tiotropium-bromide and Airway-Remodeling

Higher parasympathetic tone has been reported in asthmatics. In general, cholinergic contractile tone is increased by airway inflammation associated with asthma. Nevertheless, the role of muscarinic antagonists for the treatment of asthma has not yet been clearly defined. Areas covered: The use of SAMAs and LAMAs in asthma has been examined and discussed according with the published evidence. Particular attention has been given to the large Phase III clinical trial program designed to evaluate the efficacy and safety of tiotropium respimat added to standard treatment in adults, adolescents and children with persistent asthma across the spectrum of asthma severity. Expert commentary: The current evidence is that in patients with poorly controlled severe asthma despite the use of ICS and LABA, the addition of tiotropium significantly increases the time to the first severe exacerbation and provides a modest but sustained bronchodilation. Identical results should be produced using other LAMAs. In any case, the documentation that, at least in animal or in vitro models, LAMAs show significant anti-inflammatory and anti-proliferative capacities and are able to inhibit airway remodeling induced by allergens makes a strong presumption that the use of LAMAs in asthma may go beyond the simple bronchodilator effect.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Airway Remodeling; Asthma; Bronchodilator Agents; Clinical Trials, Phase III as Topic; Drug Therapy, Combination; Humans; Muscarinic Antagonists; Tiotropium Bromide

Airway remodeling is an important feature of chronic obstructive pulmonary disease (COPD) that is associated with disease severity and irreversible airflow limitation. An extensive alteration of the extracellular matrix (ECM) surrounding the airway smooth muscle (ASM) bundle is one of the pathological manifestations of airway remodeling, which contributes to the decline in lung function. Tiotropium, a long-acting inhaled muscarinic receptor antagonist, has been confirmed to play a role in preventing airway remodeling including ECM deposition beyond bronchodilation in vivo, but the relationship between ASM cell (ASMC) relaxation and ECM production remains unclear.. In this study, we attempted to investigate the influence of tiotropium on ECM production by ASMCs and the underlying mechanism.. Tiotropium was added 30 minutes before the addition of methacholine to primary cultured human ASMCs. Protein expression was analylized by Western Blot and mRNA abundance was determined by real-time PCR.. We found that tiotropium reduced collagen I protein expression, and the mRNA abundance of. These findings suggest that relaxation of ASMCs by tiotropium can prevent ECM production through β-catenin signaling.

Topics: Adult; Airway Remodeling; beta Catenin; Bronchi; Bronchodilator Agents; Cells, Cultured; Dose-Response Relationship, Drug; Extracellular Matrix; Extracellular Matrix Proteins; Glycogen Synthase Kinase 3 beta; Humans; Male; Methacholine Chloride; Middle Aged; Muscarinic Antagonists; Muscle, Smooth; Myocytes, Smooth Muscle; Phosphorylation; Signal Transduction; Tiotropium Bromide

The long-acting anticholinergic tiotropium has recently been registered for the treatment of asthma, and its use is associated with a reduction in exacerbation frequency. Anti-inflammatory and anti-remodeling effects of tiotropium have been demonstrated in in vitro and in vivo models. Because tiotropium treatment is used in combination with inhaled corticosteroids, potential additive effects between the two would be clinically relevant. Therefore, the aim of this study was to investigate additive effects between tiotropium and ciclesonide on airway inflammation and remodeling in guinea pig models of asthma.. Guinea pigs (n = 3-8/group) were sensitized and challenged with ovalbumin in an acute (single challenge) and a chronic model (12 weekly challenges) of allergic asthma. Animals were treated with vehicle, nebulized tiotropium (0.01-0.3 mM) and/or intranasally instilled ciclesonide (0.001-1 mg/kg) before each challenge. Bronchoalveolar lavage fluid and lungs were collected for analysis of airway inflammation and remodeling.. Tiotropium and ciclesonide treatment, alone or in combination, did not inhibit airway inflammation in the acute asthma model. In a dose-finding study, low doses of tiotropium and ciclesonide inhibited airway eosinophilia and airway smooth muscle thickening in the chronic asthma model. Threshold doses of 0.01 mM tiotropium (nebulizer concentration) and 0.01 mg/kg ciclesonide were selected to investigate potential additive effects between both drugs. At these doses, tiotropium and ciclesonide did not inhibit airway eosinophilia or airway smooth muscle thickening when administered alone, but significantly inhibited these allergen-induced responses when administered in combination.. Combined treatment with low doses of tiotropium and ciclesonide inhibits airway inflammation and remodeling in a guinea pig model of chronic asthma, suggesting that combined treatment with anticholinergics and corticosteroids may have anti-inflammatory and anti-remodeling activity in allergic airway diseases. Since tiotropium is registered as a therapy for asthma added on to corticosteroid treatment, these beneficial effects of the combination therapy may be clinically relevant.

