 Antagonists; Indomethacin; Leukotriene Antagonists; Nasal Mucosa; Ovalbumin; Phthalazines; Pyrilamine; Rhinitis, Allergic, Perennial; SRS-A; Thromboxane B2

We have investigated the effects of allergen immunotherapy on the nasal responses in the guinea-pigs with allergic rhinitis. Thirty-three male Hartley guinea-pigs with allergic rhinitis were divided into three groups; those receiving intradermal injection of saline (Group 1) or 0.1% ovalbumin (Group 2) 6 days after the last intranasal sensitization, and those injected with 0.1% ovalbumin intradermally once daily for 6 consecutive days from the next day after the last intranasal sensitization (Group 3).. The dye leakage and histamine content into the nasal lavage significantly decreased at 30 min after antigen challenge in Group 3, compared with Group 1 or 2. We also observed the change of mast cell numbers in superficial nasal mucosa, lamina propria and injected dorsal skin. The number of mast cells in superficial nasal mucosa significantly decreased in Group 3 compared with Group 1 or 2, but not those in nasal lamina propria or dorsal skin.. These results suggest that the improvements of nasal responses such as dye leakage and histamine content may be caused by the decrease of mast cell numbers in the superficial mucosal layer after the specific immunotherapy, which may be developing tolerance and one of the mechanisms underlying the beneficial effect of immunotherapy.

Topics: Administration, Intranasal; Allergens; Animals; Coloring Agents; Desensitization, Immunologic; Guinea Pigs; Histamine; Immunoglobulin E; Immunoglobulin G; Injections, Intradermal; Male; Mast Cells; Nasal Mucosa; Ovalbumin; Rhinitis, Allergic, Perennial; Skin

We applied anti-ICAM-1 and anti-LFA-1 monoclonal antibody (mAb) to ovalbumin-sensitized rats and examined the effects on nasal eosinophilia and nasal symptoms following topical antigen challenge. In a general and local immunization (GLI) group of rats, the mAbs were applied during the booster topical immunization period. In a general immunization group and a local immunization (LI) group of rats, the mAbs were applied during the immunization period. The number of sneezes and nasal scratching movements occurring soon after topical antigen (Ag) challenge was significantly suppressed in the GLI and LI group rats. Eosinophil infiltration into nasal mucosa 24 h after Ag challenge was also significantly suppressed in GLI and LI group rats. These findings suggest that the ICAM-1/LFA-1 system is important in topical allergic inflammation in rats.

Topics: Animals; Antibodies, Monoclonal; Intercellular Adhesion Molecule-1; Lymphocyte Function-Associated Antigen-1; Male; Nasal Cavity; Nasal Provocation Tests; Ovalbumin; Pulmonary Eosinophilia; Rats; Rats, Wistar; Rhinitis, Allergic, Perennial; Vaccination

We performed general and topical sensitization by ovalbumin in wild type, WBBFI6- +/+ (+/+), mice and mast cell-depleted type, WBBFI6-W/Wv (W/W)v, mice. Although both mice showed almost equal PCA liters, W/Wv mice showed a lower level of antigen-induced eosinophilia, and more significant nasal symptoms and histamine hypersensitivity than +/+ mice. Antigen-induced increased levels of histamine and IL-5 in nasal lavage fluid were noted in +/+ mice. Cyclosporin A pre-treatment inhibited the antigen-induced nasal symptoms, nasal eosinophilia and increased levels of histamine and IL-5 in nasal lavage fluid in the +/+ mice. The PCA titer was not affected by the treatment in either kind of mouse.

