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      Effect of Tiotropium Bromide on Airway Inflammation and Programmed Cell Death 5 in a Mouse Model of Ovalbumin-Induced Allergic Asthma

      research-article
      , , ,
      Canadian Respiratory Journal
      Hindawi

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          Abstract

          Rationale

          We previously demonstrated increased expression of programmed cell death 5 (PDCD5) in asthmatic patients and ovalbumin-induced allergic asthma. International guidelines (GINA 2019) have included the use of tiotropium bromide for chronic treatment of the most severe and frequently exacerbated asthma in patients ≥6 years old, who do not have good response to inhaled corticosteroids.

          Objective

          To explore the role of tiotropium and its effect on PDCD5 level in a mouse model of chronic asthma.

          Methods

          We divided 12 female mice into 2 groups: untreated asthma ( n = 6) and tiotropium-treated asthma ( n = 6). The impact of tiotropium was assessed by histology of lung tissue and morphometry. Pulmonary function was tested by using pressure sensors. The number of cells in bronchoalveolar lavage fluid (BALF) was detected. Levels of PDCD5, active caspase-3, and muscarinic acetylcholine receptors M2 (ChRM2) and M3 (ChRM3) were examined.

          Results

          Tiotropium treatment significantly reduced airway inflammation and remodeling in asthmatic mice and intensified the lung function. PDCD5 level was reduced with tiotropium ( p < 0.05). Moreover, active caspase-3 level was decreased with tiotropium ( p < 0.001), and ChRM3 level was increased.

          Conclusions

          Tiotropium treatment may alleviate the pathological changes with asthma by regulating apoptosis.

          Related collections

          Most cited references38

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          Tiotropium bromide step-up therapy for adults with uncontrolled asthma.

          Long-acting beta-agonist (LABA) therapy improves symptoms in patients whose asthma is poorly controlled by an inhaled glucocorticoid alone. Alternative treatments for adults with uncontrolled asthma are needed. In a three-way, double-blind, triple-dummy crossover trial involving 210 patients with asthma, we evaluated the addition of tiotropium bromide (a long-acting anticholinergic agent approved for the treatment of chronic obstructive pulmonary disease but not asthma) to an inhaled glucocorticoid, as compared with a doubling of the dose of the inhaled glucocorticoid (primary superiority comparison) or the addition of the LABA salmeterol (secondary noninferiority comparison). The use of tiotropium resulted in a superior primary outcome, as compared with a doubling of the dose of an inhaled glucocorticoid, as assessed by measuring the morning peak expiratory flow (PEF), with a mean difference of 25.8 liters per minute (P<0.001) and superiority in most secondary outcomes, including evening PEF, with a difference of 35.3 liters per minute (P<0.001); the proportion of asthma-control days, with a difference of 0.079 (P=0.01); the forced expiratory volume in 1 second (FEV1) before bronchodilation, with a difference of 0.10 liters (P=0.004); and daily symptom scores, with a difference of -0.11 points (P<0.001). The addition of tiotropium was also noninferior to the addition of salmeterol for all assessed outcomes and increased the prebronchodilator FEV1 more than did salmeterol, with a difference of 0.11 liters (P=0.003). When added to an inhaled glucocorticoid, tiotropium improved symptoms and lung function in patients with inadequately controlled asthma. Its effects appeared to be equivalent to those with the addition of salmeterol. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00565266.).
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            Caspases: key players in programmed cell death.

            Research in apoptosis has established a central role for caspases. The recent determination of structures of caspase-1, caspase-3 and caspase-8, together with biochemical studies, has greatly enhanced our understanding of the structure, function and specificity of these enzymes. This provides a basis for the further elucidation of the biological role of caspases and a guide to the design of selective inhibitors to treat caspase-mediated diseases.
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              Inhibition of allergen-induced airway remodelling by tiotropium and budesonide: a comparison.

              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.
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                Author and article information

                Contributors
                Journal
                Can Respir J
                Can. Respir. J
                CRJ
                Canadian Respiratory Journal
                Hindawi
                1198-2241
                1916-7245
                2019
                1 October 2019
                : 2019
                : 6462171
                Affiliations
                Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing 100191, China
                Author notes

                Guest Editor: Marco Caminati

                Author information
                https://orcid.org/0000-0002-1699-1713
                https://orcid.org/0000-0002-5413-8609
                https://orcid.org/0000-0001-5504-5132
                https://orcid.org/0000-0002-3181-6614
                Article
                10.1155/2019/6462171
                6791200
                31662808
                bebc2060-85c3-47f8-938f-e38bcbd5d5d6
                Copyright © 2019 Juan Wang et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 4 April 2019
                : 16 July 2019
                : 1 September 2019
                Funding
                Funded by: National Natural Science Foundation of China
                Award ID: 81470235
                Award ID: 81670034
                Categories
                Research Article

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