Tiotropium bromide inhibits relapsing allergic asthma in BALB/c mice

Bošnjak, Berislav; Tilp, Cornelia; Tomsic, Christopher; Dekan, Gerhard; Pieper, Michael; Erb, Klaus J.; Epstein, Michelle M.

doi:10.1016/j.pupt.2013.09.004

Cited by 34 publications

(26 citation statements)

References 32 publications

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“…The model used in these studies leads to approximately 30% eosinophils in the airways [22], which is higher than airway eosinophilia in humans. Nevertheless, this model is optimal for proof of concept for our imaging approach, because untreated EAAD mice have significantly higher lung eosinophilia compared with treated and healthy mice [37], which allows the differences between healthy, treated, and untreated groups to be easily distinguished. We would argue that our approach works well in small animals and could be used effectively in preclinical models.…”

Section: Discussionmentioning

confidence: 99%

Non-Invasive Optical Imaging of Eosinophilia during the Course of an Experimental Allergic Airways Disease Model and in Response to Therapy

et al. 2014

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BackgroundMolecular imaging of lung diseases, including asthma, is limited and either invasive or non-specific. Central to the inflammatory process in asthma is the recruitment of eosinophils to the airways, which release proteases and proinflammatory factors and contribute to airway remodeling. The aim of this study was to establish a new approach to non-invasively assess lung eosinophilia during the course of experimental asthma by combining non-invasive near-infrared fluorescence (NIRF) imaging with the specific detection of Siglec-F, a lectin found predominantly on eosinophils.Methodology/Principal FindingsAn ovalbumin (OVA)-based model was used to induce asthma-like experimental allergic airway disease (EAAD) in BALB/c mice. By means of a NIRF imager, we demonstrate that 48 h–72 h after intravenous (i.v.) application of a NIRF-labeled anti-Siglec-F antibody, mice with EAAD exhibited up to 2 times higher fluorescence intensities compared to lungs of control mice. Furthermore, average lung intensities of dexamethasone-treated as well as beta-escin-treated mice were 1.8 and 2 times lower than those of untreated, EAAD mice, respectively and correlated with the reduction of cell infiltration in the lung. Average fluorescence intensities measured in explanted lungs confirmed the in vivo findings of significantly higher values in inflamed lungs as compared to controls. Fluorescence microscopy of lung cryosections localized the i.v. applied NIRF-labeled anti-Siglec-F antibody predominantly to eosinophils in the peribronchial areas of EAAD lungs as opposed to control lungs.Conclusion/SignificanceWe show that monitoring the occurrence of eosinophils, a prominent feature of allergic asthma, by means of a NIRF-labeled antibody directed against Siglec-F is a novel and powerful non-invasive optical imaging approach to assess EAAD and therapeutic response in mice over time.

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Section: Discussionmentioning

confidence: 99%

Non-Invasive Optical Imaging of Eosinophilia during the Course of an Experimental Allergic Airways Disease Model and in Response to Therapy

et al. 2014

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“…Anti-inflammatory effect of other muscarinic receptor antagonists was also reported recently. 14,15 Among the five types of muscarinic receptors (M 1-5 R), the muscarinic M3 receptor (M 3 R) expressed in airway and intestinal smooth muscle positively regulates bronchoconstriction and intestinal motility, respectively. 16 Mepenzolate is a subtype-non-specific muscarinic antagonist 12 whose bronchodilatory effect and inhibitory effect on intestinal motility can be explained by its antagonistic action on M 3 R. On the other hand, the muscarinic M2 receptor (M 2 R) expressed in the sinoatrial node of the heart negatively regulates heart rate, 17 and we recently confirmed that mepenzolate's inhibitory action on this receptor leads to an increased heart rate in mice (Tanaka et al, unpublished results).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and biological comparison of enantiomers of mepenzolate bromide, a muscarinic receptor antagonist with bronchodilatory and anti-inflammatory activities

