ovalbumin and Respiratory-Tract-Diseases

People are often concurrently exposed to more than one air pollutant whether they are in outdoor or indoor environments. Therefore, inhalation studies that are designed to examine the toxicity of coexposures to two or more airborne toxicants may be more relevant for assessing human health risks than those studies that investigate the toxic effects of only one airborne toxicant at a time. Furthermore, airborne biogenic substances such as pollens, bacteria, fungi, and microbial toxins often coexist with common air pollutants in the ambient air, and when inhaled may also cause specific adverse effects on the respiratory tract. One such biogenic substance, bacterial endotoxin, is a potent stimulus of airway inflammation and is commonly found in domestic, agricultural, and industrial settings. Little is known about the interaction of exposures to biogenic substances and common air pollutants, such as ozone or airborne particulate matter. In the last few years, we have performed a series of in vivo studies using laboratory rodents that examined how airway surface epithelial cells are altered by coexposure to ozone and a biogenic substance, either bacterial endotoxin or a commonly used experimental aeroallergen (ovalbumin). Results from these studies indicate that the ozone-induced epithelial and inflammatory responses in laboratory rodents may be markedly enhanced by coexposure to an inhaled biogenic substance. Conversely, the adverse airway alterations caused by exposure to biogenic substances may be enhanced by coexposure to ozone. The results from these initial studies have also suggested some of the cellular and molecular mechanisms underlying the phenotypic epithelial alterations induced by these coexposures. Many more studies are needed to fully elucidate the potential risk to human health from coexposure to air pollutants and airborne biogenic substances.

Topics: Air Pollutants; Animals; Biological Factors; Disease Models, Animal; Drug Synergism; Endotoxins; Inflammation; Inhalation Exposure; Metaplasia; Neutrophils; Ovalbumin; Ozone; Rats; Rats, Inbred F344; Respiratory Mucosa; Respiratory Tract Diseases

elbion (formerly ASTA Medica) and GlaxoSmithKline are developing an inhaled formulation of AWD-12-281 for the potential treatment of chronic obstructive pulmonary disease (COPD). By May 2005, phase II trials of this 5-hydroxyindole PDE4 inhibitor for COPD were ongoing.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Administration, Inhalation; Administration, Topical; Amides; Aminopyridines; Animals; Benzamides; Clinical Trials as Topic; Cyclic Nucleotide Phosphodiesterases, Type 4; Cyclopropanes; Dermatitis, Atopic; Disease Models, Animal; Drug Evaluation, Preclinical; Humans; Indoles; Inflammation; Lipopolysaccharides; Ovalbumin; Phosphodiesterase Inhibitors; Psoriasis; Pulmonary Disease, Chronic Obstructive; Respiratory Tract Diseases; Structure-Activity Relationship

A large body of research supports a pathogenic role of Th2 cells in allergic diseases such as asthma. These disorders are characterized by recruitment to selected peripheral tissues of a mixed leukocyte inflammatory infiltrate including a predominant eosinophil component. The development of this inflammatory response is dependenton accumulation of Th2 cells in the affected tissues. Our studies aim to define the mechanisms that control the development of this tissue inflammatory response, focusing particularly on the mechanisms that recruit Th2 cells to the lung and airway. We have found that Th2 cells are on their own poorly competent for antigen-induced recruitment to the lung. By contrast, Th1 cells are avidly recruited to the lungs in response to airway antigen challenge. More important, recruitment of Th1 cells to the lung resulted in enhanced recruitment of Th2 cells to this tissue. The increased Th1 cell-induced recruitment of Th2 cells was associated with upregulation of endothelial vascular cell adhesion molecule-1 (VCAM-1) expression in airway-associated endothelial cells and could be largely blocked by systemic treatment with a monoclonal anti-VCAM-1 antibody. Systemic blocking of tumor necrosis factor (TNF) also blunted the airway inflammatory response. The prominent roles of TNF and VCAM-1 in recruitment of Th2 cells suggested that an inflammatory microenvironment was essential for the recruitment of Th2 cells. In fact, recruitment of Th2 cells to the airway could be induced in an antigen-independent fashion by proinflammatory stimuli such as intranasal instillation of endotoxin. This antigen nonspecificity of the Th2 cell recruitment suggested a model in which Th2 cell recruitment is in response to general inflammatory signals rather than to antigen itself. This model provides an explanation for the clinical observation that bacterial or viral respiratory tract infections are associated with disease exacerbations in allergic asthmatics. More generally, these data imply that Th2 cells, like other leukocytes, are recruited efficiently to sites of tissue inflammation, and that these nonspecifically recruited Th2 cells have substantial potential to modulate local inflammatory processes.

Topics: Animals; Antigens; Eosinophils; Humans; Inflammation; Lymphocyte Cooperation; Mice; Ovalbumin; Respiratory Tract Diseases; Th1 Cells; Th2 Cells; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

Asthma is an inflammatory airway disease affecting most of the population in the world. The current medication for asthma relieves airway inflammation but it has serious adverse effects. Biochanin A (BCA), a phytoestrogen, is an active component present in red clover, alfalfa, soy having anti-oxidant and anti-inflammatory properties. BCA was identified as a natural activator of peroxisome proliferator-activated receptor-gamma (PPARγ).. The study aims to evaluate the effects of BCA in ovalbumin (OVA)-induced murine model of asthma and to study the role of PPARγ.. We found that BCA administration reduced the severity of murine allergic asthma as evidenced histologically, and measurement of allergen-specific IgE levels in serum as well as in BAL fluid. BCA also reversed the elevated levels of inflammatory cytokines, cell infiltration, protein leakage into the airways and expression of hemoxygenase-1 in OVA-induced lungs. Further, we confirmed that BCA mediated inhibitory effects are mediated through PPARγ as assessed by treatment with PPARγ antagonist GW9662.. Our results suggest that BCA is efficacious in a preclinical model of asthma and may have the potential for the treatment of asthma in humans.

Topics: Animals; Anti-Inflammatory Agents; Asthma; Disease Models, Animal; Female; Genistein; Inflammation; Mice; Ovalbumin; PPAR gamma; Respiratory Tract Diseases; Signal Transduction; Treatment Outcome

T cell immunoglobulin and mucin domain-containing molecule-3 (Tim-3) has been described as a transmembrane protein, expressed on the surface of various T cells as well as different cells of innate immunity. It has since been associated with Th1 mediated autoimmune diseases and transplantation tolerance studies, thereby indicating a possible role of this receptor in counter-regulation of Th2 immune responses. In the present study we therefore directly examined the role of Tim-3 in allergic inflammation and respiratory tolerance. First, Tim-3-/- mice and wild type controls were immunized and challenged with the model allergen ovalbumin (OVA) to induce an asthma-like phenotype. Analysis of cell numbers and distribution in the bronchoalveolar lavage (BAL) fluid as well as lung histology in H&E stained lung sections demonstrated a comparable degree of eosinophilic inflammation in both mouse strains. Th2 cytokine production in restimulated cell culture supernatants and serum IgE and IgG levels were equally increased in both genotypes. In addition, cell proliferation and the distribution of different T cell subsets were comparable. Moreover, analysis of both mouse strains in our respiratory tolerance model, where mucosal application of the model allergen before immunization, prevents the development of an asthma-like phenotype, revealed no differences in any of the parameters mentioned above. The current study demonstrates that Tim-3 is dispensable not only for the development of allergic inflammation but also for induction of respiratory tolerance in mice in an OVA-based model.

