ovalbumin and ciglitazone

Asthma is characterized by airway hyperresponsiveness (AHR), inflammation and remodeling. Peroxisome proliferator-activated receptors (PPARs) were reported to regulate inflammatory responses in many cells. In this study we examined the effect of a PPAR-gamma agonist on the airway smooth muscle and the production of transforming growth factor (TGF)-beta1 and vascular endothelial growth factor (VEGF).. We developed a mouse model of airway remodeling including smooth muscle thickening in which ovalbumin (OVA)-sensitized mice were repeatedly exposed to intranasal OVA administration twice a week for 3 months. Mice were treated intranasally with ciglitazone during OVA challenge.. Mice chronically exposed to OVA developed sustained eosinophilic airway inflammation and AHR to methacholine compared with control mice. In addition, the mice chronically exposed to OVA developed features of airway remodeling, including thickening of the peribronchial smooth muscle layer. Administration of ciglitazone intranasally significantly inhibited the development of AHR, eosinophilic inflammation, and importantly, airway smooth muscle remodeling in mice chronically exposed to OVA. However, intranasal ciglitazone treatment did not reduce the level of TGF-beta1 and VEGF in bronchoalveolar lavage fluid.. These results suggest that intranasal administration of ciglitazone can prevent not only airway inflammation, but also airway remodeling associated with chronic allergen challenge. The mechanism might not be related to VEGF and TGF production. Further study is needed.

Topics: Administration, Intranasal; Animals; Anti-Asthmatic Agents; Asthma; Bronchi; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Cell Count; Disease Models, Animal; Eosinophils; Female; Mice; Mice, Inbred BALB C; Muscle, Smooth; Ovalbumin; PPAR gamma; Respiratory Hypersensitivity; Thiazolidinediones; Transforming Growth Factor beta1; Vascular Endothelial Growth Factor A

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

Previously, we found pulmonary gas trapping to be a rapid, simple and objective measure of methacholine-induced airway obstruction in naïve mice. In this study we extended that finding by using methacholine-induced pulmonary gas trapping to differentiate airway responses of ovalbumin-sensitized, ovalbumin-exposed (Positive Control) and ovalbumin-sensitized, sodium chloride-exposed (Negative Control) mice. Additionally, pulmonary gas trapping and enhanced pause were compared following methacholine exposure in sensitized and nonsensitized mice. Finally, we examined by nose-only inhalation the ability of the glucocorticosteroid budesonide and the peroxisome proliferator-activated receptor-gamma agonist ciglitazone to modify methacholine-induced airway responses in ovalbumin-sensitized mice. Positive Controls exhibited a 7.8-fold increase in sensitivity and a 2.4-fold enhancement in the maximal airway obstruction to methacholine versus Negative Controls. Following methacholine, individual Positive and Negative Control mouse enhanced pause values overlapped in 9 of 9 studies, whereas individual Positive and Negative Control mouse excised lung gas volume values overlapped in only 1 of 9 studies, and log[excised lung gas volume] correlated (P=0.023) with in vivo log[enhanced pause] in nonsensitized mice. Finally, budesonide (100.0 or 1000.0 microg/kg) reduced methacholine-mediated airway responses and eosinophils and neutrophils, whereas ciglitazone (1000.0 microg/kg) had no effect on methacholine-induced pulmonary gas trapping, but reduced eosinophils. In conclusion, pulmonary gas trapping is a more reproducible measure of methacholine-mediated airway responses in ovalbumin-sensitized mice than enhanced pause. Also, excised lung gas volume changes can be used to monitor drug interventions like budesonide. Finally, this study highlights the importance of running a positive comparator when examining novel treatments like ciglitazone.

Topics: Administration, Inhalation; Airway Obstruction; Animals; Anti-Asthmatic Agents; Asthma; Bronchial Hyperreactivity; Bronchodilator Agents; Budesonide; Disease Models, Animal; Dose-Response Relationship, Drug; Eosinophils; Male; Methacholine Chloride; Mice; Mice, Inbred BALB C; Neutrophils; Ovalbumin; PPAR gamma; Thiazolidinediones

