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      The mode of action of anticholinergics in asthma

      research-article
      1 , 2
      The European Respiratory Journal
      European Respiratory Society

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          Abstract

          Acetylcholine binds to muscarinic receptors to play a key role in the pathophysiology of asthma, leading to bronchoconstriction, increased mucus secretion, inflammation and airway remodelling. Anticholinergics are muscarinic receptor antagonists that are used in the treatment of chronic obstructive pulmonary disease and asthma. Recent in vivo and in vitro data have increased our understanding of how acetylcholine contributes to the disease manifestations of asthma, as well as elucidating the mechanism of action of anticholinergics. This review assesses the latest literature on acetylcholine in asthma pathophysiology, with a closer look at its role in airway inflammation and remodelling. New insights into the mechanism of action of anticholinergics, their effects on airway remodelling, and a review of the efficacy and safety of long-acting anticholinergics in asthma treatment will also be covered, including a summary of the latest clinical trial data.

          Abstract

          Pre-clinical data suggest that anticholinergics can reduce acetylcholine-induced airway inflammation and remodelling http://ow.ly/xqAQ30loP8F

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          Most cited references86

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          The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation

          Neuromedin receptor NMUR1 is specifically expressed by a subpopulation of type 2 innate lymphoid cells and promotes the inflammatory response of these cells in response to allergens, indicating the importance of neuro-immune crosstalk in allergic responses.
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            The neuropeptide Neuromedin U stimulates innate lymphoid cells and type 2 inflammation

            The type 2 cytokines interleukin (IL)-4, IL-5, IL-9 and IL-13 play critical roles in stimulating innate and adaptive immune responses required for resistance to helminth infection and promotion of allergic inflammation, metabolic homeostasis and tissue repair 1–3 . Group 2 innate lymphoid cells (ILC2s) are a potent source of type 2 cytokines and while significant advances have been made in understanding the cytokine milieu that promotes ILC2 responses 4–9 , there are fundamental gaps in knowledge regarding how ILC2 responses are regulated by other stimuli. In this report, we demonstrate that ILC2s in the gastrointestinal tract co-localize with cholinergic neurons that express the neuropeptide neuromedin U (NMU) 10,11 . In contrast to other hematopoietic cells, ILC2s selectively express the NMU receptor 1 (NMUR1). In vitro stimulation of ILC2s with NMU induced rapid cell activation, proliferation and secretion of type 2 cytokines IL-5, IL-9 and IL-13 that was dependent on cell-intrinsic expression of NMUR1 and Gαq protein. In vivo administration of NMU triggered potent type 2 cytokine responses characterized by ILC2 activation, proliferation and eosinophil recruitment that was associated with accelerated expulsion of the gastrointestinal nematode Nippostrongylus brasiliensis or induction of lung inflammation. Conversely, worm burden was higher in Nmur1 −/− mice compared to control mice. Further, use of gene-deficient mice and adoptive cell transfer experiments revealed that ILC2s were necessary and sufficient to mount NMU-elicited type 2 cytokine responses. Together, these data indicate that the NMU-NMUR1 neuronal signaling circuit provides a selective and previously unrecognized mechanism through which the enteric nervous system and innate immune system integrate to promote rapid type 2 cytokine responses that can induce anti-microbial, inflammatory and tissue-protective type 2 responses at mucosal sites.
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              Tiotropium in asthma poorly controlled with standard combination therapy.

              Some patients with asthma have frequent exacerbations and persistent airflow obstruction despite treatment with inhaled glucocorticoids and long-acting beta-agonists (LABAs). In two replicate, randomized, controlled trials involving 912 patients with asthma who were receiving inhaled glucocorticoids and LABAs, we compared the effect on lung function and exacerbations of adding tiotropium (a total dose of 5 μg) or placebo, both delivered by a soft-mist inhaler once daily for 48 weeks. All the patients were symptomatic, had a post-bronchodilator forced expiratory volume in 1 second (FEV(1)) of 80% or less of the predicted value, and had a history of at least one severe exacerbation in the previous year. The patients had a mean baseline FEV(1) of 62% of the predicted value; the mean age was 53 years. At 24 weeks, the mean (±SE) change in the peak FEV(1) from baseline was greater with tiotropium than with placebo in the two trials: a difference of 86±34 ml in trial 1 (P=0.01) and 154±32 ml in trial 2 (P<0.001). The predose (trough) FEV(1) also improved in trials 1 and 2 with tiotropium, as compared with placebo: a difference of 88±31 ml (P=0.01) and 111±30 ml (P<0.001), respectively. The addition of tiotropium increased the time to the first severe exacerbation (282 days vs. 226 days), with an overall reduction of 21% in the risk of a severe exacerbation (hazard ratio, 0.79; P=0.03). No deaths occurred; adverse events were similar in the two groups. In patients with poorly controlled asthma despite the use of inhaled glucocorticoids and LABAs, the addition of tiotropium significantly increased the time to the first severe exacerbation and provided modest sustained bronchodilation. (Funded by Boehringer Ingelheim and Pfizer; ClinicalTrials.gov numbers, NCT00772538 and NCT00776984.).
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                Author and article information

                Journal
                Eur Respir J
                Eur. Respir. J
                ERJ
                erj
                The European Respiratory Journal
                European Respiratory Society
                0903-1936
                1399-3003
                October 2018
                04 October 2018
                : 52
                : 4
                : 1701247
                Affiliations
                [1 ]University of Groningen, Groningen, The Netherlands
                [2 ]University Medical Research LLC, St Francis Hospital, Hartford, CT, USA
                Author notes
                Reinoud Gosens, Dept of Molecular Pharmacology, Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands. E-mail: r.gosens@ 123456rug.nl
                Article
                ERJ-01247-2017
                10.1183/13993003.01247-2017
                6340638
                30115613
                b9cc50c2-1b71-444f-9f24-8ec68b25994a
                Copyright ©ERS 2018

                This ERJ Open article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0.

                History
                : 22 December 2017
                : 09 August 2018
                Categories
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                Respiratory medicine
                Respiratory medicine

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