The heterogeneity of asthma endotypes
Environmental stressors such as allergen, air pollution and climate factors can lead to the activation of stromal cells such as airway epithelial cells, glands and goblet cells, fibroblasts etc. Subsequently, innate immune cells will be activated including innate lymphoid cells, dendritic cells, and mast cells. These cells will initiate the activation of adaptive immune cells, bringing lymphocyte and immunoglobulins into play. Consequently, these processes will result into airflow obstruction and bronchial hyperresponsiveness, via the dysregulation of adrenergic and cholinergic innervation, and fibrosis and remodelling, via cholinergic signalling of stromal cells. Also muscarinic receptors on inflammatory cells will be activated and lead into either T1, T2 or T3 immune responses, including the synthesis of allergen-specific antibodies. The relative contribution of the mentioned mechanisms will vary across the asthma population and accounts to the different disease types.
The acetylcholine/muscarinic axis in asthma pathogenesis
The vagus nerve releases the neurotransmitter acethylcholine (ACh), which can stimulate lung cells expressing muscarinic receptors of class M1, M2 or M3. In submucosal glands, this induces the secretion of mucus, and smooth muscle cells activation and bronchoconstriction. The cholinergic system is important for airway homeostasis, its dysfunction can lead to different asthma endotypes.
Airway smooth muscle tone is regulated by muscarinic receptors
M3 receptors play the main role in ACh-mediated bronchoconstriction. In patients with asthma, there is a higher sensitivity in regards to M3 signalling. Moreover, ACh availability is increased in asthma, and even more so during viral infections.
Airway mucus secretion is regulated by muscarinic receptors
ACh is the main driver of mucus production from goblet cells and submucosal glands. Moreover, the stimulation of muscarinic receptors M1 and M3 in submucosal glands makes them more prone for epithelial-growth factor-mediated goblet cell hyperplasia.
Did you know?
Mucus in asthma is thick and non-viscous. Its consistency is described as “gluey” or “as peanut-butter”. As mucus plugs form in the lungs of asthmatics over a period of years, some researchers refer to them as “tissue” due to the complex structure of inflammatory cells and fibrin that develops in the matrix of water, electrolytes and glycoproteins. The mucus plugs are securely attached to the airway wall by a barbed wire of Charcot Leyden crystals.
Muscarinic receptors in airway inflammation and remodelling
Hematopoetic cells are a source of ACh and respond to it in an autocrine/paracrine manner. This can lead to a long row of consequences: The cytotoxicity of CD8+ T cells is enhanced, leukotriene B4 is synthesised and chemotaxis induced, and other inflammation cascades initiated.
ACh stimulation directly induces the proliferation of airway fibroblasts, and leads to other features of remodelling in the asthmatic airways.
Anti-inflammatory effects of LAMA
In in vitro and in vivo studies, LAMA, and here especially tiotropium, has shown anti-inflammatory effects, but definitive evidence for a clinical effect of LAMA in asthma beyond bronchodilation is still missing.
LAMA is an effective component of triple therapy in asthma
In patients treated with a triple combination of medium-dose ICS/LABA/LAMA, exacerbations are less frequent than with high dose ICS/LABA treatment, and FEV1 significantly improves. There are studies showing that addition of LAMA to treatment reduces the use of short-acting beta2-agonists ad improves sleep quality.
Addition of LAMA will also increase the likelihood for unfavourable effects, such as dry mouth and dysphonia.
Who would benefit from addition of LAMA to asthma therapy?
The EAACI position paper lists five visible properties to identify patients for triple therapy of asthma.
- Older age
- Low FEV1 with preserved FEF25-75 or R25-R5
- Frequent and abundant mucus production,
- Exacerbations triggered by infections,
- Low expression of T2 biomarkers.
Barbara Fuchs
Medical Lead, Chiesi Nordic
Reference:
Agache I, Adcock IM, Akdis CA, Akdis M, Bentabol-Ramos G, van den Berge M, Boccabella C, Canonica WG, Caruso C, Couto M, Davila I, Drummond D, Fonseca J, Gherasim A, Del Giacco S, Jackson DJ, Jutel M, Licari A, Loukides S, Moreira A, Mukherjee M, Ojanguren I, Palomares O, Papi A, Perez de Llano L, Price OJ, Rukhazde M, Shamji MH, Shaw D, Sanchez-Garcia S, Testera-Montes A, Torres MJ, Eguiluz-Gracia I. The Bronchodilator and Anti-Inflammatory Effect of Long-Acting Muscarinic Antagonists in Asthma: An EAACI Position Paper. Allergy. 2025 Feb;80(2):380-394. doi: 10.1111/all.16436. Epub 2024 Dec 16. PMID: 39676750. https://onlinelibrary.wiley.com/doi/epdf/10.1111/all.16436
ID 15719-09.07.2025