Topics: Allergens; Animals; Asthma; Cytokines; Female; Hepatitis A Virus Cellular Receptor 2; Immune Tolerance; Immunization; Immunoglobulin E; Inflammation; Mice; Mice, Inbred BALB C; Mice, Knockout; Ovalbumin; Respiratory Tract Diseases; Th2 Cells

Increased IL-8 levels and neutrophil accumulation in the airways are common features found in patients affected by pulmonary diseases such as Asthma, Idiopathic Pulmonary Fibrosis, Influenza-A infection and COPD. Chronic neutrophilic inflammation is usually corticosteroid insensitive and may be relevant in the progression of those diseases.. To explore the role of Ladarixin, a dual CXCR1/2 antagonist, in several mouse models of airway inflammation with a significant neutrophilic component.. Ladarixin was able to reduce the acute and chronic neutrophilic influx, also attenuating the Th2 eosinophil-dominated airway inflammation, tissue remodeling and airway hyperresponsiveness. Correspondingly, Ladarixin decreased bleomycin-induced neutrophilic inflammation and collagen deposition, as well as attenuated the corticosteroid resistant Th17 neutrophil-dominated airway inflammation and hyperresponsiveness, restoring corticosteroid sensitivity. Finally, Ladarixin reduced neutrophilic airway inflammation during cigarette smoke-induced corticosteroid resistant exacerbation of Influenza-A infection, improving lung function and mice survival.. CXCR1/2 antagonist Ladarixin offers a new strategy for therapeutic treatment of acute and chronic neutrophilic airway inflammation, even in the context of corticosteroid-insensitivity.

Topics: Animals; Anti-Inflammatory Agents; Asthma; Biomarkers; Biopsy; Bleomycin; Cytokines; Disease Models, Animal; Disease Progression; Disease Susceptibility; Eosinophils; Female; Fibrosis; Immunohistochemistry; Leukocytes; Male; Mice; Mice, Knockout; Neutrophils; Ovalbumin; Oxidation-Reduction; Receptors, Interleukin-8A; Receptors, Interleukin-8B; Respiratory Hypersensitivity; Respiratory Tract Diseases; Sulfonamides; T-Lymphocyte Subsets

We established a selection strategy to identify new models for an altered airway inflammatory response from a large compendium of mutant mouse lines that were systemically phenotyped in the German Mouse Clinic (GMC). As selection criteria we included published gene functional data, as well as immunological and transcriptome data from GMC phenotyping screens under standard conditions. Applying these criteria we identified a few from several hundred mutant mouse lines and further characterized the Cox4i2tm1Hutt, Ifit2tm1.1Ebsb, and Prdm11tm1.1ahl lines following ovalbumin (OVA) sensitization and repeated OVA airway challenge. Challenged Prdm11tm1.1ahl mice exhibited changes in B cell counts, CD4+ T cell counts, and in the number of neutrophils in bronchoalveolar lavages, whereas challenged Ifit2tm1.1Ebsb mice displayed alterations in plasma IgE, IgG1, IgG3, and IgM levels compared to the challenged wild type littermates. In contrast, challenged Cox4i2tm1Hutt mutant mice did not show alterations in the humoral or cellular immune response compared to challenged wild type mice. Transcriptome analyses from lungs of the challenged mutant mouse lines showed extensive changes in gene expression in Prdm11tm1.1ahl mice. Functional annotations of regulated genes of all three mutant mouse lines were primarily related to inflammation and airway smooth muscle (ASM) remodeling. We were thus able to define an effective selection strategy to identify new candidate genes for the predisposition to an altered airway inflammatory response under OVA challenge conditions. Similar selection strategies may be used for the analysis of additional genotype-envirotype interactions for other diseases.

Topics: Animals; Apoptosis Regulatory Proteins; Bronchoalveolar Lavage Fluid; Carrier Proteins; Cytokines; Disease Models, Animal; Female; Gene Expression Profiling; Genetic Predisposition to Disease; Immunoglobulin E; Immunoglobulins; Inflammation; Lymphocyte Activation; Mice; Molecular Sequence Annotation; Mutation; Ovalbumin; Proteins; Respiratory Tract Diseases; RNA-Binding Proteins; Selection, Genetic; Transcription Factors; Transcriptome

Optimization of lead compound 1, through extensive use of structure-based design and a focus on PI3Kδ potency, isoform selectivity, and inhaled PK properties, led to the discovery of clinical candidates 2 (GSK2269557) and 3 (GSK2292767) for the treatment of respiratory indications via inhalation. Compounds 2 and 3 are both highly selective for PI3Kδ over the closely related isoforms and are active in a disease relevant brown Norway rat acute OVA model of Th2-driven lung inflammation.

Topics: Administration, Inhalation; Animals; Asthma; Female; Humans; Indazoles; Indoles; Isoenzymes; Male; Microsomes; Molecular Docking Simulation; Ovalbumin; Oxazoles; Phosphoinositide-3 Kinase Inhibitors; Piperazines; Pneumonia; Pulmonary Disease, Chronic Obstructive; Rabbits; Rats; Rats, Sprague-Dawley; Respiratory Tract Diseases; Stereoisomerism; Structure-Activity Relationship; Sulfonamides; Th2 Cells

In this study the role of sitagliptin, dipeptidyl peptidase inhibitor, DPP-4, and dexamethasone in ameliorating inflammation and remodeling of chronic asthma in a mouse model were investigated. Mice sensitized to ovalbumin were chronically challenged with aerosolized antigen for 3days a week continued for 8weeks. During this period animals were treated with sitagliptin or dexamethasone daily. Assessment of inflammatory cell, oxidative markers, total nitrate/nitrite (NOx), interleukin (IL)-13, transforming growth factor-beta1 (TGF-β1) in bronchoalveolar lavage (BAL) and/or lung tissue were done. Also histopathological and immuno-histochemical analysis for lung was carried out. Compared with vehicle alone, treatment with sitagliptin or dexamethasone significantly reduced accumulation of eosinophils and chronic inflammatory cells, subepithelial collagenization, and thickening of the airway epithelium. Also both drug reduced goblet cell hyperplasia, oxidative stress, TGF-β1, IL-13 and epithelial cytoplasmic immunoreactivity for nuclear factor κ-B (NFκ-B). These data indicate that sitagliptin like dexamethasone may play a beneficial role reducing airway inflammation and remodeling in chronic murine model of asthma.

