Asthma Clinical Trial
Official title:
Towards Restoring the Physiological Inhibition of Airway Narrowing in Asthma
Asthma and COPD are characterized by airway narrowing. The most potent, physiological mechanism leading to bronchodilation is taking a deep inspiration. This protects healthy subjects against bronchoconstrictive stimuli, and reverses pre-existing bronchoconstriction. However, the deep breath-induced bronchoprotection and -bronchodilation is impaired in asthma. We questioned whether this is specific for asthma (in comparison to COPD), and whether this is associated with bronchial inflammation and -remodelling. The study is a two-groups comparison, of physiological and pathological disease markers, obtained by methacholine challenges, monitoring airways resistance, and by taking bronchial biopsies.
Rationale. Asthma is associated with variable airways obstruction and airways inflammation.
It is generally assumed that inflammatory mechanisms are promoting airway narrowing, by
stimulating airway smooth muscle and by geometrical changes of the airway wall. Healthy
subjects are very effectively protected against stimuli of airway narrowing, by mechanisms
that are apparently failing in asthma. The most potent inhibitor of airway narrowing in
healthy subjects is taking a deep inspiration. This prevents and reverses
bronchoconstriction (DI-induced bronchoprotection and -bronchodilation, respectively), which
is less effective or absent in asthma. The DI-induced inhibition of airway narrowing in
normal subjects is presumably due to relaxation of smooth muscle after mechanical stretch or
to the release of relaxant mediators (such as endogenous NO). Such mechanisms might have
become impaired in asthma, secondary to e.g. mechanical uncoupling of smooth muscle from the
surrounding parenchyma (e.g. by congestion or edema), by altered structure and function of
airway smooth muscle, and/or by reduced inhibitory mediator release.
It can be postulated that the impaired response to deep inspiration is a central
pathophysiological feature of asthma at all ages. Therefore, we believe that it is
imperative to address this, by identifying and restoring these inhibitory pathways in
patients with asthma.
Hypotheses.
We hypothesize that DI-induced bronchoprotection and –broncho¬dilation:
1. are associated with cellular and morphological features of airways inflammation,
2. can be restored by deep insufflation rather than deep inspiration, and by
pharmacological interventions aimed to reduce microvascular congestion or to increase
endogenous nitric oxide synthesis..
Design and methods. To examine to what extent DI-responses differ between asthma and COPD in
adulthood, and whether this is associated with features of airways inflammation and changes
in smooth muscle function. 12 Adult patients with asthma and 12 with COPD will undergo
single-dose methacholine challenge, with prohibition of DI's or 5 DI's prior to challenge in
a cross-over design, measuring airways resistance. On a separate day bronchial biopsies will
obtained with immunohistochemistry for inflammatory cell markers, vascularity, microvascular
leakage, myosin light chain kinase, NO-synthases, and arginase.
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Observational Model: Defined Population, Time Perspective: Cross-Sectional
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