Topics: Administration, Inhalation; Airway Remodeling; Animals; Anti-Allergic Agents; Asthma; Bronchodilator Agents; Chronic Disease; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Guinea Pigs; Male; Ovalbumin; Pregnenediones; Tiotropium Bromide; Treatment Outcome

Recurrent relapses of allergic lung inflammation in asthmatics may lead to airway remodeling and lung damage. We tested the efficacy of tiotropium bromide, a selective long-acting, muscarinic receptor antagonist as an adjunct therapy in relapses of allergic asthma in mice. We compared the effectiveness of local intranasal administration of tiotropium and dexamethasone in acute and relapsing allergic asthma in BALB/c mice. Although tiotropium at low doses is a potent bronchodilator, we tested higher doses to determine effectiveness on inflammation and mucus hypersecretion. A 5-day course of twice daily intranasal tiotropium or dexamethasone (1 mg/kg (b.w.)) suppressed airway eosinophils by over 87% during disease initiation and 88% at relapse compared to vehicle alone. Both drugs were comparable in their capacity to suppress airway and parenchymal inflammation and mucus hypersecretion, though tiotropium was better than dexamethasone at reducing mucus secretion during disease relapse. Despite treatment with either drug, serum antigen-specific IgE or IgG1 antibody titres remained unchanged. Our study indicates that tiotropium at higher doses than required for bronchodilation, effectively suppresses inflammation and mucus hypersecretion in the lungs and airways of mice during the initiation and relapse of asthma. Tiotropium is currently not approved for use in asthma. Clinical studies have to demonstrate the efficacy of tiotropium in this respiratory disease.

Topics: Airway Remodeling; Animals; Anti-Inflammatory Agents; Asthma; Bronchodilator Agents; Dexamethasone; Disease Models, Animal; Dose-Response Relationship, Drug; Eosinophils; Female; Immunoglobulin E; Immunoglobulin G; Mice; Mice, Inbred BALB C; Mucus; Recurrence; Scopolamine Derivatives; Tiotropium Bromide

Recent evidence suggests that acetylcholine acting through muscarinic receptors may play an inhibitory role in the mechanisms that drive the structural changes in the airways called airway remodeling. The novel anticholinergic drug tiotropium bromide, which selectively antagonizes muscarinic receptors, especially the M3 subtype, and is long acting, could be beneficial in attenuating airway remodeling in chronic asthma.. To investigate the effect of tiotropium bromide on parameters of airway remodeling, including smooth muscle hypertrophy and peribronchial thickening, in a mouse model of chronic asthma.. To develop the murine models of acute and chronic asthma, BALB/c mice were sensitized and challenged to ovalbumin for 1 and 3 months, respectively. The effect of tiotropium bromide (0.1mM in 50 μL of phosphate-buffered saline) on pulmonary inflammation and remodeling was evaluated. The expression of muscarinic receptors M2 and M3 was analyzed.. In the chronic asthma model, the tiotropium-treated group significantly decreased smooth muscle thickening and peribronchial collagen deposition. As for pulmonary inflammation, the chronic asthma model had a reduction of inflammatory cells and T(H)2 cytokines by tiotropium bromide, but the effects in the asthma acute model were reversed. In the chronic asthma model, expression of the M3 receptor was inhibited and that of the M2 receptor was elevated by the administration of tiotropium bromide.. This study suggests that tiotropium bromide might have an inhibitory effect on airway remodeling in a murine model of chronic asthma. Differential effects on muscarinic receptor subtypes may explain why tiotropium bromide has different effects on acute and chronic asthma.

