ovalbumin and Lung-Diseases--Obstructive

Haemophilus influenzae is a bacterium that often can be isolated from the deeper respiratory airways of patients with chronic asthmatic bronchitis. In the present study the effects of H. influenzae vaccination on guinea pig pulmonary beta-adrenoceptor number and function (in vitro and in vivo) have been evaluated. Functioning of beta-adrenoceptors is determined by measuring the beta-mimetic effect of isoprenaline on the inhibition of anaphylactic mediator release and isolated tracheal strip relaxation. The number of beta-adrenoceptor binding sites was measured by means of a 3H-dihydroalprenolol binding assay. Also the mechanism of action underlying the changes in beta-adrenoceptor functioning was evaluated. Furthermore, it was established that the effect on the beta-adrenoceptor system was not specific for H. influenzae and that other respiratory pathogens were also biologically active in this respect.

Topics: Animals; Antigens, Bacterial; Asthma; Carbachol; Guinea Pigs; Haemophilus influenzae; Histamine Release; Humans; Isoproterenol; Lung; Lung Diseases, Obstructive; Ovalbumin; Polysaccharides, Bacterial; Receptors, Adrenergic; Receptors, Adrenergic, beta; Trachea

Topics: Animals; Chemokine CCL2; Disease Models, Animal; Humans; Intercellular Adhesion Molecule-1; Kaempferols; Lung Diseases, Obstructive; Macrophages; Male; Mast Cells; Mice; Mice, Inbred BALB C; Ovalbumin

The first steps in the selection process of a new anti-inflammatory drug for the inhaled treatment of asthma and chronic obstructive pulmonary disease are herein described. A series of novel ester derivatives of 1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloropyridin-4-yl) ethanol have been synthesized and evaluated for inhibitory activity toward cAMP-specific phosphodiesterase-4 (PDE4). In particular, esters of variously substituted benzoic acids were extensively explored, and structural modification of the alcoholic and benzoic moieties were performed to maximize the inhibitory potency. Several compounds with high activity in cell-free and cell-based assays were obtained. Through the evaluation of opportune in vitro ADME properties, a potential candidate suitable for inhaled administration in respiratory diseases was identified and tested in an in vivo model of pulmonary inflammation, proving its efficacy.

Topics: Administration, Inhalation; Animals; Anti-Inflammatory Agents, Non-Steroidal; Asthma; Benzoates; Cell Line; Chronic Disease; Crystallography, X-Ray; Eosinophilia; Esters; Guinea Pigs; Humans; Leukocytes, Mononuclear; Lung; Lung Diseases, Obstructive; Molecular Docking Simulation; Ovalbumin; para-Aminobenzoates; Phosphodiesterase 4 Inhibitors; Protein Conformation; Rats; Stereoisomerism; Structure-Activity Relationship; Sulfonamides

The incretin hormone glucagon-like peptide-1 (GLP-1) is an important insulin secretagogue and GLP-1 analogs are used for the treatment of type 2 diabetes. GLP-1 displays antiinflammatory and surfactant-releasing effects. Thus, we hypothesize that treatment with GLP-1 analogs will improve pulmonary function in a mouse model of obstructive lung disease. Female mice were sensitized with injected ovalbumin and treated with GLP-1 receptor (GLP-1R) agonists. Exacerbation was induced with inhalations of ovalbumin and lipopolysaccharide. Lung function was evaluated with a measurement of enhanced pause in a whole-body plethysmograph. mRNA levels of GLP-1R, surfactants (SFTPs), and a number of inflammatory markers were measured. GLP-1R was highly expressed in lung tissue. Mice treated with GLP-1R agonists had a noticeably better clinical appearance than the control group. Enhanced pause increased dramatically at day 17 in all control mice, but the increase was significantly less in the groups of GLP-1R agonist-treated mice (P < .001). Survival proportions were significantly increased in GLP-1R agonist-treated mice (P < .01). SFTPB and SFTPA were down-regulated and the expression of inflammatory cytokines were increased in mice with obstructive lung disease, but levels were largely unaffected by GLP-1R agonist treatment. These results show that GLP-1R agonists have potential therapeutic potential in the treatment of obstructive pulmonary diseases, such as chronic obstructive pulmonary disease, by decreasing the severity of acute exacerbations. The mechanism of action does not seem to be the modulation of inflammation and SFTP expression.

Topics: Animals; Biomarkers; Exenatide; Female; Gene Expression Regulation; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Inflammation; Liraglutide; Lung Diseases, Obstructive; Mice; Mice, Inbred C57BL; Ovalbumin; Peptides; Receptors, Glucagon; RNA, Messenger; Venoms

The D6 chemokine receptor can bind and scavenge several chemokines, including the T-helper 2 (Th2)-associated chemokines CCL17 and CCL22. Although D6 is constitutively expressed in the lung, its pulmonary function is unknown.. This study tested whether D6 regulates pulmonary chemokine levels, inflammation, or airway responsiveness during allergen-induced airway disease.. D6-deficient and genetically matched C57BL/6 mice were sensitized and challenged with ovalbumin. ELISA and flow cytometry were used to measure levels of cytokines and leukocytes, respectively. Mechanical ventilation was used to measure airway reactivity.. The ability of D6 to diminish chemokine levels in the lung was chemokine concentration dependent. CCL17 and CCL22 were abundant in the airway, and their levels were attenuated by D6 when they were within a defined concentration range. By contrast, airway concentrations of CCL3, CCL5, and CCL11 were low and unaffected by D6. Allergen-challenged D6-deficient mice had more dendritic cells, T cells, and eosinophils in the lung parenchyma and more eosinophils in the airway than similarly challenged C57BL/6 mice. By contrast, D6-deficient mice had reduced airway responses to methacholine compared with C57BL/6 mice. Thus, D6 has opposing effects on inflammation and airway reactivity.. The ability of D6 to scavenge chemokines in the lung is dependent on chemokine concentration. The absence of D6 increases inflammation, but reduces airway reactivity. These findings suggest that inhibiting D6 function might be a novel means to attenuate airway responses in individuals with allergic asthma.