Topics: Airway Remodeling; Animals; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Bronchoalveolar Lavage Fluid; Chronic Disease; Cytokines; Dexamethasone; Female; Goblet Cells; Inflammation; Mice; Mice, Inbred BALB C; Ovalbumin; Oxidative Stress; Respiratory Tract Diseases; Sitagliptin Phosphate

The anti-malaria drug artesunate has been shown to attenuate experimental allergic asthma via inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. This study was to further determine the effects of artesunate on cigarette smoke and ovalbumin (OVA) concurrent exposure-induced airway inflammation, the related mechanism, and glucocorticoid insensitivity.. In vivo: Female BALB/c mice concurrently exposed to cigarette smoke and OVA developed mixed eosinophilic and neutrophilic airway inflammation. Airway hyper-responsiveness, total and differential cell counts, and pro-inflammatory cytokine levels (interleukin (IL)-4, IL-8, IL-13 and tumor necrosis factor (TNF)-α) in bronchoalveolar lavage fluid (BALF) were measured. Lung tissue sections were stained for histological analysis, and proteins were extracted for Western blotting. Artesunate reduced methacholine-induced airway hyper-responsiveness, suppressed pulmonary inflammation cell recruitment and IL-4, IL-8, IL-13 and TNF-α levels, selectively inhibited PI3Kδ/Akt pathway, and restored HDAC2 activity. In vitro: BEAS-2B cells were exposed to cigarette smoke extract (CSE) for 6h and then stimulated with TNF-α overnight. Glucocorticoid sensitivity was evaluated by the inhibition of TNF-α-induced IL-8 production by dexamethasone. CSE reduced the effects of dexamethasone on TNF-α-induced IL-8 production in BEAS-2B cells, while artesunate reversed CSE-induced glucocorticoid insensitivity and restored HDAC2 deactivation induced by CSE.. Artesunate ameliorated cigarette smoke and OVA concurrent exposure-induced airway inflammation, inhibited the PI3Kδ/Akt pathway, restored HDAC2 activity, and reversed CSE-induced glucocorticoid insensitivity in BEAS-2B cells. These findings indicate that artesunate might play a protective role in asthma induced by cigarette smoke and glucocorticoid insensitivity.

Topics: Animals; Antimalarials; Artemisinins; Artesunate; Asthma; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Cell Line; Cytokines; Dexamethasone; Drug Resistance; Eosinophils; Female; Glucocorticoids; Inflammation; Lung; Mice; Mice, Inbred BALB C; Nicotiana; Ovalbumin; Respiratory Tract Diseases; Smoke

γδT cells play a crucial immunoregulatory role in the lung, maintaining normal airway tone and preventing hyperresponsiveness to innocuous allergen. During acute inflammatory episodes, γδT cells promote resolution of acute inflammation. However, their contribution to inflammation-associated airway remodelling remains unexplored. Here we investigate the effects of γδT cell blockade on established allergic airway inflammation and development of remodelling.. Sensitised mice were exposed to prolonged ovalbumin challenge or continuous house-dust mite exposure to induce chronic inflammation and remodelling. Functional blocking anti-TCRδ antibody was administered therapeutically, and parameters of airway inflammation and remodelling were examined.. Therapeutic blockade of γδT cells prevented the typical resolution of acute airway inflammation characterised by elevated eosinophil and Th2 cell numbers. Moreover, the lung displayed exacerbated airway remodelling, typified by excess peribronchiolar collagen deposition.. These results demonstrate a unique role for γδT cells in constraining allergen-induced airway remodelling. Manipulating the γδT cell compartment may therefore contribute to strategies to prevent and treat remodelling.

Topics: Airway Remodeling; Animals; Chronic Disease; Disease Models, Animal; Eosinophils; Female; Inflammation; Mice; Ovalbumin; Proliferating Cell Nuclear Antigen; Receptors, Antigen, T-Cell, gamma-delta; Respiratory Tract Diseases; T-Lymphocyte Subsets; Th2 Cells

Among the 22 members of the nucleotide binding-domain, leucine rich repeat-containing (NLR) family, less than half have been functionally characterized. Of those that have been well studied, most form caspase-1 activating inflammasomes. NLRP12 is a unique NLR that has been shown to attenuate inflammatory pathways in biochemical assays and mediate the lymph node homing of activated skin dendritic cells in contact hypersensitivity responses. Since the mechanism between these two important observations remains elusive, we further evaluated the contribution of NLRP12 to organ specific adaptive immune responses by focusing on the lung, which, like skin, is exposed to both exogenous and endogenous inflammatory agents. In models of allergic airway inflammation induced by either acute ovalbumin (OVA) exposure or chronic house dust mite (HDM) antigen exposure, Nlrp12(-/-) mice displayed subtle differences in eosinophil and monocyte infiltration into the airways. However, the overall development of allergic airway disease and airway function was not significantly altered by NLRP12 deficiency. Together, the combined data suggest that NLRP12 does not play a vital role in regulating Th2 driven airway inflammation using common model systems that are physiologically relevant to human disease. Thus, the allergic airway inflammation models described here should be appropriate for subsequent studies that seek to decipher the contribution of NLRP12 in mediating the host response to agents associated with asthma exacerbation.

Topics: Animals; Antigens, Dermatophagoides; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Female; Inflammation; Intracellular Signaling Peptides and Proteins; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Ovalbumin; Respiratory Hypersensitivity; Respiratory Tract Diseases

Intravenous immunoglobulin (IVIG) displays anti-inflammatory activities in many diseases. Subcutaneous administration of anti-IgE in humans provides benefit in severe persistent allergic asthma. Given the well established efficacy of sublingual allergen immunotherapy in respiratory type I allergies, we investigated the therapeutic potential of sublingual immunoglobulin (SLIG), most particularly anti-IgE SLIG, in a murine model of allergen-driven airway inflammation.. BALB/c mice sensitized with ovalbumin (OVA) were treated sublingually with rat monoclonal IgG1 or IgG2a, either directed to mouse IgE or with no reported specificity. Airway hyperresponsiveness (AHR) was assessed by whole body plethysmography, and eosinophil infiltrates were characterized in bronchial alveolar lavages (BAL). OVA-specific antibody and T cell responses were analyzed in sera and saliva or lung and draining lymph nodes, by ELISA or CBA measurement of cytokine production, respectively.. AHR and BAL eosinophil infiltrates were substantially decreased in mice treated sublingually with particulate OVA (positive control), as well as in animals receiving various rat IgG1, irrespective of their specificity for murine IgE. In contrast, no improvement was observed in mice treated with PBS (negative control) or various rat IgG2a. SLIG anti-inflammatory activity is not related to a downregulation of Th2, Th17 or an induction of Foxp3(+) CD4(+) regulatory T cell responses. Mass spectrometry analysis of glycan moieties, such as sialic acid, suggests that the differential efficacy of rat IgG1 and IgG2a is not related to their capacity to interact with lectins borne by oral immune cells.. In a murine model of allergen-driven airway inflammation, SLIG exhibits an anti-inflammatory activity irrespective of the immunoglobulin specificity, and in the absence of allergen. As a noninvasive approach, SLIG deserves to be further studied as a treatment for other inflammatory diseases beyond allergic asthma.