We have shown previously that specific ligands of the peroxisome proliferator-activated receptor-gamma (PPARgamma) inhibit the systemic allergic immune response. The objective of this study was to investigate the impact of PPARgamma-ligand treatment on the local allergic immune response. We established a murine model exhibiting clinical and histological features of AD-like skin lesions with high reproducibility. In this model, the PPARgamma ligand was applied in an either preventive or therapeutic manner via systemic and local routes. The affected skin areas were assessed by standardized skin score, histological analyses, and immunohistochemical examinations. Our data show that systemic application of PPARgamma ligand by a preventive protocol led to significantly reduced onset of eczematous skin lesions. This was confirmed by histology, showing decreased skin thickness accompanied by significantly reduced infiltrations of CD4+ and CD8+ lymphocytes but also mast cells. Additionally, early allergen-specific IgE and IgG1 responses were reduced (day 21/35), whereas IgG2a levels remained unchanged. In conclusion, our results demonstrate that PPARgamma-ligand treatment inhibits not only systemic allergic immune response, but also local allergen-mediated dermatitis. Our findings point to therapeutic strategies, including a PPARgamma-ligand-based treatment.

Topics: Animals; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Dermatitis, Atopic; Disease Models, Animal; Female; Hypersensitivity; Immunoglobulin E; Immunoglobulin G; Ligands; Mast Cells; Mice; Mice, Inbred BALB C; Ovalbumin; PPAR gamma; Skin; Thiazolidinediones

There is considerable interest in the role of peroxisome proliferator activated receptors (PPARs) as ligand-activated transcription factors in the airways. This study examines the effects of a potent synthetic PPARgamma ligand, rosiglitazone (RG), in a murine model of allergen-induced inflammation, to explore its potential regulation of airways inflammation, structure and function. C57BL/6 mice were sensitised with ovalbumin (OVA, 50 microg i.p., days 0, 12) and challenged with aerosolized OVA (1% w v(-1), 30 min day(-1)) for 7 days (days 20-26). Mice were treated with RG (5 mg kg(-1) i.p.) or vehicle during the challenge period. The OVA challenge induced increases in leukocyte number and MMP-2 activity in bronchoalveolar lavage fluid and in goblet cell number in lung tissue obtained on Day 27. RG failed to inhibit inflammatory cell infiltration, MMP-2 activity or goblet cell hyperplasia. Respiratory resistance in response to methacholine (MCh i.v.) was greater in OVA-challenged mice than saline-challenged mice and this airways hyperresponsiveness (AHR) was reduced by RG. However, RG did not affect MCh-induced contraction in isolated guinea-pig tracheal rings, nor did it influence the airway obstruction induced by MCh in saline-challenged mice, so a direct effect on airway obstruction is unlikely. These data suggest that RG modulates AHR in this model, by a mechanism that is also potentially independent of an anti-inflammatory action.

Topics: Allergens; Animals; Bronchoalveolar Lavage Fluid; Bronchoconstrictor Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Goblet Cells; Guinea Pigs; Hyperplasia; In Vitro Techniques; Injections, Intraperitoneal; Ligands; Matrix Metalloproteinase 2; Methacholine Chloride; Mice; Mice, Inbred C57BL; Muscle Contraction; Ovalbumin; Pneumonia; PPAR gamma; Respiratory Hypersensitivity; Rosiglitazone; Thiazolidinediones; Time Factors; Trachea; Vasodilator Agents

Peroxisome proliferator-activated receptors (PPARs) are activated by an array of polyunsaturated fatty acid derivatives, oxidized fatty acids, and phospholipids and are proposed to be important modulators of immune and inflammatory responses. Recently, we showed that activation of PPAR-gamma alters the maturation process of dendritic cells (DCs), the most potent antigen-presenting cells. In the present report, we investigated the possibility that, by targeting DCs, PPAR-gamma activation may be involved in the regulation of the pulmonary immune response to allergens. Using a model of sensitization, based on the intratracheal transfer of ovalbumin (OVA)-pulsed DCs, we show that rosiglitazone, a selective PPAR-gamma agonist, reduces the proliferation of Ag-specific T cells in the draining mediastinal lymph nodes but, surprisingly enough, dramatically increases the production of the immunoregulatory cytokine interleukin (IL)-10 by T cells, as compared to control mice sensitized with OVA-pulsed DCs. After aerosol challenge, the recruitment of eosinophils in the bronchoalveolar lavage fluids was strongly reduced compared to control mice. Finally, T cells from the mediastinal lymph nodes produced higher amounts of IL-10 and interferon-gamma. Inhibition of IL-10 activity with anti-IL-10R antibodies partly restored the inflammation. The specificity of the phenomenon was confirmed by treating OVA-pulsed DCs with ciglitazone, another PPAR-gamma agonist, and by using GW9662, a PPAR-gamma antagonist. Our data suggest that PPAR-gamma activation prevents induction of Th2-dependent eosinophilic airway inflammation and might contribute to immune homeostasis in the lung.

