tiotropium-bromide and Inflammation

The journey of using anticholinergics in the treatment of asthma started with anticholinergic-containing plants such as Datura stramonium and Atropa belladonna, followed by ipratropium bromide and continued with tiotropium, glycopyrronium, and umeclidinium. Although antimuscarinics were used in the maintenance treatment of asthma over a century ago, after a long time (since 2014), it has been recommended to be used as an add-on long-acting antimuscarinic agent (LAMA) therapy in the maintenance treatment of asthma. The airway tone controlled by the vagus nerve is increased in asthma. Allergens, toxins, or viruses cause airway inflammation and inflammation-related epithelial damage, increased sensory nerve stimulation, ganglionic and postganglionic acetylcholine (ACh) release by inflammatory mediators, intensification of ACh signaling at M1 and M3 muscarinic ACh receptors (mAChRs), and dysfunction of M2 mAChR. Optimal anticholinergic drug for asthma should effectively block M3 and M1 receptors, but have minimal effect on M2 receptors. Tiotropium, umeclidinium, and glycopyrronium are anticholinergic agents with this feature. Tiotropium has been used in a separate inhaler as an add-on treatment to inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA), and glycopyrronium and umeclidinium have been used in a single inhaler as a combination of ICS/LABA/LAMA in asthma in recent years. Guidelines recommend this regimen as an optimization step for patients with severe asthma before initiating any biologic or systemic corticosteroid therapy. In this review, the history of antimuscarinic agents, their effectiveness and safety in line with randomized controlled trials, and real-life studies in asthma treatment will be discussed according to the current data.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Asthma; Bronchodilator Agents; Cholinergic Antagonists; Glycopyrrolate; Humans; Inflammation; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide

In chronic obstructive pulmonary disease (COPD) airways inflammation is associated in more advanced stages with systemic inflammation. COPD-associated systemic inflammation syndrome is defined currently with rather non-specific biomarkers such as C-reactive protein (CRP) but there are also other 'organ-specific' biomarkers such as surfactant protein-D which are still not well characterized but might represent more appropriate and reliable alternatives to the non-specific biomarkers. Inhaled therapies are the mainstay in stable COPD and they were demonstrated to reduce airway inflammation and more recently in the case of inhaled corticosteroids alone or combined with long-acting beta-2 agonists to reduce systemic inflammation as well. This paper focuses on current and potential biomarkers of systemic inflammation in COPD and on the systemic anti-inflammatory effects of inhaled therapies in stable COPD.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-Agonists; Biomarkers; C-Reactive Protein; Cholinergic Antagonists; Drug Therapy, Combination; Fibrinogen; Humans; Inflammation; Interleukin-6; Pulmonary Disease, Chronic Obstructive; Pulmonary Surfactant-Associated Protein D; Receptors, Adrenergic, beta-2; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome; Tumor Necrosis Factor-alpha; Uteroglobin

The long acting inhaled muscarinic antagonist tiotropium (Spiriva) improves lung function in patients with COPD. In addition, tiotropium reduces exacerbation frequency, dyspnoea and improves exercise capacity. As the latter has been associated with airway inflammation then this suggests that, in addition to the well-known anti-bronchoconstrictor effect, tiotropium might also display anti-inflammatory properties. With our current state of knowledge, however, it is not necessary to postulate an anti-inflammatory effect for tiotropium (Spiriva), rather inhibition of smooth muscle constriction with subsequent effects on lung hyperinflation (and possibly pulmonary circulation) can explain the effects on exacerbation frequency, dyspnoea and exercise capacity. Recent reports suggest that tiotropium can inhibit viral activation of inflammation and vagal nerve stimulation, suggesting a mechanism by which tiotropium can inhibit viral induction of exacerbations in COPD.