Yamashita

Tanaka

Asano

et al. 2014

Bioorganic & Medicinal Chemistry

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Chronic obstructive pulmonary disease (COPD) is characterized by abnormal inflammatory responses and airflow limitations. We recently proposed that the muscarinic antagonist mepenzolate bromide (mepenzolate) would be therapeutically effective against COPD due to its muscarinic receptor-dependent bronchodilatory activity as well as anti-inflammatory properties. Mepenzolate has an asymmetric carbon atom, thus providing us with the opportunity to synthesize both of its enantiomers ((R)- and (S)-mepenzolate) and to examine their biochemical and pharmacological activities. (R)- or (S)-mepenzolate was synthesized by condensation of benzilic acid with (R)- or (S)-alcohol, respectively, followed by quaternization of the tertiary amine. As predicted by computational simulation, a filter-binding assay in vitro revealed that (R)-mepenzolate showed a higher affinity for the muscarinic M3 receptor than (S)-mepenzolate. In vivo, the bronchodilatory activity of (R)-mepenzolate was superior to that of (S)-mepenzolate, whereas anti-inflammatory activity was indistinguishable between the two enantiomers. We confirmed that each mepenzolate maintained its original stereochemistry in the lung when administered intratracheally. These results suggest that (R)-mepenzolate may have superior properties to (S)-mepenzolate as a drug to treat COPD patients given that the former has more potent bronchodilatory activity than the latter.

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“…Eosinophils are responsible for M 2R dysfunction in the lungs [16], while ACh is known to mediate the production of leukotriene-B4 (LTB4) and thus to lead neutrophil recruitment [97]. In animal models of allergic asthma, the protective effect of Tiotropium against airway hyper-responsiveness and airway inflammation was shown to be paralleled by a reduction in the eosinophil deposition in the airways [23, 98]. The authors speculate that in this case Tiotropium acted through non conventional pathways, non-neuronal ACh release from macrophages and epithelial cells or acting directly on M 3R present on eosinophils, although the existence of the latter is to be confirmed yet.…”

Section: Introductionmentioning

confidence: 99%

“…Selective M 3R with tiotropium showed an inhibition of neutrophil elastase-induce goblet cell metaplasia and neutrophil-elastase induced MUC5AC production [113]. Concomitant administration of tiotropium and inhaled steroids like budesonide [103] and dexamethasone [98] showed to reduce allergen-induced mucus gland hypertrophy and mucus hyper secretion in mice models of allergic asthma. Although having an effect on mucus production, tiotropium was not demonstrated to alter the rheological properties of mucus.…”

Section: Introductionmentioning

confidence: 99%

The evidence on tiotropium bromide in asthma: from the rationale to the bedside

Radovanovic

Santus

Blasi

et al. 2017

Multidiscip Respir Med

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Severe and poorly controlled asthma still accounts for a great portion of the patients affected. Disease control and future risk management have been identified by international guidelines as the main goals in patients with asthma. The need for new treatment approaches has led to reconsider anticholinergic drugs as an option for asthma treatment. Tiotropium is the first anticholinergic drug that has been approved for children and adults with poorly controlled asthma and is currently considered as an option for steps 4 and 5 of the Global Initiative for Asthma. In large randomized clinical trials enrolling patients with moderate to severe asthma, add-on therapy with tiotropium has demonstrated to be efficacious in improving lung function, decreasing risk of exacerbation and slowing the worsening of disease; accordingly, tiotropium demonstrated to be non inferior compared to long acting beta-agonists in the maintenance treatment along with medium to high inhaled corticosteroids. In view of the numerous ancillary effects acting on inflammation, airway remodeling, mucus production and cough reflex, along with the good safety profile and the broad spectrum of efficacy demonstrated in different disease phenotypes, tiotropium can represent a beneficial alternative in the therapeutic management of poorly controlled asthma. The present extensive narrative review presents the pharmacological and pathophysiological basis that guided the rationale for the introduction of tiotropium in asthma treatment algorithm, with a particular focus on its conventional and unconventional effects; finally, data on tiotropium efficacy and safety. from recent randomized clinical trials performed in all age categories will be extensively discussed.

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Tiotropium bromide inhibits relapsing allergic asthma in BALB/c mice

Cited by 34 publications

References 32 publications

Non-Invasive Optical Imaging of Eosinophilia during the Course of an Experimental Allergic Airways Disease Model and in Response to Therapy

Non-Invasive Optical Imaging of Eosinophilia during the Course of an Experimental Allergic Airways Disease Model and in Response to Therapy

Synthesis and biological comparison of enantiomers of mepenzolate bromide, a muscarinic receptor antagonist with bronchodilatory and anti-inflammatory activities

The evidence on tiotropium bromide in asthma: from the rationale to the bedside

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