Topics: Administration, Sublingual; Animals; Anti-Inflammatory Agents; Antibodies, Anti-Idiotypic; Antibodies, Monoclonal; Bronchoalveolar Lavage Fluid; Eosinophils; Female; Humans; Hypersensitivity; Immunoglobulin G; Immunotherapy; Lung; Mice; Mice, Inbred BALB C; Ovalbumin; Plethysmography, Whole Body; Respiratory Tract Diseases; Treatment Outcome

The ligand-activated transcription factor, peroxisome proliferator-activated receptor (PPAR)gamma, and its ligands inhibit pro-inflammatory cytokine production by immune cells, thus exerting anti-inflammatory activity. As a non-thiazolidinedione PPARgamma ligand, KR62980 has anti-diabetic and anti-adipogenic activities, but its anti-inflammatory function has yet to be characterized. In this study, we investigated the functions and mechanisms of KR62980 in the activation and differentiation of CD4+ T helper (Th) cells by comparing its effects with those of a thiazolidinedione PPARgamma ligand, rosiglitazone. KR62980 dose-dependently and significantly suppressed TCR-triggered Th cell proliferation by suppressing IL-2/IL-2Ralpha-mediated signaling. Both KR62980 and rosiglitazone suppressed IFNgamma production in a dose-dependent manner, whereas IL-4 gene expression was specifically suppressed by only KR62980. In addition, sustained KR62980 treatment diminished Th2 cytokine production by inhibiting c-Maf expression. In vivo administration of KR62980 in a model of allergic asthma significantly attenuated eotaxin-induced eosinophil infiltration, allergic cytokine production and collagen deposition in the lung. KR62980 also decreased goblet cell hyperplasia in the airway and mucous cell metaplasia in nasal epithelium, concurrent with decreases of allergic Th2 cytokines and IL-17 in the draining lymph node. In conclusion, a novel PPARgamma ligand, KR62980, suppresses in vitro Th2 cell differentiation and attenuates in vivo OVA-induced airway inflammation, suggesting a beneficial role for KR62980 in the treatment of allergic asthma and allergic rhinitis.

Topics: Allergens; Animals; Anti-Allergic Agents; Apoptosis; CD4-Positive T-Lymphocytes; Cells, Cultured; Gene Expression Regulation; Indenes; Inflammation; Interleukin-2 Receptor alpha Subunit; Interleukin-4; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Molecular Structure; Morpholines; Ovalbumin; Respiratory Tract Diseases; Rosiglitazone; Th2 Cells; Thiazolidinediones

Interleukin-5 (IL-5) is a cytokine which is essential for the maturation of eosinophils in bone marrow and for their release into the blood. Eotaxin is a CC type chemokine implicated in the recruitment of eosinophils in a variety of inflammatory disorders. Since eosinophil-activity is governed by these two pathways, we targeted both IL-5 and eotaxin by active vaccination to block eosinophilia. We produced two vaccines by chemically cross-linking IL-5 or eotaxin to a virus-like particle (VLP) derived from the bacteriophage Qbeta, yielding highly repetitive arrays of these cytokines on the VLP surface. Both vaccines overcame self-tolerance and induced high antibody titers against the corresponding self-molecules in mice. Immunization with either of the two vaccines reduced eosinophilic inflammation of the lung in an ovalbumin (OVA) based mouse model of allergic airway inflammation. Animals immunized with the two vaccines at the same time developed high antibody titers against both cytokines and also reduced eosinophil-infiltration of the lung. These data demonstrate that targeting either IL-5 or eotaxin may lower eosinophilia. Simultaneous immunization against IL-5 and eotaxin demonstrates that such a therapeutic approach may be used to treat complex disorders in which multiple mediators are involved.

Topics: Allergens; Allolevivirus; Animals; Autoantibodies; Chemokine CCL11; Eosinophilia; Female; Hypersensitivity; Interleukin-5; Mice; Mice, Inbred BALB C; Ovalbumin; Respiratory Tract Diseases; Vaccination; Vaccines, Virosome; Viral Proteins

We have previously demonstrated that intranasal administration of ambient ultrafine particles (UFP) acts as an adjuvant for primary allergic sensitization to ovalbumin (OVA) in Balb/c mice. It is important to find out whether inhaled UFP exert the same effect on the secondary immune response as a way of explaining asthma flares in already-sensitized individuals due to traffic exposure near a freeway. The objective of this study is to determine whether inhalation exposure to ambient UFP near an urban freeway could enhance the secondary immune response to OVA in already-sensitized mice. Prior OVA-sensitized animals were exposed to concentrated ambient UFP at the time of secondary OVA challenge in our mobile animal laboratory in Los Angeles. OVA-specific antibody production, airway morphometry, allergic airway inflammation, cytokine gene expression, and oxidative stress marker were assessed. As few as five ambient UFP exposures were sufficient to promote the OVA recall immune response, including generating allergic airway inflammation in smaller and more distal airways compared with the adjuvant effect of intranasally instilled UFP on the primary immune response. The secondary immune response was characterized by the T helper 2 and IL-17 cytokine gene expression in the lung. In summary, our results demonstrated that inhalation of prooxidative ambient UFP could effectively boost the secondary immune response to an experimental allergen, indicating that vehicular traffic exposure could exacerbate allergic inflammation in already-sensitized subjects.

