Acetylcholine beyond bronchoconstriction
|PhD ceremony:||Ms L.E.M. Kistemaker|
|When:||March 06, 2015|
|Supervisors:||prof. dr. R. (Reinoud) Gosens, prof. dr. H. (Herman) Meurs, prof. dr. H.A.M. (Huib) Kerstjens|
|Where:||Academy building RUG|
|Faculty:||Science and Engineering|
The studies of Loes Kistemaker described in her thesis have revealed that acetylcholine contributes to airway inflammation and remodeling in asthma and Chronic Obstructive Pulmonary Disease (COPD) specifically via M3 muscarinic receptors. In addition, she provided the first evidence that inflammation in COPD is in part mediated by the neurotransmitter acetylcholine. This suggests that patients with asthma or COPD might benefit from M3-selective antagonists to a much larger extent than previously appreciated.
Asthma and COPD are common obstructive pulmonary diseases, characterized by airway obstruction, which results in problems with breathing. The neurotransmitter acetylcholine is an important mediator of airway obstruction in these diseases by inducing airway smooth muscle contraction and mucus secretion. Therefore, patients with obstructive airway diseases are often treated with bronchodilator drugs called muscarinic receptor antagonists, to prevent acetylcholine-induced airway smooth muscle contraction via muscarinic receptors. Increasing evidence suggests that acetylcholine can also contribute to airway inflammation and remodeling in these diseases. The aim of Kistemaker’s thesis was to characterize this new role of acetylcholine in inflammation and remodeling in asthma and COPD, and to investigate which muscarinic receptor subtypes are involved. The studies described in her thesis reveal that there is a critical regulatory role for the muscarinic M3 receptor in these processes. Thus, in mouse models of COPD and allergic asthma, respectively, it was demonstrated that inflammation in response to cigarette smoke exposure and remodeling in response to allergen exposure are partly prevented in mice deficient of the M3 receptor, and not in mice deficient of the M1 or M2 receptor. By using mice that specifically lack the M3 receptor in structural or in inflammatory cells, she demonstrated that cigarette smoke-induced inflammation is primarily mediated via M3 receptors on structural cells, and not via M3 receptors on inflammatory cells. Acetylcholine is not only released as a neurotransmitter, but can also be produced by non-neuronal cells. Studies in cultured human airway epithelial cells demonstrated that non-neuronal acetylcholine contributes to goblet cell metaplasia, and might therefore be involved in mucus hyper secretion. Importantly, inhibition of acetylcholine release by nerve denervation attenuated inflammation in the airways of COPD patients, indicating that acetylcholine may indeed promote inflammation in these patients.