Topics: Administration, Inhalation; Animals; Anti-Inflammatory Agents; Bronchodilator Agents; Humans; Inflammation; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Virus Diseases

Tiotropium is commonly used in the treatment of chronic obstructive pulmonary disease. Although largely considered to be a long-acting bronchodilator, its demonstrated efficacy in reducing the frequency of exacerbations and preliminary evidence from early studies indicating that it might slow the rate of decline in lung function suggested mechanisms of action in addition to simple bronchodilation. This hypothesis was examined in the recently published UPLIFT study and, although spirometric and other clinical benefits of tiotropium treatment extended to four years, the rate of decline in lung function did not appear to be reduced by the addition of tiotropium in this study. This article summarizes data from a variety of investigations that provide insights into possible mechanisms to account for the effects of tiotropium. The report summarizes the discussion on basic and clinical research in this field.

Topics: Acetylcholine; Animals; Bronchodilator Agents; Cholinergic Antagonists; Cough; Humans; Inflammation; Lung; Mucus; Parasympathetic Nervous System; Respiratory System; Scopolamine Derivatives; Tiotropium Bromide

Topics: Adrenergic beta-Agonists; Airway Resistance; Albuterol; Anti-Inflammatory Agents; Beclomethasone; Bronchodilator Agents; Drug Monitoring; Ethanolamines; Exercise Tolerance; Forced Expiratory Volume; Formoterol Fumarate; Humans; Inflammation; Plethysmography, Whole Body; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Smoking Cessation; Tiotropium Bromide; Treatment Outcome

BACKGROUND The aim of this study was to evaluate the therapeutic effects of tiotropium bromide on asthma. MATERIAL AND METHODS A total of 160 patients with moderate persistent asthma were randomly divided into 4 groups (n=40): the 3 control groups were given fluticasone propionate aerosol (group A), salmeterol-fluticasone propionate inhalant (group B), and tiotropium bromide inhalation powder combined with salmeterol-fluticasone propionate inhalant (group C), respectively, and the experimental group received tiotropium bromide inhalation powder combined with fluticasone propionate aerosol (group D) and salbutamol was used to relieve symptoms when necessary. RESULTS After 8 weeks of treatment, the pulmonary function of group D, which was significantly better than those of group A (P<0.05), was similar to those of groups B and C (P>0.05). Group D had significantly better asthma control test scores and nighttime symptom scores than in group A (P<0.05), without significant differences from those of group B or group C (P>0.05). The number of times salbutamol was used to alleviate symptoms was significantly different (P<0.05) between group D and group A (P<0.05), as well as between group C and group D (P<0.05). Groups D and B had similar results (P>0.05). IL-13 levels in induced sputum had significant differences (P<0.05). The levels in group D, which were higher than those of groups A and B (P<0.05), were similar to those of group C (P>0.05). CONCLUSIONS Tiotropium bromide combined with fluticasone propionate improved the respiratory function and quality of life, and is a new therapy for moderate, persistent asthma.

Topics: Adult; Albuterol; Asthma; Cholinergic Antagonists; Female; Humans; Inflammation; Interleukin-13; Male; Respiratory Function Tests; Sputum; Tiotropium Bromide; Treatment Outcome

The anti-inflammatory effects of salmeterol/fluticasone (SFP), tiotropium/fluticasone (Tio+FP) and tiotropium (Tio) alone were investigated on the inflammatory cells and mediators in sputum induced from chronic obstructive pulmonary disease patients. Subjects were either newly diagnosed or had not taken any medication for 3 months prior to the study. Subjects (n = 99) were randomised (not double blinded) and received either SFP (100/1,000 microg daily), Tio+FP (18/1,000 microg daily) or Tio (18 microg daily) for 12 weeks. Induced sputum and serum C-reactive protein (CRP) were analysed prior to and at the end of treatment. The results showed that treatment with SFP caused a significant reduction in interleukin (IL)-8 and matrix metalloprotease (MMP)-9 in induced sputum, compared with treatment with Tio alone. There were no treatment differences between the SFP and Tio+FP groups in decreasing IL-8 and MMP-9 levels. The reduction in IL-8 showed significant association with the reduction in MMP-9. All treatment groups failed to significantly reduce the numbers of total cells, neutrophils, macrophages and eosinophils in induced sputum; in addition, there were no treatment differences in terms of improvement of forced expiratory volume in one second, forced vital capacity, CRP or quality of life between the three groups. The anti-inflammatory effects of salmeterol/fluticasone probably contribute to the clinical benefits seen in chronic obstructive pulmonary disease patients.

