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
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