Topics: Acetylcholine; Acute Disease; Airway Remodeling; Animals; Asthma; Bronchoalveolar Lavage Fluid; Cholinergic Antagonists; Chronic Disease; Cytokines; Disease Models, Animal; Eosinophils; Female; Macrophages; Mice; Mice, Inbred BALB C; Muscle, Smooth; Neutrophils; Ovalbumin; Pneumonia; Receptor, Muscarinic M2; Receptor, Muscarinic M3; Scopolamine Derivatives; Th2 Cells; Tiotropium Bromide

Topics: Airway Remodeling; Asthma; Bronchodilator Agents; Humans; Randomized Controlled Trials as Topic; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Airway remodelling and emphysema are major structural abnormalities in chronic obstructive pulmonary disease (COPD). In addition, pulmonary vascular remodelling may occur and contribute to pulmonary hypertension, a comorbidity of COPD. Increased cholinergic activity in COPD contributes to airflow limitation and, possibly, to inflammation and airway remodelling. This study aimed to investigate the role of acetylcholine in pulmonary inflammation and remodelling using an animal model of COPD. To this aim, guinea pigs were instilled intranasally with lipopolysaccharide (LPS) twice weekly for 12 weeks and were treated, by inhalation, with the long-acting muscarinic receptor antagonist tiotropium. Repeated LPS exposure induced airway and parenchymal neutrophilia, and increased goblet cell numbers, lung hydroxyproline content, airway wall collagen and airspace size. Furthermore, LPS increased the number of muscularised microvessels in the adventitia of cartilaginous airways. Tiotropium abrogated the LPS-induced increase in neutrophils, goblet cells, collagen deposition and muscularised microvessels, but had no effect on emphysema. In conclusion, tiotropium inhibits remodelling of the airways as well as pulmonary inflammation in a guinea pig model of COPD, suggesting that endogenous acetylcholine plays a major role in the pathogenesis of this disease.

Topics: Acetylcholine; Airway Remodeling; Animals; Animals, Outbred Strains; Cholinergic Antagonists; Disease Models, Animal; Emphysema; Goblet Cells; Guinea Pigs; Lipopolysaccharides; Lung; Male; Mucin 5AC; Muscarinic Antagonists; Neutrophils; Pneumonia; Pulmonary Disease, Chronic Obstructive; Pulmonary Fibrosis; Scopolamine Derivatives; Tiotropium Bromide

Topics: Airway Remodeling; Cholinergic Antagonists; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Tiotropium bromide, a long acting muscarinic receptor inhibitor, is a potent agent for patients with bronchial asthma as well as chronic obstructive pulmonary disease.. The aim of this study was to evaluate whether tiotropium bromide can inhibit allergen-induced acute and chronic airway inflammation, T helper (Th)2 cytokine production, and airway remodelling in a murine model of asthma.. Balb/c mice were sensitized and challenged acutely or chronically to ovalbumin (OVA). The impact of tiotropium bromide was assessed using these mice models by histologic, morphometric, and molecular techniques. Moreover, the effect of tiotropium bromide on Th2 cytokine production from purified human peripheral blood mononuclear cells (PBMCs) was assessed.. Treatment with tiotropium bromide significantly reduced airway inflammation and the Th2 cytokine production in bronchoalveolar lavage fluid (BALF) in both acute and chronic models of asthma. The levels of TGF-beta1 were also reduced by tiotropium bromide in BALF in a chronic model. The goblet cell metaplasia, thickness of airway smooth muscle, and airway fibrosis were all significantly decreased in tiotropium bromide-treated mice. Moreover, airway hyperresponsiveness (AHR) to serotonin was significantly abrogated by tiotropium bromide in a chronic model. Th2 cytokine production from spleen cells isolated from OVA-sensitized mice was also significantly inhibited by tiotropium bromide and 4-diphenylacetoxy-N-methylpiperidine methiodide, which is a selective antagonist to the M3 receptor. Finally, treatment with tiotropium bromide inhibited the Th2 cytokine production from PBMCs.. These results indicate that tiotropium bromide can inhibit Th2 cytokine production and airway inflammation, and thus may reduce airway remodelling and AHR in a murine model of asthma.

Topics: Airway Remodeling; Animals; Asthma; Bronchoalveolar Lavage Fluid; Bronchodilator Agents; Cytokines; Disease Models, Animal; Female; Humans; Leukocytes, Mononuclear; Mice; Mice, Inbred BALB C; Pneumonia; Scopolamine Derivatives; Th2 Cells; Tiotropium Bromide