ovalbumin and suplatast-tosilate

Airway hyperreactivity and inflammation are important factors in the aggravation of lung function. Suplatast tosilate (IPD) is a novel and unique anti‑asthma clinical compound. However, the mechanisms of IPD action in the inhibition of asthma remain to be elucidated. The present study aimed to investigate the role of the GATA binding protein 3 (GATA‑3)/interleukin (IL)‑5 signaling pathway in IPD‑induced inhibition of asthma. Sprague‑Dawley rats were sensitized by intraperitoneal injection with ovalbumin (OVA) to establish an animal model of asthma. IPD was administered continuously (C‑IPD) or at a later stage (L‑IPD). Budesonide (BUD) was used as a positive control. Airway resistance and the expression of genes at the mRNA and protein levels were measured. Morphological changes in lung tissue and the percentage of eosinophils (EOS) in peripheral blood were observed and correlation analysis was performed. The results revealed that sensitization by OVA significantly increased airway resistance and the percentage of EOS in peripheral blood and induced significant inflammatory changes in lung tissue, as demonstrated by thick epithelium, goblet cell hyperplasia and submucosal cell infiltration. In addition, sensitization by OVA was found to markedly upregulate IL‑5 mRNA and protein expression. Airway resistance was found to positively correlate with the expression of IL‑5 in the rat lung tissues. Sensitization by OVA was also observed to markedly enhance GATA‑3 protein expression and GATA‑3 levels were found to positively correlate with airway resistance and IL‑5 levels. Similar to the effect of BUD, treatment with C‑IPD or L‑IPD was found to significantly attenuate OVA‑induced increases in airway resistance and the percentage of EOS in peripheral blood. Notably, treatment with C‑IPD or L‑IPD markedly reduced the OVA-induced expression of IL‑5 and GATA‑3. In the present study, IPD intervention was demonstrated to ameliorate airway hyperreactivity and inflammation and the mechanisms may involve inhibition of the GATA‑3/IL‑5 signaling pathway.

Topics: Airway Resistance; Animals; Arylsulfonates; Asthma; Bronchial Hyperreactivity; Disease Models, Animal; Eosinophils; GATA3 Transcription Factor; Histamine Antagonists; Inflammation; Interleukin-5; Leukocyte Count; Lung; Male; Ovalbumin; Rats; Signal Transduction; Sulfonium Compounds

Cough receptor hypersensitivity is a fundamental feature of some conditions presenting with chronic non-productive cough. Suplatast tosilate, an anti-allergic agent, is a T helper (Th)2 cytokine inhibitor that inhibits the synthesis of interleukin (IL)-4, IL-5, immunoglobulin (Ig)E production, and local eosinophil accumulation.. The purpose of this study was to investigate the effect of suplatast on antigen-induced airway cough hypersensitivity and eosinophil infiltration into the airway.. Number of coughs elicited by inhalation of increasing concentrations of capsaicin (10-8, 10-6 and 10-4 M) was counted 24 h after an antigen challenge in conscious guinea-pigs and then bronchoalveolar lavage was performed. We investigated the effect of single (before antigen challenge or capsaicin provocation) or repetitive treatment with intraperitoneal suplatast at a dose of 10 or 30 mg/kg on antigen-induced cough hypersensitivity.. Twenty-four hours after antigen challenge, guinea-pigs developed an increase in cough receptor sensitivity to inhaled capsaicin and eosinophil infiltration in the airways. After a 2-week treatment with suplatast, but not after only a single treatment before antigen challenge or capsaicin provocation, the antigen-induced early phase bronchoconstriction, cough hypersensitivity, and airway eosinophilia were inhibited in a dose-dependent manner.. These results indicate that suplatast inhibits airway cough hypersensitivity underlying allergic eosinophilic inflammation.