Topics: Adjuvants, Immunologic; Administration, Inhalation; Animals; Antibody Formation; Asthma; Cytokines; Female; Gene Expression; Hypersensitivity; Inflammation; Lung; Mice; Mice, Inbred BALB C; Ovalbumin; Particulate Matter; Respiratory System; Respiratory Tract Diseases; Severity of Illness Index; Vehicle Emissions

Archaeal lipid mucosal vaccine adjuvant and delivery (AMVAD) is a safe mucosal adjuvant that elicits long lasting and memory boostable mucosal and systemic immune responses to model antigens such as ovalbumin. In this study, we evaluated the potential of the AMVAD system for eliciting protective immunity against mucosal bacterial infections, using a mouse model of intranasal Francisella tularensis LVS (LVS) challenge. Intranasal immunization of mice with cell free extract of LVS (LVSCE) adjuvanted with the AMVAD system (LVSCE/AMVAD) induced F. tularensis-specific antibody responses in sera and bronchoalveolar lavage fluids, as well as antigen-specific splenocyte proliferation and IL-17 production. More importantly, the AMVAD vaccine partially protected the mice against a lethal intranasal challenge with LVS. Compared to LVSCE immunized and naïve mice, the LVSCE/AMVAD immunized mice showed substantial to significant reduction in pathogen burdens in the lungs and spleens, reduced serum and pulmonary levels of proinflammatory cytokines/chemokines, and longer mean time to death as well as significantly higher survival rates (p<0.05). These results suggest that the AMVAD system is a promising mucosal adjuvant and vaccine delivery technology, and should be explored further for its applications in combating mucosal infectious diseases.

Topics: Administration, Intranasal; Animals; Antigens, Bacterial; Cell-Free System; Chemokines; Cytokines; Francisella tularensis; Humans; Immunization; Inflammation; Interleukin-17; Mice; Mucous Membrane; Ovalbumin; Respiratory Tract Diseases; Tissue Distribution

Although chronic intestinal helminth infections may suppress allergen-induced airway pathology by inducing a combination of modified T-helper (Th) 2 and immunosuppressive cytokines, a similar capacity of natural acute intestinal infections has remained untested, despite their global prevalence. Here, we show that allergic airway phenotypes including eosinophilia, eotaxin mRNA, and Th2 cytokines are significantly suppressed in animals that were infected by and that have cleared the intestinal parasite Eimeria vermiformis. Unlike in helminth-infected animals, regulation requires temporal coincidence of infection with sensitization; depends on interferon-gamma; and is not associated with an enhanced antigen-specific immunoglobulin G1 response. Moreover, regulation was effective following allergen sensitization in different anatomical sites, and in young and adult mice. These data highlight a transient anatomical dissemination of "functional immunologic dominance" following infection of the gut mucosa. They strongly support the hypothesis that airway allergies are naturally suppressed by both acute and chronic mucosal pathogens, but by different mechanisms.

Topics: Aging; Animals; Chemokine CCL11; Chronic Disease; Coccidiosis; Cytokines; Eimeria; Eosinophilia; Hypersensitivity; Immunization; Immunoglobulin G; Interferon-gamma; Intestinal Mucosa; Mice; Mice, Inbred C57BL; Oocysts; Ovalbumin; Respiratory System; Respiratory Tract Diseases; Th2 Cells

Asthma is a chronic inflammatory disease of the airways characterized by an associated increase in airway responsiveness. In this study, we investigated the inhibitory effect of an aqueous extract from the root of Platycodi Radix (Changkil: CK) on airway inflammation in a murine model of asthma. Mice were sensitized and challenged by ovalbumin (OVA) inhalation to induce chronic airway inflammation and airway remodeling. CK markedly decreased the number of infiltrated inflammatory cells and the levels of Th1 and Th2 cytokines and chemokines compared with those in the OVA-induced group. In addition, CK reduced OVA-specific IgE levels in bronchoalveolar lavage (BAL) fluid. Based on lung histopathological studies, inflammatory cell infiltration and mucus hypersecretion were inhibited by CK administration compared to that in the OVA-induced group. Lung weight was reduced after CK administration. Also, increased generation of ROS in BAL fluid, as well as NF-kappaB nuclear translocation, by inhalation of OVA was diminished by CK. Moreover, CK reduced the OVA-induced upregulation of matrix metalloproteases activity. These findings indicate that oxidative stress may play a crucial role in the pathogenesis of bronchial asthma induced by OVA and that CK may be useful as an adjuvant therapy for the treatment of bronchial asthma.

Topics: Animals; Anti-Asthmatic Agents; Asthma; Bronchoalveolar Lavage Fluid; Chemokine CCL2; Cytokines; Female; Immunoglobulin E; Inflammation; Leukocyte Count; Matrix Metalloproteinases; Mice; Mice, Inbred ICR; NF-kappa B; Ovalbumin; Phytotherapy; Plant Extracts; Platycodon; Reactive Oxygen Species; Respiratory Tract Diseases; Th1 Cells; Th2 Cells

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

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

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

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

Both mast cells and IL-17 can contribute to host defense and pathology in part by orchestrating neutrophil recruitment, but the possible role of mast cells in IL-17-induced inflammation remains to be defined. We found that mast cells and IL-17, but neither IFN-gamma nor FcRgamma signaling, contributed significantly to the antigen (Ag)-dependent airway neutrophilia elicited in ovalbumin-specific T-cell receptor (TCR)-expressing C57BL/6-OTII mice, and that IFN-gamma significantly suppressed IL-17-dependent airway neutrophilia in this setting. IL-18, IL-1beta, and TNF each contributed significantly to the development of Ag- and T helper 17 (Th17 cell)-mediated airway neutrophilia. Moreover, IL-17 enhanced mast cell TNF production in vitro, and mast cell-associated TNF contributed significantly to Ag- and Th17 cell-mediated airway neutrophilia in vivo. By contrast, we detected no significant role for the candidate mediators histamine, PGD(2), LTB(4), CXCL10, or IL-16, each of which can be produced by mast cells and other cell types, in the neutrophil infiltration elicited in this model. These findings establish that mast cells and mast cell-derived TNF can significantly enhance, by FcRgamma-independent mechanisms, the Ag- and Th17 cell-dependent development of a neutrophil-rich inflammatory response at a site of Ag challenge.