Topics: Allergens; Animals; Bronchial Hyperreactivity; Chemokine Receptor D6; Chemokines, CC; Eosinophils; Inflammation; Leukocytes; Lung; Lung Diseases, Obstructive; Lymph Nodes; Methacholine Chloride; Mice; Mice, Knockout; Ovalbumin; Receptors, CCR10; Receptors, Chemokine; Respiratory Hypersensitivity; Transforming Growth Factor beta1

We have investigated the bronchodilator and anti-inflammatory properties of roflumilast (3-cyclopropylmethoxy-4-difluoromethoxy-N-[3,5-dichloropyrid-4-yl]-benzamide), a novel, highly potent, and selective phosphodiesterase 4 (PDE4) inhibitor. Additionally, we compared the effects of roflumilast and its N-oxide, the primary metabolite in vivo, with those of the PDE4 inhibitors piclamilast, rolipram, and cilomilast. Roflumilast inhibited the ovalbumin-evoked contractions of tracheal chains prepared from sensitized guinea pigs (EC(50) = 2 x 10(-7) M) but showed no relaxant effect on tissues contracted spontaneously. In spasmogen-challenged rats and guinea pigs, intravenously administered roflumilast displayed bronchodilatory activity (ED(50) = 4.4 and 7.1 micromol/kg, respectively). Furthermore, roflumilast dose dependently attenuated allergen-induced bronchoconstriction in guinea pigs (ED(50) = 0.1 micromol/kg i.v.). Roflumilast given orally (ED(50) = 1.5 micromol/kg) showed equal potency to its N-oxide (ED(50) = 1.0 micromol/kg) but was superior to piclamilast (ED(50) = 8.3 micromol/kg), rolipram (ED(50) = 32.5 micromol/kg), and cilomilast (ED(50) = 52.2 micromol/kg) in suppressing allergen-induced early airway reactions. To assess the anti-inflammatory potential of orally administered roflumilast, antigen-induced cell infiltration, total protein, and TNFalpha concentration in bronchoalveolar lavage fluid of Brown Norway rats were determined. Roflumilast and its N-oxide equally inhibited eosinophilia (ED(50) = 2.7 and 2.5 micromol/kg, respectively), whereas the reference inhibitors displayed lower potency (ED(50) = 17-106 micromol/kg). Besides, orally administered roflumilast abrogated LPS-induced circulating TNFalpha in the rat (ED(50) = 0.3 micromol/kg), an effect shared by its N-oxide, with both molecules exhibiting 8-, 25-, and 310-fold superiority to piclamilast, rolipram, and cilomilast, respectively. These results, coupled with the in vitro effects of roflumilast on inflammatory cells, suggest that roflumilast represents a potential new drug for the treatment of asthma and chronic obstructive pulmonary disease.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Administration, Oral; Aminopyridines; Animals; Anti-Asthmatic Agents; Benzamides; Bronchoconstriction; Cyclic Nucleotide Phosphodiesterases, Type 4; Cyclopropanes; Dose-Response Relationship, Drug; Guinea Pigs; Lipopolysaccharides; Lung Diseases, Obstructive; Male; Ovalbumin; Phosphodiesterase Inhibitors; Rats; Rats, Inbred BN; Rats, Sprague-Dawley; Trachea; Tumor Necrosis Factor-alpha

The usefulness of tidal breathing flow-volume loops (TBFVL) to evaluate pulmonary function was investigated in 6 Standardbreds during treadmill exercise. Tidal breathing flow-volume loops are a graphic representation of airflow rate vs tidal volume for each individual breath. These TBFVL were obtained from horses exercising at speeds corresponding to 75 and 100% of maximum heart rate. Measurements were recorded in each horse before and after ovalbumin-induced allergic lung disease. Moderate obstructive lung disease, characterized by a significant increase in pulmonary resistance, was observed while the horses were at rest. We found that in horses with airway obstruction exercising at 75 or 100% of maximum heart rate, the quantitative indices describing TBFVL shape and size were not markedly different from those in clinically normal horses exercising at similar speeds.

Topics: Analysis of Variance; Animals; Heart Rate; Horses; Immunization; Lung Diseases, Obstructive; Ovalbumin; Physical Conditioning, Animal; Reference Values; Respiration; Respiratory Function Tests; Tidal Volume

Exposure of actively sensitized boosted guinea pigs to aerosolized antigen, 3 times on alternate days, produced pulmonary eosinophilia but not pulmonary hyperresponsiveness to methacholine Cl measured 3 days after the last antigen challenge. These data suggest that the presence of large numbers of eosinophils in the airways and tissues of the lungs is not sufficient to produce nonspecific pulmonary hyperresponsiveness. These data also suggest that actively sensitized and boosted guinea pigs respond differently to repeated antigen exposure than do asthmatics or wild caught allergic cynomolgus monkeys.

Topics: Aerosols; Animals; Antigens; Bronchoalveolar Lavage Fluid; Guinea Pigs; Immunoglobulin E; Immunoglobulin G; Lung Diseases, Obstructive; Lung Volume Measurements; Male; Methacholine Compounds; Ovalbumin; Pulmonary Eosinophilia; Respiratory Hypersensitivity