Topics: Administration, Inhalation; Adult; Aged; Aged, 80 and over; Albuterol; Androstadienes; Biomarkers; C-Reactive Protein; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Female; Fluticasone; Humans; Inflammation; Interleukin-8; Male; Matrix Metalloproteinase 9; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Salmeterol Xinafoate; Scopolamine Derivatives; Sputum; Tiotropium Bromide

Type 2 immune cells play a pivotal role in allergic rhinitis (AR). Increasing evidence shows that inhibition of cholinergic nerve activity decreases the severity of airway diseases including asthma and AR. However, the role of the cholinergic receptor muscarinic 3 (m3) in type 2 inflammation in AR is unknown.. We aimed to investigate the effect of m3 on the type 2 immune response, including both T helper 2 (Th2)-mediated and type 2 innate lymphocyte (ILC2)-mediated inflammation, in AR.. Peripheral blood mononuclear cells (PBMCs) from human were cultured in vitro. Treatment with the m3 antagonist 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide (4-DAMP) was used. The percentages of Th2 and ILC2 cells in PBMCs were evaluated by flow cytometry. AR mouse models were established by house dust mite (HDM) sensitization, and treated with tiotropium intranasally. The expression of Th2 cytokines, ILC2 cytokines and related factors in the nasal mucosa was assessed by immunohistochemistry and quantitative real-time polymerase chain reaction. Serum HDM-specific immunoglobulin E (sIgE) level was detected by enzyme-linked immunosorbent assay.. Both Th2 and ILC2 percentages in PBMCs were decreased after 4-DAMP treatment. Similarly, the levels of Th2 cytokines (interleukin 4 [IL-4] and IL-13) and ILC2 cytokines and related factors (IL-25, IL-33, GATA3 and RORα) were significantly decreased in the nasal mucosa of AR mice after tiotropium treatment. Furthermore, tiotropium treatment decreased the nasal symptom score, the serum sIgE level and eosinophil infiltration in AR mice. In addition, tiotropium decreased phospholipase Cγ1 (PLCγ1), PLCγ2, nuclear factor of activated T cell 1 (NFATc1), and NFATc2 mRNA levels in AR mice.. Antagonism of m3 alleviated type 2 inflammation in the nasal mucosa of AR mice.

Topics: Animals; Cytokines; Disease Models, Animal; Humans; Immunity, Innate; Immunoglobulin E; Inflammation; Leukocytes, Mononuclear; Lymphocytes; Mice; Mice, Inbred BALB C; Nasal Mucosa; Rhinitis, Allergic; Th2 Cells; Tiotropium Bromide

The value of tiotropium bromide (TIO) in neutrophilic asthma was meaningful in previous study. We hypothesized that TIO's mechanism of action is associated with histone deacetylase 2 (HDAC2) activity, which is key for controlling the transcription of inflammatory cytokines and usually downregulated in neutrophilic asthma.. The effects of TIO and dexamethasone (DEX) on HDAC2 activity, nuclear factor kappa B (NF-κB), and C-X-C motif chemokine ligand 1 (CXCL1) were evaluated in neutrophilic asthma mouse model (C57BL, 6-week-old). An in-vitro study was conducted using primary human bronchial/tracheal epithelial (HBE) cells from asthma patients. Western blot analyses were performed for phospho-phospholipase Cγ-1 (PLCγ-1) and inositol trisphosphate (IP. Ovalbumin was used to induce eosinophilic inflammation in this study. After neutrophilic asthma was induced by LPS (O+L group), HDAC2 activity was diminished with increased NF-κB activity and CXCL1 compared to the control group. TIO significantly improved NF-κB activity, CXCL1, and HDAC2 activity compared with the O+L group in in-vivo study (. These results support the hypothesis that TIO modulates inflammation by recovering HDAC2 activity from the acetylcholine-stimulated inflammation cascade in neutrophilic asthma. The detailed inflammation cascade of recovering HDAC2 activity by TIO might be associated with PLCγ-1-IP