Topics: Animals; Antigens; Disease Models, Animal; Inflammation; Inflammation Mediators; Interleukin-17; Lipopolysaccharides; Mast Cells; Mice; Mice, Knockout; Neutrophil Infiltration; Ovalbumin; Respiratory Tract Diseases; T-Lymphocytes, Helper-Inducer; Tumor Necrosis Factor-alpha

Two experiments were conducted to evaluate receiving-period performance, morbidity, and humoral immune response, as well as finishing performance and carcass characteristics of heifers fed different sources of supplemental Zn. In Exp. 1, 97 crossbred beef heifers (initial BW = 223.4 kg) were fed a 65% concentrate diet with no supplemental Zn (control) or 75 mg of supplemental Zn/kg of DM from Zn sulfate, Zn methionine, or Zn propionate. During a 35-d receiving period, heifers were monitored daily for signs of bovine respiratory disease. Serum samples were collected for Zn analysis on d 0, 14, and 28. After the receiving period, heifers were adapted to and fed a high-concentrate diet with no supplemental Zn for 42 d. Heifers were then assigned to finishing diet treatments, with the same concentrations and sources of supplemental Zn as during the receiving period and fed for an average of 168 d. Serum samples also were obtained on d 0 and 56 of the finishing period and at the end of the study. During the receiving period, control heifers had a greater (P < or = 0.05) BW and G:F on d 35 than heifers in the other treatments, but no differences were observed among treatments for morbidity or serum Zn concentrations (P > or = 0.50). For the finishing period, DMI and ADG did not differ among treatments; however, overall G:F tended (P = 0.06) to be less for control heifers than for heifers in the 3 supplemental Zn treatments. On d 56 of the finishing period, control heifers tended (P = 0.06) to have a lower serum Zn concentration than heifers in the 3 supplemental Zn treatments. In Exp. 2, 24 crossbred beef heifers (initial BW = 291.1 kg) were fed the same 4 treatments as in Exp. 1 for a 21-d period. The humoral immune response to treatments was determined by measuring specific antibody titers after s.c. injection of ovalbumin on d 0 and 14. Body weights and blood samples for serum Zn concentration and ovalbumin IgG titers were collected on d 0, 7, 14, and 21. Serum Zn concentration and specific ovalbumin IgG titers did not differ (P > 0.10) among the 4 treatments on any sampling day. Results from these 2 studies showed no major differences among the sources of supplemental Zn for receiving period morbidity, ADG, DMI, and humoral immune response of beef heifers; however, a lack of supplemental Zn during an extended finishing period tended to negatively affect G:F.

Topics: Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Antibody Formation; Cattle; Cattle Diseases; Dietary Supplements; Energy Intake; Female; Ovalbumin; Random Allocation; Respiratory Tract Diseases; Trace Elements; Weight Gain; Zinc

Inflammatory effects in the rat lung have been investigated, non-invasively by MRI, at early time points (3 and 6 h) after ovalbumin (OA) or endotoxin (LPS) challenges. Six hours after challenge with OA, a strong, even inflammatory signal was present around the periphery of the lung in a region corresponding to the pleura. Histological analysis confirmed the presence of marked edema associated with the pleural cavity of OA-treated animals. Lower levels of pleural edema were observed in MRI and histological evaluation of LPS-treated animals and no abnormality was observed in actively sensitized and naïve, saline-treated groups. Diffuse edematous signals were detected in the lung 3 and 6 h after challenge with OA or LPS; the signal volumes were larger at both time points following OA instillation. Bronchoalveolar lavage (BAL) fluid analysis performed 6 h after challenge revealed increased levels of protein and greater cellular activation in OA- than in LPS-treated animals. Furthermore, increased levels of peribronchial edema were found by histology 6 h after OA. BAL fluid and histological assessments demonstrated that the inflammatory signals were due to edema and not mucus as no significant changes in BAL mucin concentrations or differences in goblet cells were identified between OA or LPS challenge and their respective vehicle groups. Our data show that MRI is able to detect, non-invasively, inflammatory signals in both the lung and the pleura in spontaneously breathing animals, highlighting its potential to study the consequences of pulmonary insults on both sites.

Topics: Acute Disease; Animals; Bronchoalveolar Lavage Fluid; Edema; Inflammation; Lipopolysaccharides; Magnetic Resonance Imaging; Male; Ovalbumin; Pleura; Pleural Diseases; Rats; Rats, Inbred BN; Respiratory Tract Diseases

To gain more insight into the mechanisms of particulate matter (PM)-induced adjuvant activity, we studied the kinetics of airway toxicity/inflammation and allergic sensitization to ovalbumin (OVA) in response to ultrafine carbon black particles (CBP). Mice were exposed intranasally to OVA alone or in combination with different concentrations of CBP. Airway toxicity and inflammation were assessed at days 4 and 8. Immune adjuvant effects were studied in the lung draining peribronchial lymph nodes (PBLN) at day 8. Antigen-specific IgE was measured at days 21 and 28, whereas allergic airway inflammation was studied after OVA challenges (day 28). Results show that a total dose of 200 microg CBP per mouse, but not 20 microg or 2 microg, induced immediate airway inflammation. This 200 microg CBP was the only dose that had immune adjuvant activity, by inducing enlargement of the PBLN and increasing OVA-specific production of Th2 cytokines (IL-4, IL-5, and IL-10). The immune adjuvant activity of 200 microg CBP dosing was further examined. Whereas increased OVA-specific IgE levels in serum on day 21 confirms systemic sensitization, this was further supported by allergic airway inflammation after challenges with OVA. Our data show a link between early airway toxicity and adjuvant effects of CBP. In addition, results indicate that local cytokine production early after exposure to CBP is predictive of allergic airway inflammation. In addition this model appears suitable for studying the role of airway toxicity, inflammation and other mechanisms of particle adjuvant activity, and predicting the adjuvant potential of different particles.

Topics: Administration, Intranasal; Animals; Asthma; Bronchoalveolar Lavage Fluid; Carbon; Dose-Response Relationship, Drug; Female; Flow Cytometry; Immunoglobulin E; Inflammation; Lung; Lymph Nodes; Lymphocyte Count; Mice; Mice, Inbred BALB C; Ovalbumin; Respiratory Hypersensitivity; Respiratory Tract Diseases; Th2 Cells

A murine model of allergen-induced airway inflammation was used to examine the effects of exposure to ozone on airway inflammation and remodeling. Sensitized BALB/c mice were exposed to ovalbumin aerosol for 4 wk before and after 2 wk of exposure to either 0.2 ppm or 0.5 ppm ozone. Other groups of mice were exposed to ovalbumin aerosol for 6 wk with continuous concurrent exposure to ozone during wk 1-6, or during intermittent concurrent exposure to ozone. Lung inflammation was measured by quantitative differential evaluation of lung lavage cells and by histological evaluation of stained lung sections. Alterations in lung structure (airway fibrosis) were evaluated by quantitative biochemical analysis of microdissected airways. The same total number of cells was observed in lavage fluid from animals exposed for 4 wk to ovalbumin alone or to ovalbumin for 4 wk immediately before or after exposure to 2 wk of 0.2 or 0.5 ppm ozone. Mice exposed to ovalbumin for 6 wk with concurrent exposure to either 0.2 ppm or 0.5 ppm ozone during wk 3-6 had a significant decrease in the total number of cells recovered by lavage. Values as low as 7% of the cell number found in mice exposed to ovalbumin aerosol alone were observed in the mice exposed to ovalbumin plus 0.2 ppm ozone during wk 3-6. There were significant differences in the cell differential counts in the lavage fluid from mice exposed to ovalbumin alone as compared with values from mice exposed to ovalbumin and ozone under all of the protocols studied. When ozone was given for 2 wk prior to ovalbumin exposure (Experiment 1), there were a high percentage of macrophages and low percentages of lymphocytes and eosinophils in the lung lavage. When ozone was given for 2 wk after ovalbumin exposure (Experiment 2), there were a moderate percentage of macrophages, a low percentage of eosinophils, and a high percentage of lymphocytes in the lung lavage. When ozone and ovalbumin were given simultaneously (Experiments 3 and 4), there were a high percentage of macrophages in the lavage with 0.2 ppm ozone and a high percentage of eosinophils. Ozone appears to antagonize the specific inflammatory effects of ovalbumin exposure, especially when given before or during exposure to ovalbumin. Airway remodeling was examined by two different quantitative methods. None of the groups exposed concurrently to ovalbumin and ozone had a significant increase in airway collagen content as compared to the matched groups of mice exposed to oval