Topics: Airway Resistance; Animals; Anti-Allergic Agents; Arylsulfonates; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Bronchoconstriction; Cough; Disease Models, Animal; Eosinophils; Guinea Pigs; Japan; Male; Ovalbumin; Respiratory Hypersensitivity; Sensitivity and Specificity; Sulfonium Compounds; Time Factors

Suplatast tosilate (IPD) is a newly developed 'anti-allergic' drug. It seems to be a unique compound because of its ability to suppress IgE but not IgG or IgM production in vivo and cytokine production from type 2 helper T cells (Th2) in vitro. However, information on its in vivo effect on an animal model of asthma is limited.. BALB/c mice sensitized to ovalbumin (3 times, 2-week interval) were challenged with ovalbumin by inhalation (50 mg/ml for 20 min, once a day for 6 days). In this study, we explored the influence of IPD on eosinophil infiltration into the airways, bronchial hyperresponsiveness (BHR) to methacholine, specific IgE antibody production, and cytokines in bronchoalveolar lavage fluid (BALF) using this murine model.. Treatment with IPD significantly reduced the number of total cells and eosinophils in BALF (around -40%) and almost completely inhibited the development of antigen-induced BHR. Histological findings confirmed the reduction of submucosal cell infiltration in the lung, and disclosed the marked inhibition of bronchial epithelial cell damage. Ovalbumin-specific IgE was slightly but significantly reduced. The levels of IL-4, IL-5 and IL-13 in BALF were significantly decreased in mice treated with the compound compared to those in untreated mice.. These results suggest that IPD is capable of inhibiting the production of Th2 cytokines, which inhibit eosinophil infiltration into the murine airway, IgE synthesis, and development of BHR, in a murine model of asthma.

Topics: Animals; Anti-Allergic Agents; Arylsulfonates; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Cytokines; Disease Models, Animal; Eosinophilia; Female; Immunoglobulin E; Immunoglobulin G; Lung; Methacholine Chloride; Mice; Ovalbumin; Sulfonium Compounds

IL-4 and IL-13 play a putative role in mucus hypersecretion in asthma. Suplatast tosilate prevents the synthesis of T(H2) cytokines.. Because suplatast tosilate inhibits T(H2) cytokines but does not inhibits IFN-gamma production, we examined the effect of suplatast on IL-4- or IL-13- and ovalbumin (OVA)-induced mucin synthesis in NCI-H292 cells in vitro and in bronchi of pathogen-free BALB/c mice in vivo.. In vitro, NCI-H292 cells were preincubated with suplatast tosilate (0.1-100 microgram/mL) 1 hour before adding human recombinant IL-4 (10 ng/mL). In vivo, mouse recombinant IL-4 or IL-13 (250 ng per/mouse) was instilled intranasally in mice pretreated with suplatast tosilate (50 mg.kg(-1).d(-1)). Mucous glycoconjugates were stained with Alcian blue (AB)/periodic acid-Schiff (PAS) stain. To evaluate effects of suplatast tosilate on goblet-cell metaplasia in OVA-sensitized mice, animals were pretreated with suplatast tosilate (1-50 mg.kg(-1).d(-1)) intragastrically. IL-4 and IL-13 were measured, and allergic inflammatory cells were analyzed in bronchoalveolar lavage fluid of OVA-sensitized mice.. Pretreatment with suplastast did not prevent IL-4- or IL-13-induced increase in mucous glycoconjugate production in NCI-H292 cells or in mice. OVA sensitization increased AB/PAS-stained area of the epithelium (48.1% +/- 2.4%, P <.01 compared with control mice). Suplatast tosilate inhibited OVA-induced goblet-cell metaplasia in airway epithelium in a dose-dependent fashion; 50 mg.kg(-1).d(-1) decreased the AB/PAS area to 22.7% +/- 2.7% (P <.05 compared with OVA sensitization alone). Pretreatment with suplatast tosilate also prevented OVA-induced increase in IL-4 and IL-13 levels and decreased the number of lymphocytes and eosinophils in bronchoalveolar lavage fluid (P <.05 compared with values of mice given OVA alone).. These results indicate that suplatast tosilate prevents allergen-induced goblet-cell metaplasia and the recruitment of eosinophils and lymphocytes into the airways. These results suggest that this effect is due to the prevention of the production of T(H2) cytokines in airways.