Topics: Animals; Asthma; Histone Deacetylase 2; Humans; Inflammation; Lipopolysaccharides; Mice; Mice, Inbred C57BL; NF-kappa B; Tiotropium Bromide

Topics: Administration, Inhalation; Allergens; Asthma; Bronchial Provocation Tests; Double-Blind Method; Humans; Inflammation; Tiotropium Bromide

One of the major goals of asthma therapy is to maintain asthma control and prevent acute exacerbations. Long-acting bronchodilators are regularly used for the treatment of asthma patients and in clinical studies the anti-cholinergic tiotropium has recently been shown to reduce exacerbations in patients with asthma. So far it is unclear how tiotropium exerts this effect. For this purpose, we designed an allergen-driven rechallenge model of allergic airway inflammation in mice, to assess the effectiveness of tiotropium and the long-acting β-2 adrenoceptor agonist olodaterol on allergen-induced exacerbations of airway disease. Female C57BL/6J mice were sensitized intranasally (i.n.) with 1 μg of house dust mite (HDM) extract followed by a challenge regime (5 consecutive days 10 μg HDM extract i.n.) after one week. Mice were exposed to a secondary challenge five weeks after sensitization and were treated i.n. with different concentrations of tiotropium or olodaterol (1, 10 and 100 μg/kg) or a combination thereof (10 μg/kg each) prior to and during the secondary challenge period. Three days after the last challenge, bronchoalveolar lavage (BAL) fluid and lung tissue were collected for flow cytometry and histologic analysis, respectively. Secondary challenge with HDM extract strongly induced allergic airway disease reflected by inflammatory cell infiltration and goblet cell metaplasia. Treatment with tiotropium, but not with olodaterol reduced tissue inflammation and goblet cell metaplasia in a dose-dependent manner. The combination of tiotropium and olodaterol was more effective in significantly reducing tissue inflammation compared to tiotropium treatment alone, and also led to a decrease in BAL cell counts. These data suggest that in a model of relapsing allergic airway disease tiotropium directly prevents exacerbations by reducing inflammation and mucus production in the airways. In addition, the combination of tiotropium and olodaterol exerts synergistic effects.

Topics: Allergens; Animals; Asthma; Benzoxazines; Bronchoalveolar Lavage Fluid; Bronchodilator Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Female; Flow Cytometry; Goblet Cells; Inflammation; Mice; Mice, Inbred C57BL; Pyroglyphidae; Tiotropium Bromide

Chronic obstructive pulmonary disease (COPD) is related to infiltration and activation of inflammatory cells in airways and pulmonary tissue. In COPD, neutrophils are prominent, while eosinophilic influx is typical to asthma. Inflammatory cells express sialic acid-binding immunoglobulin like lectins called Siglecs, a family of innate immune receptors that are transmembrane I-type lectins binding sialic acid. One member of the Siglec family, Siglec-8, is expressed mostly in eosinophils and may be an important therapeutic target in asthma or COPD. The aim of our project was to quantify Siglec-8 expression in induced sputum cells of COPD patients treated with long-acting beta2-agonists (LABA) or combined with long-acting antimuscarinic agents (LAMA) - tiotropium bromide. Thirty stable COPD patients (21 males and 9 females, mean age 67 years) receiving 12 μg BID formoterol therapy were assessed before and after 3 months' add-on therapy consisting of 18 μg QID tiotropium. In all patients, spirometry, lung volumes, and DLCO were performed before and after therapy. The patients were subjected to sputum induction before and after therapy. Sputum cells were isolated and processed to obtain cell membranes. Siglec-8 protein expression was assessed using Western blot. In patients receiving tiotropium and formoterol, improved FEV1 and lung volumes were observed compared with formoterol-only treated patients. The mean Siglec-8 level was significantly higher in eosinophilic subgroup of COPD patients compared with non-eosinophilic patients before therapy 40,000 vs. 15,000 Adj. Vol. INT/mm(2). Our data show that Siglec-8 may be involved in COPD pathogenesis and may influence COPD phenotyping.