Topics: Animals; Cyclosporine; Immunization; Immunosuppressive Agents; Male; Mast Cells; Mice; Mice, Inbred Strains; Ovalbumin; Passive Cutaneous Anaphylaxis; Rhinitis, Allergic, Perennial

To determine the role of cell adhesion molecules, we evaluated the in vivo effects of anti-intercellular adhesion molecule-1 (ICAM-1) monoclonal antibody (1A29) and anti-leukocyte function associated molecule-1 (LFA-1) monoclonal antibody (WT-1) on ovalbumin (OA) sensitized rats. Both sneezing discharges and nasal rubbing movements after nasal OA challenge were significantly inhibited by these monoclonal antibody administrations (control vs treated group; 20.5 +/- 5.0 vs 7.0 +/- 2.9 times/minutes, p < 0.01 and and 56.8 +/- 7.1 vs 26.9 +/- 2.9 times/15 minutes, p < 0.01, for sneezing and rubbing, respectively). The number of eosinophils in nasal mucosa 24 hours after the challenge was also inhibited by the treatment (control vs treatment group; 108.8 +/- 27.3 vs 13.8 +/- 6.9 p < 0.01). These results suggest some pathophysiological roles of ICAM-1 and LFA-1 in nasal allergy.

Topics: Animals; Antibodies, Monoclonal; Cell Adhesion Molecules; Disease Models, Animal; Intercellular Adhesion Molecule-1; Lymphocyte Function-Associated Antigen-1; Male; Ovalbumin; Rats; Rats, Wistar; Rhinitis, Allergic, Perennial

To define the role of platelet activating factor (PAF) in allergic rhinitis, we examined the effects of anti-PAF agents (WEB2086, SM10661) on the changes of nasal airway resistance (NAR) and nasal symptoms after topical antigen challenge in actively sensitized guinea pigs and compared these with the changes brought by anti-leukotriene (LT) agent (FPL 55712), 5-lipoxygenase inhibitor (E6080), anti-allergic agent (azelastine), and anti-histamine agent (mepyramine maleate). We noted biphasic increase in NAR after antigen challenge; the first peak, 146.3 +/- 4.3% at 10 min and the second peak, 163.3 +/- 7.8% at 240 min after antigen challenge. The first peak response of NAR was not affected by anti-PAF agents, anti-LT agent, 5-lipoxygenase inhibitor, or azelastine; it was slightly but significantly inhibited by anti-histamine. The second NAR response was significantly inhibited by anti-PAF agents, anti-LT agent, 5-lipoxygenase inhibitor, and azelastine, but was not affected by anti-histamine. The nasal symptoms which occurred within 30 min after antigen challenge were significantly inhibited by WEB2086, E6080, azelastine, and mepyramine, but were not affected by SM10661. Our results suggest that PAF activities and LTs may play an important role in the later phase increase of NAR after topical antigen challenge.

Topics: Airway Resistance; Animals; Azepines; Chromones; Guinea Pigs; Histamine H1 Antagonists; Immunization; Lipoxygenase Inhibitors; Male; Ovalbumin; Phthalazines; Platelet Activating Factor; Pyrilamine; Rhinitis, Allergic, Perennial; Sneezing; SRS-A; Thiazoles; Thiazolidines; Triazoles

The in vivo effects of the antiallergic drug azelastine were investigated in sensitized guinea pigs. Topical administration of antigen into the nasal cavity produced an increase in nasal vascular permeability together with an increase in both the histamine and leukotriene C4 (LTC4) concentrations of nasal lavage fluid. Pre-treatment with azelastine significantly inhibited both the LTC4 release and the increase in nasal vascular permeability. These results suggest that azelastine inhibits the release of antigen-induced leukotrienes and increases nasal vascular permeability in vivo.