Topics: Aerosols; Animals; Bronchoalveolar Lavage Fluid; Cell Count; Coloring Agents; Fibrosis; Hydroxyproline; Inflammation; Lung; Mice; Mice, Inbred BALB C; Ovalbumin; Ozone; Proteins; Respiratory Tract Diseases; Reverse Transcriptase Polymerase Chain Reaction; Tissue Fixation

The immediate responses of the upper respiratory tract (URT) to the irritants acrolein and acetic acid were examined in healthy and allergic airway-diseased C57Bl/6J mice. Acrolein (1.1 ppm) and acetic acid (330 ppm) vapors induced an immediate increase in flow resistance, as measured in the surgically isolated URT of urethane-anesthetized healthy animals. Acrolein, but not acetic acid, induced a small URT vasodilatory response. In awake spontaneously breathing mice, both vapors induced a prolonged pause at the start of expiration (a response mediated via stimulation of nasal trigeminal nerves) and an increase in total respiratory specific airway flow resistance, the magnitude of which was similar to that observed in the isolated URT. Both responses were significantly reduced in animals pretreated with large doses of capsaicin to defunctionalize sensory nerves, strongly suggesting a role for sensory nerves in development of these responses. The breathing pattern and/or obstructive responses were enhanced in mice with ovalbumin-induced allergic airway disease. These results suggest that the primary responses to acrolein and acetic acid vapors are altered breathing patterns and airway obstruction, that sensory nerves play an important role in these responses, and that these responses are enhanced in animals with allergic airway disease.

Topics: Acetic Acid; Acrolein; Administration, Inhalation; Airway Obstruction; Airway Resistance; Animals; Female; Hypersensitivity; Irritants; Male; Mice; Mice, Inbred C57BL; Neurons, Afferent; Ovalbumin; Pulmonary Ventilation; Respiration; Respiratory Mechanics; Respiratory Physiological Phenomena; Respiratory System; Respiratory Tract Diseases; Vasodilation

There is evidence that the cytokine IL-5 is a prominent feature of airway inflammation in asthma.. The aim of this study was to determine whether exogenous IL-5 could cause changes in lung physiology, the early and late airway response after antigen challenge, and airway inflammation in rats that do not have a propensity to develop these changes after sensitization and challenge.. Intratracheal administration of IL-5 to ovalbumin sensitized Brown Norway SSN rats increased the airway responsiveness to methacholine (AHR) 20 hours after administration of IL-5 at the same time as an increase in neutrophils occurred in the lung lavage. This effect was dose dependent and was not caused by endotoxin. Concurrent intratracheal administration of 50 ng of anti-IL-5 monoclonal antibody with 10 microg of recombinant human IL-5 decreased the AHR and neutrophil influx. Pretreatment with 3 microg of IL-5 had no effect on the early and late airway response or on AHR after ovalbumin challenge. However, IL-5 increased lung re-sistance 20 hours after antigen challenge. Although total lung cells and differential counts did not differ significantly 8 hours after antigen challenge, the blood lymphocyte CD4/CD8 ratio decreased in IL-5 pretreated rats (P <.05). In addition, in situ hybridization showed a significant increase in cells within the airway wall expressing IL-4 and IL-5 mRNA in IL-5 treated/challenged rats compared to controls (P <.05).. The intratracheal administration of IL-5 causes only part of the physiologic changes that are associated with asthma. Other factors are necessary to obtain the complete asthma phenotype.

Topics: Animals; Blood Cells; Bronchoalveolar Lavage Fluid; Cell Differentiation; Cytokines; Dose-Response Relationship, Drug; Eosinophils; Humans; Immunization; Immunoglobulin E; Inflammation; Interleukin-5; Intubation, Intratracheal; Lung; Lymphocyte Subsets; Male; Methacholine Chloride; Ovalbumin; Rats; Rats, Inbred BN; Recombinant Proteins; Respiratory System; Respiratory Tract Diseases; RNA, Messenger; Stem Cells

Three experiments were conducted to examine the effect of dietary vitamin E on receiving performance and health and on finishing performance of beef cattle. One hundred twenty beef steers (Exp. 1; initial BW = 173 kg) and 200 beef heifers (Exp. 2; initial BW = 204 kg) were assigned randomly to one of three treatment diets formulated to supply 285, 570, or 1,140 IU/animal daily of supplemental vitamin E during the receiving period. Average daily gain, gain:feed, and DMI were calculated every 14 d, with pen as the experimental unit. Morbidity and retreatment data were analyzed using a nonparametric procedure. After the receiving period, cattle were assigned to a grazing period followed by a finishing program and fed until slaughter. In Exp. 3, 17 beef steers were used to evaluate effects of the same three vitamin E levels on humoral immune response to an ovalbumin vaccine given on d 0 and 14. Jugular blood samples were collected on d 0, 7, 14, and 21. In Exp. 1, vitamin E did not affect (P > 0.10) ADG, DMI, or gain:feed for d 0 to 14, 14 to 28, or 0 to 28. No effects were noted for percentage of morbidity; however, cattle receiving 1,140 IU/d had a numerically (P = 0.15) lower incidence of retreatment. During the 91-d finishing phase, a quadratic effect (P < 0.08) was noted for DMI, ADG, backfat thickness, longissimus muscle area, and yield grade. In Exp. 2, a tendency for a linear (P = 0.10) increase in ADG was observed for the first 14 d of receiving; however, ADG decreased linearly (P = 0.06) with vitamin E concentration thereafter. For the 28-d period, ADG and DMI did not differ among treatments, but gain:feed decreased linearly (P < 0.05) for d 14 to 28 and for d 0 to 28. No effects on percentage morbidity were noted in Exp. 2, and no differences were detected for ADG, gain:feed, or DMI for the 98-d finishing period. There was a linear increase in yield grade (P < 0.05) and a linear (P < 0.08) decrease in longissimus muscle area with increasing vitamin E. Heifers receiving 570 IU of vitamin E during the receiving period tended to have a higher (P < 0.09) dressing percentage at slaughter. In Exp. 3, no significant differences were detected in serum IgG titers to ovalbumin on d 0, 7 or 14; however, on d 21, a linear increase (P = 0.07) in serum IgG titers was noted with supplemental vitamin E. Supplemental vitamin E had limited effects on performance; however, effects on humoral immune response and recovery from respiratory disease warrant further resear

