PhD ceremony Ms. T.A. Oenema: Muscarinic receptors in airway smooth muscle. Functional roles in inflammation and remodelling

PhD ceremony: Ms. T.A. Oenema, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Muscarinic receptors in airway smooth muscle. Functional roles in inflammation and remodelling

Promotor(s): prof. H. Meurs

Faculty: Mathematics and Natural Sciences

Anticholinergics, that inhibit the action of acetylcholine on muscarinic receptors, represent the cornerstone bronchodilator treatment for COPD. This thesis describes an additional important role of muscarinic receptors in inflammation and tissue remodelling by airway smooth muscle cells. Muscarinic receptor activation enhanced cigarette smoke induced-IL-8 production through activation of intracellular signalling pathways dependent on PKC, NF-κB and ERK1/2. We also demonstrate that muscarinic receptor activation enhanced the effects of the growth factor TGF-β, which is elevated in COPD, on airway smooth muscle cell maturation and cell proliferation. Thus, muscarinic receptor activation enhances the expression of contractile proteins induced by TGF-β, which leads to the maturation of airway smooth muscle cells. GSK-3 plays a central role in the intracellular signalling involved in this process. In addition, prolonged exposure to TGF-β induces airway smooth muscle cell proliferation. This is due to an increased deposition of matrix proteins, including collagen I and fibronectin, and their interaction with integrins on the muscle cell. Muscarinic M2 receptors enhance this response by augmenting fibronectin production. This is the first study showing that muscarinic M2 receptors are involved in airway smooth muscle remodelling. Furthermore, we developed an in vitro model to study airway remodelling using precision cut lung slices of the guinea pig. Using this model, we showed that bronchoconstriction induced by muscarinic receptor activation triggers the release of TGF-β to induce contractile protein expression. Overall, the mechanisms described in this thesis shed new light on the role of muscarinic receptors in airway inflammation and remodelling, which may be of importance for COPD patients using anticholinergics.