Muscarinic receptors and their antagonists in COPD: anti-inflammatory and antiremodeling effects

Abstract

Muscarinic receptors are expressed by most cell types and mediate cellular signaling of their natural ligand acetylcholine. Thereby, they control numerous central and peripheral physiological organ responses to neuronal activity. In the human lung, muscarinic receptors are predominantly expressed by smooth muscle cells, epithelial cells, and fibroblasts. Antimuscarinic agents are used for the treatment of chronic obstructive pulmonary disease and to a lesser extent for asthma. They are primarily used as bronchodilators, but it is now accepted that they are also associated with anti-inflammatory, antiproliferative, and antiremodeling effects. Remodeling of the small airways is a major pathology in COPD and impairs lung function through changes of the extracellular matrix. Glycosaminoglycans, particularly hyaluronic acid, and matrix metalloproteases are among extracellular matrix molecules that have been associated with tissue inflammation and remodeling in lung diseases, including chronic obstructive pulmonary disease and asthma. Since muscarinic receptors have been shown to influence the homeostasis of glycosaminoglycans and matrix metalloproteases, these molecules may be proved valuable endpoint targets in clinical studies for the pharmacological exploitation of the anti-inflammatory and antiremodeling effects of muscarinic inhibitors in the treatment of chronic obstructive pulmonary disease and asthma.

Figure 1

Receptor-specific G-protein coupling and signaling for the five human muscarinic receptors: (a) M₁, (b) M₂, (c) M₃, (d) M₄, and (e) M₅.

Figure 2

Synergistic effects of acetylcholine (ACH) and cigarette smoke on M₁, M₂, and M₃ receptors. LTB4: leukotriene B4, PKC: protein kinase C, NFκB: nuclear factor kappaB, and IκB: inhibitor of NFκB.

Figure 3

Cell type and muscarinic receptor specific effects on airway wall remodeling.