Airway Mucus Secretion - Chronic Obstructive Pulmonary Disease - page 92

Anticholinergics

The parasympathetic (cholinergic) nervous pathway is the dominant neural
drive to mucus output in the airways (67). Cholinergic stimulation has been
shown experimentally to affect a variety of responses pertaining to mucus
hypersecretion in the airways, including stimulation of mucin output,
electrolyte, water, and albumin flux and, when administered repeatedly
to induce goblet cell hyperplasia and submucosal gland hypertrophy
(Table 2). The muscarinic M3 receptor mediates airway mucin secretion,
whilst the Ml receptor type appears to mediate water secretion. Cholinergic
stimulation also increases albumin flux across the epithelium (68). The com-
bined effect of stimulation of these receptors would be expected to be secre-
tion of a hydrated, albumin-rich mucus (Fig. 8). Interestingly, in concert
with increasing mucus secretion, cholinergic agonists increase mucociliary
clearance in a number of experimental preparations (69-71). Anticholiner-
gics block muscarinic receptors on secretory cells and, theoretically, may
reduce production of airway mucus (Fig. 8) and have an effect on cough-
induced clearance, as well as reduce the influence of vagal tone on bronchial
smooth muscle. However, beneficial effects on mucociliary clearance with
ipratropium bromide in COPD patients have been difficult to demonstrate.
Notably, ipratropium bromide reduced the effectiveness of cough for clear-
ing mucus from the airways compared with placebo (72). This may be a
result of changes in airflow dynamics caused by bronchodilation, or altered
rheology or depth of airway secretions following treatment. A clinical study
with oxitropium bromide in patients with COPD showed a reduction in
mucus secretion (73). The onset of the effect was slow and the mechanism
by which it was mediated was not elucidated. The newer long-acting antic-
holinergic agent, tiotropium, has kinetic selectivity for both the Ml and M3

Table 2 Effect of Cholinergic Stimulation on Production of Airway Mucus

Stimulus Target Response Species

Nerve stimulation Goblet cell Mucin secretion Rodent

Submucosal gland Mucin secretion Human

Epithelium NR NR

Cholinoceptor agonists Goblet cell Mucin secretion Rodent

Hyperplasia a Rat, cat

Submucosal gland Mucin secretion Human

Hypertrophy Rat, cat

Electrolyte = water flux Pig

Epithelium Electrolyte = water flux Human

Albumin flux Ferret

NR, not reported;
a After subacute repeated injection.