Topics: Adrenergic beta-2 Receptor Agonists; Aged; Antigens, CD; Antigens, Differentiation, B-Lymphocyte; Drug Combinations; Eosinophils; Ethanolamines; Female; Formoterol Fumarate; Gene Expression Regulation; Humans; Inflammation; Lectins; Male; Phenotype; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Sputum; Tiotropium Bromide

The study included 38 men with moderately severe chronic obstructive pulmonary disease (COPD) (mean age 60.6 ± 10.2 yr) and 42 ones with severe COPD (mean age 61.2 ± 7.2 yr). They were treated with tiotropium bromide, formoterol and beclomethasone dipropionate for 24 weeks (stage 1), TB alone for 12 weeks (stage 2) and TB+formoterol (long-acting bronchodilators, LABD) for another 12 weeks. Each stage was followed by evaluation of COPD symptoms using the St-George's Hospital questionnaire, daily requirements for short-acting beta-2 agonists (SABA), heart rate (HR), forced expiratory volume in the 1st second (FEV-1) before and after SABA test, hemoglobin saturation with oxygen in arterial blood during pulse oxymetry before and after 6 min walking test, blood surfactant protein D level (SP-D). The control group was comprised of 34 healthy men (mean age 62.3 ± 5.8 yr). Patients with moderately severe COPD experienced worsening of clinical symptoms (p < 0.001), required more SABA (p < 0.001), had increased HR (p = 0.01) and SP-D levels (p = 0.01) whereas FEV-1 (p = 0.05) decreased during stage 2 as compared with stage 1. Positive dynamics of all these variables except COPD symptoms and HR was observed at stage 3. Alteration in the extent of basal therapy in patients with stage III COPD did not result in dynamics of clinical and laboratory characteristics. The data obtained suggest the necessity of combined therapy with LABD or triple basal therapy of moderately severe COPD and the possibility of therapy with one or two LABD having different sites of action in the patients with clinically stable stage II COPD.

Topics: Aged; Anti-Asthmatic Agents; Beclomethasone; Bronchodilator Agents; Drug Therapy, Combination; Ethanolamines; Formoterol Fumarate; Humans; Inflammation; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Asthma is characterized by reversible bronchoconstriction and airway hyperreactivity. Although M(3) muscarinic receptors mediate bronchoconstriction, non-selective muscarinic receptor antagonists are not currently recommended for chronic control of asthma. We tested whether selective blockade of M(3) receptors, at the time of antigen challenge, blocks subsequent development of airway hyperreactivity in antigen-challenged guinea-pigs.. Ovalbumin-sensitized guinea-pigs were pretreated with 1 µg·kg(-1) of a kinetically selective M(3) receptor antagonist, tiotropium, or 1 mg·kg(-1) of a non-selective muscarinic receptor antagonist, atropine, and challenged with inhaled ovalbumin. Animals were anaesthetized, paralyzed, ventilated and vagotomized 24 h later. We measured vagally mediated bronchoconstriction and i.v. ACh-induced bronchoconstriction.. Electrical stimulation of both vagus nerves induced frequency-dependent bronchoconstriction in sensitized animals that was significantly increased after antigen challenge. Antigen-induced hyperreactivity was completely blocked by tiotropium pretreatment but only partially blocked by atropine pretreatment. Surprisingly, although tiotropium blocked bronchoconstriction induced by i.v. ACh, it did not inhibit vagally-induced bronchoconstriction in sensitized controls, suggesting that tiotropium does not block hyperreactivity by blocking receptors for vagally released ACh. Rather, tiotropium may have worked through an anti-inflammatory mechanism, since it inhibited eosinophil accumulation in the lungs and around nerves.. These data confirm that testing M(3) receptor blockade with exogenous ACh does not predict vagal blockade. Our data also suggest that selective blockade of M(3) receptors may be effective in asthma via mechanisms that are separate from inhibition of bronchoconstriction.

