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receptors much slower (around 100-fold) than from the M 2 receptor, a prejunctional autoinhibitory receptor that restricts acetylcholine (ACh) release when activated. By allowing the M 2 receptor to resume its action as the ‘handbrake’ of ACh-induced bronchoconstriction, whilst providing durable M 3 receptor antagonism, tiotropium has an advantage over its non-selective antimuscarinic counterparts atropine and ipratropium bromide. 16 Tiotropium has been shown to reduce exacerbations and improve lung function in asthma poorly controlled on an inhaled corticosteroid and long-acting beta-agonist. In a randomised placebo-controlled trial, tiotropium improved FEV1 by 154ml and reduced severe exacerbations by 21%. 17 It has also been shown to improve symptoms and lung function in patients uncontrolled on inhaled corticosteroids alone. 18 The reduction in exacerbations by both tiotropium and surgical denervation leads to the exciting possibility that anti-vagal therapies cause a reduction in airways inflammation. From animal models and in vitro studies, acetylcholine has been shown to have a role in allergen-induced airways inflammation and remodelling. 19 Furthermore, a pilot study of TLD in COPD showed reductions in neutrophils as well as the chemokines CXCL8 and CCL4 at 30 days post- treatment. RNA profiling also highlighted reduced gene expression of TGF-β, IL-6 and MUC5AC. 20 Acetylcholine release on airway smooth muscle and submucosal glands is curtailed, causing a reduction in the cholinergic effects of broncho-constriction and mucous secretion respectively Conclusions TLD is a treatment in its infancy. The evidence base for TLD is limited in COPD, and even more so in asthma. Here, we have attempted to make a case for a denervation procedure in asthma. Invasive interventions for obstructive airways diseases have not always, and perhaps still do not have the uptake that their respective evidence bases should afford them. Lung volume reduction in emphysema and bronchial thermoplasty in asthma are two examples of such procedures. The anti-vagal therapies described above illustrate the benefits that this approach can potentially confer in severe asthma. In particular, while the surgical denervation data are not of the high scientific quality we expect in the current age of evidence-based medicine, it certainly does enough to stoke our interest and curiosity into the potential value of a denervation procedure of some form. A safety and feasibility trial of TLD in severe asthma (NCT02872298) is currently recruiting across Europe and its results are eagerly awaited. mostly published as case series and therefore prone to measurement bias. Nonetheless, it cannot be dismissed that a significant proportion of patients reported subjective improvement of their asthma, and that this was the experience across several different treating centres. The literature on surgical intervention for asthma is more sparse after the 1950s, coinciding with improvements in pharmacological treatments during this period. Inhaled anti-vagal medications (that is, antimuscarinics) are introduced in asthma later in the century in the form of atropine 14 and ipratropium bromide. 15 The most established of the antimuscarinics in asthma is tiotropium bromide, which has also been used in COPD maintenance therapy for a number of years. Tiotropium’s success has been attributed to its kinetic selectivity for the M 1 and M 3 muscarinic receptors. It dissociates from these References: 1 Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. www.ginasthma.org. 2018. 2 Slebos D-J et al. A double- blind, randomized, sham- controlled study of Targeted Lung Denervation in patients with moderate to severe COPD. Eur Respir J 2018;52(suppl 62):OA4929. 3 Kuntz A, Louis S. The autonomic nervous system in relation to the thoracic viscera. Chest 1944;10(1):1–18. 4 Gross N, Skorodin M. Role of the parasympathetic system in airway obstruction due to emphysema. 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J Thorac Surg 1957;33(2):166–84. 13 Rienhoff W, Gay L. Treatment of intractable bronchial asthma by bilateral resection of the posterior pulmonary plexus. Arch Surg 1938;37(3):456–69. 14 Snow R et al. Inhaled atropine in asthma. Ann Allergy 9 HHE 2019 | hospitalhealthcare.com 1979;42(5):286–9. 15 Ward M et al. Ipratropium bromide in acute asthma. Br Med J (Clin Res Ed). 1981;282(10):598–600. 16 Barnes PJ et al. Tiotropium bromide (Ba 679 BR), a novel long-acting muscarinic antagonist for the treatment of obstructive airways disease. Life Sci 1995;56(11-12):853–9. 17 Kerstjens HAM et al. Tiotropium in asthma poorly controlled with standard combination therapy. N Engl J Med 2012;367(13):1198–1207. 18 Peters SP et al. Tiotropium bromide step-up therapy for adults with uncontrolled asthma. N Engl J Med 2010;363(18):1715–26. 19 Kistemaker LEM, Gosens R. Acetylcholine beyond bronchoconstriction: Roles in inflammation and remodeling. Trends Pharmacol Sci 2015;36(3):164–71. 20 Kistemaker LEM et al. Anti-inflammatory effects of targeted lung denervation in patients with COPD. Eur Respir J 2015;46(5):1489–92.