Topics: Anilides; Animals; Asthma; Cell Movement; Cytokines; Dendritic Cells; Disease Models, Animal; Eosinophils; Inflammation; Lung; Mice; Mice, Inbred BALB C; Ovalbumin; Receptors, Cytoplasmic and Nuclear; Rosiglitazone; T-Lymphocytes; Thiazolidinediones; Transcription Factors; Vasodilator Agents

Allergic asthma is associated with persistent functional and structural changes in the airways and involves many different cell types. Peroxisome proliferator-activated receptor gamma (PPAR-gamma), a member of the nuclear hormone receptor superfamily, is predominantly expressed in adipose tissue and plays a major role in regulating adipocyte differentiation and glucose metabolism. Recently, PPAR-gamma has been shown to play an important role in the control of inflammatory responses, including within the lung, acting on both immune and nonimmune cells.. Our aim was to assess the anti-inflammatory potential of a PPAR-gamma agonist locally delivered by means of nebulization.. We used a mouse model of asthma induced by sensitization and airway challenge with ovalbumin. Ciglitazone, a PPAR-gamma agonist, was administered by means of nebulization alone at the time of antigen challenge or by means of gavage and nebulization. Treatments with both ciglitazone and GW9662, a specific antagonist, were also performed to verify that ciglitazone's effects were mediated through PPAR-gamma activation.. Our results show that PPAR-gamma is mainly expressed in airway epithelium on antigen sensitization. Treatment with ciglitazone reduced PPAR-gamma levels in the lung, whereas combined treatment with GW9662 abrogated this inhibition. Importantly, nebulization with ciglitazone decreased airway hyperresponsiveness, basement membrane thickness, mucus production, collagen deposition, and TGF-beta synthesis. A significant correlation was also found between airway hyperresponsiveness, basement membrane thickness, and TGF-beta levels.. These results demonstrate that inhaled agonistic ligands of PPAR-gamma might have new therapeutic potential for airway asthmatic inflammation.

Topics: Animals; Anti-Asthmatic Agents; Asthma; Female; Immunohistochemistry; Lung; Mice; Mice, Inbred BALB C; Nebulizers and Vaporizers; Ovalbumin; Receptors, Cytoplasmic and Nuclear; Thiazolidinediones; Trachea; Transcription Factors; Transforming Growth Factor beta

In this study we analyzed the effect of peroxisome proliferator-activated receptor-alpha and -gamma ligands on immunoglobulin synthesis and cytokine production in non-allergic and atopic dermatitis donors in vitro, but also in vivo ovalbumin-sensitized mice. A significant inhibition in CD40+ interleukin-4-mediated, but also basal IgE synthesis from peripheral blood mononuclear cells of atopic dermatitis donors was observed in the presence of the peroxisome proliferator-activated receptor-alpha ligand (up to 47+/-12%) and peroxisome proliferator-activated receptor-gamma ligand (69+/-5%). By contrast, the production of other isotypes such as IgA, IgG, and IgM was only modest inhibited. Analysis of cytokine production from the peripheral blood mononuclear cells shows inhibition of several cytokines by both peroxisome proliferator-activated receptor ligands. The most inhibitory effect on cytokine production was observed by the peroxisome proliferator-activated receptor-gamma ligand in peripheral blood mononuclear cells from atopic dermatitis donors with high IgE baseline production. Coculture experiments show that the decrease of IgE production by ciglitazone was monocyte dependent (up to 63+/-7%). Finally, in vivo experiments from ovalbumin-sensitized mice confirmed the in vitro findings showing that the interleukin-4-mediated immune response was inhibited in ciglitazone-treated mice.

Topics: Animals; CD40 Antigens; Cells, Cultured; Dermatitis, Atopic; Female; Humans; Hypoglycemic Agents; Immunoglobulin E; Immunoglobulin G; Interleukin-4; Leukocytes, Mononuclear; Ligands; Mice; Mice, Inbred Strains; Monocytes; Ovalbumin; Receptors, Cytoplasmic and Nuclear; Thiazolidinediones; Transcription Factors