Topics: Acetylcholine; Animals; Asthma; Atropine; Bronchial Hyperreactivity; Bronchoconstriction; Disease Models, Animal; Eosinophils; Female; Guinea Pigs; Inflammation; Ovalbumin; Receptor, Muscarinic M3; Scopolamine Derivatives; Tiotropium Bromide; Vagus Nerve

Tiotropium bromide is a long acting muscarinic antagonist (LAMA), marketed under the brand name Spiriva, for the treatment of chronic obstructive pulmonary disease (COPD). Besides its proven direct bronchodilatory activity, recent clinical studies demonstrated that tiotropium is able to reduce the exacerbation rate and impact the clinical course of COPD. One significant pathological feature believed to be causative for the progressive nature of COPD is chronic pulmonary inflammation. The aim of the present study was to investigate the anti-inflammatory activity of tiotropium on cigarette smoke-induced pulmonary inflammation in mice. C57Bl/6 mice were exposed to cigarette smoke (CS) for four days with increasing exposure time for up to 6h per day to elicit pulmonary inflammation and mediator release. One hour before smoke exposure, animals were treated with tiotropium by inhalation (0.01-0.3mg/mL) for 5 min; 18h after the last CS exposure a bronchoalveolar lavage was performed. Tiotropium concentration-dependently inhibited pulmonary neutrophilic inflammation with an IC(50) of 0.058 mg/mL and a maximum inhibition of 60% at 0.3mg/mL. Furthermore, the CS-induced pulmonary release of leukotriene B(4), interleukin-6, keratinocyte-derived chemokine, monocyte chemotactic protein-1, macrophage inflammatory protein-1 alpha and -2, and tumor necrosis factor alpha was dose-dependently reduced. The bronchodilatory activity of tiotropium against acetycholine-induced bronchoconstriction was found to be in the same dose range as the anti-inflammatory activity with an IC(50) of 0.045 mg/mL and a maximum bronchodilation of 90% at 0.3mg/mL. Our data suggest that the beneficial effects of tiotropium on the course of COPD shown in patients may be associated with an anti-inflammatory activity.

Topics: Acetylcholine; Administration, Inhalation; Animals; Bronchoconstriction; Bronchodilator Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Inflammation; Inhibitory Concentration 50; Mice; Mice, Inbred C57BL; Neutrophils; Nicotiana; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Smoke; Time Factors; Tiotropium Bromide

Chronic inflammation in asthma and chronic obstructive pulmonary disease drives pathological structural remodelling of the airways. Using tiotropium bromide, acetylcholine was recently identified as playing a major regulatory role in airway smooth muscle remodelling in a guinea pig model of ongoing allergic asthma. The aim of the present study was to investigate other aspects of airway remodelling and to compare the effectiveness of tiotropium to the glucocorticosteroid budesonide. Ovalbumin-sensitised guinea pigs were challenged for 12 weeks with aerosolised ovalbumin. The ovalbumin induced airway smooth muscle thickening, hypercontractility of tracheal smooth muscle, increased pulmonary contractile protein (smooth-muscle myosin) abundance, mucous gland hypertrophy, an increase in mucin 5 subtypes A and C (MUC5AC)-positive goblet cell numbers and eosinophilia. It was reported previously that treatment with tiotropium inhibits airway smooth muscle thickening and contractile protein expression, and prevents tracheal hypercontractility. This study demonstrates that tiotropium also fully prevented allergen-induced mucous gland hypertrophy, and partially reduced the increase in MUC5AC-positive goblet cell numbers and eosinophil infiltration. Treatment with budesonide also prevented airway smooth muscle thickening, contractile protein expression, tracheal hypercontractility and mucous gland hypertrophy, and partially reduced MUC5AC-positive goblet cell numbers and eosinophilia. This study demonstrates that tiotropium and budesonide are similarly effective in inhibiting several aspects of airway remodelling, providing further evidence that the beneficial effects of tiotropium bromide might exceed those of bronchodilation.

Topics: Adrenal Cortex Hormones; Allergens; Animals; Bronchodilator Agents; Budesonide; Cholinergic Antagonists; Eosinophilia; Extracellular Matrix; Glucocorticoids; Guinea Pigs; Humans; Hypersensitivity; Inflammation; Male; Muscle, Smooth; Ovalbumin; Scopolamine Derivatives; Tiotropium Bromide; Trachea