Topics: Animals; Anti-Allergic Agents; Arylsulfonates; Bronchi; Cell Line; Goblet Cells; Humans; Immunization; Interleukin-4; Male; Metaplasia; Mice; Mice, Inbred BALB C; Mucins; Ovalbumin; Sulfonium Compounds

We examined the effect of Y-24180, a potent antagonist to platelet-activating factor (PAF), on allergic cutaneous reactions in actively sensitized mice.. Male BALB/c and BALB/c-nu/nu mice were used.. Y-24180, ketotifen fumarate (ketotifen), and suplatast tosilate (suplatast) were orally administered twice a day for 3 days beginning 2 days before an ovalbumin (OA) challenge. Hydrocortisone 17-butyrate (hydrocortisone) was applied topically to ear surface once a day for 3 days, beginning 2 days before the OA challenge.. Mice actively sensitized with OA were challenged by intradermally injecting OA into both ears. Ear thickness was measured with a dial thickness gauge.. Increase in ear thickness, with peak responses at 1 h (immediate phase reaction, IPR) and 24 h (late phase reaction, LPR) after the challenge, were induced in actively sensitized BALB/c mice. The reactions were not induced in T cell-deficient BALB/c-nu/nu mice. Y-24180 suppressed both the IPR and LPR of BALB/c mice. Although suplatast suppressed the LPR, the IPR was not affected. Ketotifen suppressed the IPR, but not the LPR. Hydrocortisone suppressed both the IPR and LPR of BALB/c mice. Furthermore, Y-24180 in combination with hydrocortisone significantly enhanced the effect of hydrocortisone on both the reactions.. Y-24180 was demonstrated not only to suppress the IPR and LPR, but also to show strong suppressive effects in combination with topical hydrocortisone. Therefore, Y-24180 is expected to contribute to the treatment of inflammatory skin diseases including atopic dermatitis.

Topics: Administration, Oral; Administration, Topical; Allergens; Animals; Anti-Allergic Agents; Anti-Inflammatory Agents; Arylsulfonates; Azepines; Dermatitis, Allergic Contact; Ear; Eosinophils; Histamine H1 Antagonists; Hydrocortisone; Immunoglobulin E; Immunoglobulin G; Ketotifen; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Ovalbumin; Platelet Membrane Glycoproteins; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Sulfonium Compounds; Time Factors; Triazoles

To investigate the development of airway hyperresponsiveness in infantile guinea pigs, animals (10 days old) were immunized twice and challenged by inhalation of 1% ovalbumin for 10 min with 7 days intervals. Similar to adult guinea pigs, infantile ones developed an increased airway responsiveness to acetylcholine 24 hr after antigen challenge. There was a marked increase in the number of total leukocytes, eosinophils and lymphocytes in bronchoalveolar lavage fluid (BALF). Suplatast tosilate (suplatast) and pemirolast potassium (pemirolast) given orally throughout the experiments suppressed the development of airway hyperresponsiveness in infantile animals. They showed similar potency in the suppression of eosinophil accumulation in BALF and lung tissue, while suplatast inhibited lymphocyte accumulation stronger than pemirolast. Collectively, the present model of airway hyperresponsiveness in infantile guinea pigs may be useful in predicting the efficacy of antiallergic agents in the treatment of asthmatic children.

Topics: Animals; Anti-Allergic Agents; Antigens; Arylsulfonates; Asthma; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Guinea Pigs; Histamine Antagonists; Leukocyte Count; Male; Ovalbumin; Pyridines; Pyrimidinones; Respiratory Hypersensitivity; Sulfonium Compounds