Pathophysiology, Therapeutic Targets, and Future Therapeutic Alternatives in COPD: Focus on the Importance of the Cholinergic System

Abstract

Chronic obstructive pulmonary disease (COPD) is a progressive disease characterized by airway limitation and changes in airway structure. It has a high global burden of mortality and morbidity. The etiology of COPD is complex, but exposure to tobacco smoke and other inhaled lung oxidants are major risk factors. Both pharmacological and non-pharmacological approaches are used to manage COPD, but there remains an urgent unmet need for drugs that can modify the course of the disease. This review focuses on the role of acetylcholine and other components of the pulmonary cholinergic system in the pathogenesis of COPD, and the inhaled pharmacological agents that target it. In addition to its role as a neurotransmitter, acetylcholine regulates diverse aspects of COPD pathogenesis including bronchoconstriction, airway remodeling, mucus secretion and inflammation. Inhaled antimuscarinic drugs are a key component of therapy for COPD, as monotherapy or in combination with inhaled β2 agonists or corticosteroids. We review the evidence supporting the use of current anticholinergic agents in COPD and preview novel drugs targeting the cholinergic system and agents from other classes in clinical development, such as phosphodiesterase-4 inhibitors and monoclonal antibodies targeting inflammatory mediators.

Keywords: PDE4 inhibitors; acetylcholine; chronic obstructive pulmonary disease; inflammation; muscarinic antagonists; β2 agonists.

Figure 1

Acetylcholine in the pathogenesis of COPD. Adapted from Buels et al., 2012 [15], Kummer et al., 2008 [16], and Kolahian et al., 2012 [22].

Figure 2

Recommendations for initial bronchodilator therapy from the 2023 Global Initiative for Chronic Obstructive Lung Disease. Adapted from GOLD 2023 [1]. CAT, COPD Assessment Test; GOLD, Global Initiative for Chronic Obstructive Lung Disease; LABA, long-acting β2 agonist; LAMA, long-acting muscarinic antagonist; mMRC, modified Medical Research Council dyspnea questionnaire.

Figure 3

Beneficial effects of PDE4 inhibition in airway diseases. Adapted from Contreras et al., 2017 [62] and Joskova et al., 2020 [63]. (c)AMP, (cyclic) adenosine monophosphate; PDE4(i), phosphodiesterase-4 (inhibitor); PKa, protein kinase A.