Topics: Age Factors; Animals; Antibody Formation; Antioxidants; Body Composition; Cattle; Cattle Diseases; Dietary Supplements; Dose-Response Relationship, Drug; Energy Intake; Female; Health Status; Male; Ovalbumin; Random Allocation; Respiratory Tract Diseases; Vaccination; Vitamin E; Weight Gain

The increased prevalence of asthma has become a major public health issue worldwide. It has been proposed that this increase is due to the steady decline of infectious diseases such as tuberculosis.. Supporting this view was, the suppressive effect of live Bacillus Calmette-Guerin (BCG) infection on allergen (ovalbumin) induced airway eosinophilia was published previously.. Next the authors compared the effects of live, heat killed BCG and purified protein derivative of Mycobacterium tuberculosis (PPD) on a murine model of ovalbumin induced airway eosinophilia.. The results showed that both live and heat killed BCG, but not PPD strongly suppressed airway eosinophilia. This inhibition was correlated with the reduced number of Th2 cells in the lung.. Their data support the hypothesis that the application of bacterial antigens may be a safe vaccination method against asthma in the future.

Topics: Animals; Disease Models, Animal; Eosinophilia; Hot Temperature; Mice; Mice, Inbred C57BL; Mycobacterium bovis; Ovalbumin; Respiratory Tract Diseases; Tuberculin

We have recently demonstrated that airway eosinophilic inflammation can be transferred to unprimed mice by infusion of IL-5-producing T cell clones. In this study, we investigated the effects of dexamethasone and cyclosporin A on the airway eosinophilic inflammation in mice transferred with T cell clones. An ovalbumin-reactive T cell clone, KW29, produced IL-5 as well as IL-2 and IL-4 upon stimulation with relevant antigen. Dexamethasone and cyclosporin A dose-dependently suppressed the production of these cytokines in vitro. The number of eosinophils recovered in the bronchoalveolar lavage fluid and the airway responsiveness to acetylcholine were increased in KW29-transferred mice after antigen provocation. Both responses were dose-dependently suppressed by the administration of dexamethasone or cyclosporin A in vivo. We concluded that airway eosinophilic inflammation can be controlled by agents capable of downregulating IL-5 production in T cells.

Topics: Adoptive Transfer; Animals; Bronchial Hyperreactivity; CD4-Positive T-Lymphocytes; Clone Cells; Cyclosporine; Dexamethasone; Eosinophilia; Immunosuppressive Agents; Interleukin-5; Mice; Mice, Inbred BALB C; Ovalbumin; Respiratory Tract Diseases

In the cystic fibrosis (CF) patient, lung function decreases throughout life as a result of continuous cycles of infection, particularly with Pseudomonas aeruginosa and Staphylococcus aureus. The mechanism underlying the pathophysiology of the disease in humans has not been established. However, it has been suggested that abnormal, tenacious mucus, resulting perhaps from improper hydration from loss of Cl- secretion via the cystic fibrosis transmembrane conductance regulator (CFTR) protein, impairs clearance of bacteria from the CF airway and provides an environment favorable to bacterial growth. If this hypothesis is correct, it could explain the absence of respiratory disease in CFTR-deficient mice, since mice have only a single submucosal gland and display few goblet cells in their lower airways, even when exposed to bacteria. To test this hypothesis further, we induced allergic airway disease in CFTR-deficient mice. We found that induction of allergic airway disease in mice, unlike bacterial infection, results in an inflammatory response characterized by goblet cell hyperplasia, increased mucin gene expression, and increased production of mucus. However, we also found that disease progression and resolution is identical in Cftr-/- mice and control animals. Furthermore, we show that the presence of mucus in the Cftr-/- airway does not lead to chronic airway disease, even upon direct inoculation with S. aureus and P. aeruginosa. Therefore, factors in addition to the absence of high levels of mucus secretion protect the mouse from the airway disease seen in human CF patients.

Topics: Animals; Cystic Fibrosis Transmembrane Conductance Regulator; Gene Expression; Goblet Cells; Hyperplasia; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred DBA; Mucins; Ovalbumin; Pseudomonas Infections; Respiratory Hypersensitivity; Respiratory Tract Diseases; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Staphylococcal Infections

The effect of a thromboxane A2 (TXA2) receptor antagonist, ON-579, on experimental allergic skin and airway reactions was studied in vivo. ON-579 at doses of 1 and 20 mg/kg clearly inhibited U-46619-induced increases in respiratory resistance (Rrs) in guinea pigs. ON-579 at doses of 1, 20 and 50 mg/kg inhibited the aerosolized antigen-induced biphasic increase in Rrs in guinea pigs. Moreover, ON-579 clearly inhibited repeated aeroantigen-induced airway hyperreactivity in guinea pigs. ON-579, however, did not have any significant effects on allergic cutaneous reactions in rats. These results suggest that ON-579 is a relatively selective TXA2 antagonist, especially in the airways, and indicate the efficacy of ON-579 on antigen-induced increase in airway resistance and antigen-induced airway hyperreactivity in guinea pigs.

Topics: Aerosols; Airway Resistance; Animals; Antigens; Arthus Reaction; Bronchoalveolar Lavage Fluid; Concanavalin A; Dinitrophenols; Guinea Pigs; Histamine; Hypersensitivity; Ketotifen; Leukocyte Count; Male; Mice; Ovalbumin; Passive Cutaneous Anaphylaxis; Phenoxyacetates; Rats; Receptors, Thromboxane; Respiratory Tract Diseases; Serum Albumin, Bovine; Skin Diseases; Sulfonamides

Topics: Adolescent; Adult; Albumins; Animals; Antibodies; Antigen-Antibody Reactions; Cardiovascular Diseases; Cattle; Child; Collagen Diseases; Communicable Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Female; gamma-Globulins; Gastrointestinal Diseases; Hematologic Diseases; Humans; Hypersensitivity; Infant; Infant, Newborn; Insulin; Iodine Isotopes; Lactalbumin; Maternal-Fetal Exchange; Milk; Nervous System Diseases; Ovalbumin; Pregnancy; Respiratory Tract Diseases; Serum Albumin; Serum Albumin, Bovine; Skin Tests; Viral Vaccines