Topics: Animals; Capillary Permeability; Guinea Pigs; Histamine H1 Antagonists; Histamine Release; Immunization; Male; Ovalbumin; Phthalazines; Rhinitis, Allergic, Perennial; SRS-A

An animal disease model of allergic rhinitis was developed with Brown Norway (BN) rat, a high immunoglobulin E responder strain. BN rats were immunized with ovalbumin (OA) and made to suffer from allergic rhinitis. The severity of allergic rhinitis was assessed by determining the extent of the three kinds of markers, Evan's blue, histamine and N-acetyl-beta-D-glucosaminidase, released into the nasal perfusate following the OA challenge to the nasal cavity of OA-sensitized BN rats. This experimental system was appreciated by antiallergic drugs; chlorpheniramine maleate inhibited the release of Evan's blue and elevated that of histamine, but did not affect the N-acetyl-beta-D-glucosaminidase level. Halopredone acetate inhibited the releases of all the three markers. The estimation of the released markers using allergic rhinitis brought about in BN rats was found to be a useful experimental system for evaluating the effect of drugs on allergic rhinitis.

Topics: Acetylglucosaminidase; Administration, Topical; Animals; Anti-Inflammatory Agents; Antigens; Biomarkers; Chlorpheniramine; Disease Models, Animal; Evans Blue; Fluprednisolone; Histamine Release; Immunization; Immunoglobulin E; Male; Nasal Cavity; Nasal Mucosa; Ovalbumin; Rats; Rats, Inbred BN; Rats, Inbred Strains; Rhinitis, Allergic, Perennial

Topics: Animals; Nasal Mucosa; Ovalbumin; Pollen; Rabbits; Rhinitis, Allergic, Perennial

Receptor-binding assays were performed to evaluate the changes of beta- and alpha 1-adrenergic and muscarinic receptors in the nasal mucosa of subjects with nasal allergy and in guinea pigs sensitized with ovalbumin using radioligands 3H-DHA, 3H-prazosin and 3H-QNB, respectively. In subjects with nasal allergy, a decrease in density of beta- and alpha 1-adrenergic receptors and an increase in density of muscarinic cholinergic receptors were observed. An increase in density of muscarinic cholinergic receptors could be reproduced in the nasal mucosa of guinea pigs which were sensitized with ovalbumin and had typical hyperreactive nasal symptoms. These results indicate that the increase in the density of muscarinic receptors observed in the nasal mucosa of subjects with nasal allergy has been induced secondarily by an allergic reaction in the nasal mucosa with hyperreactive nasal symptoms, which in turn acts as an aggravating factor in the vicious circle promoting hyperreactivity of the nasal mucosa.

Topics: Adolescent; Adult; Animals; Dihydroalprenolol; Guinea Pigs; Humans; Nasal Mucosa; Ovalbumin; Prazosin; Quinuclidinyl Benzilate; Radioligand Assay; Receptors, Adrenergic; Receptors, Adrenergic, alpha; Receptors, Adrenergic, beta; Receptors, Muscarinic; Rhinitis, Allergic, Perennial; Tritium

The prevalence rate of allergic rhinitis caused by pollen has strikingly increased in Japan in the last three decades. The number of diesel cars in use has also rapidly increased in the country. This fact urged us to study the effects of particulates emitted from diesel cars on the production of IgE antibody. The primary IgE antibody responses in mice immunized with intraperitoneal injection of ovalbumin (OA) mixed with diesel-exhaust particulates (DEP) were higher than those in the animals immunized with OA alone. This effect of DEP on the production of IgE antibody in mice was also demonstrated when mice were immunized with repeated injections of dinitrophenylated-OA. In addition, persistent IgE-antibody response to major allergen of Japanese cedar pollen (JCPA), a most common pollen causing allergic rhinitis in Japan, was observed in mice immunized with JCPA mixed with DEP but not in the animals immunized with JCPA alone. The results do indicate that the adjuvant activity of DEP can not be excluded as a possible cause of the associated change in the number of diesel cars and allergic rhinitis caused by pollen in Japan.

Topics: Adjuvants, Immunologic; Animals; Antibody Formation; Female; Gasoline; Immunoglobulin E; Mice; Mice, Inbred Strains; Ovalbumin; Petroleum; Rhinitis, Allergic, Perennial; Vehicle Emissions