The future of inhalation therapy in chronic obstructive pulmonary disease

Abstract

The inhaled route is critical for the administration of drugs to treat patients suffering from COPD, but there is still an unmet need for new and innovative inhalers to address some limitations of existing products that do not make them suitable for many COPD patients. The treatment of COPD, currently limited to the use of bronchodilators, corticosteroids, and antibiotics, requires a significant expansion of the therapeutic armamentarium that is closely linked to the widening of knowledge on the pathogenesis and evolution of COPD. The great interest in the development of new drugs that may be able to interfere in the natural history of the disease is leading to the synthesis of numerous new molecules, of which however only a few have entered the stages of clinical development. On the other hand, further improvement of inhaled drug delivery could be an interesting possibility because it targets the organ of interest directly, requires significantly less drug to exert the pharmacological effect and, by lowering the amount of drug needed, reduces the cost of therapy. Unfortunately, however, the development of new inhaled drugs for use in COPD is currently too slow.

Keywords: Anti-inflammatory drugs; Antimicrobial agents; Bronchodilators; COPD; Inhalation route; Inhaler devices; Monoclonal antibodies; Vaccines.

Graphical abstract

Fig. 1

MABA dual pharmacology molecule concept of combining the mAChR antagonist and β₂-AR agonist moieties into a single molecule and synthesis of the cross-talk between the two moieties. AC: adenylyl cyclase; ACh: acetylcholine; cAMP: cyclic adenosine monophosphate; ERK: extracellular signal-regulated kinase; GR: glucocorticoid receptor; IP₃: inositol-3-phosphate; KCa⁺⁺: calcium-activated potassium channel; mAChR: muscarinic ACh receptor; MAPK: p38 mitogen-activated protein kinase; MLCP: myosin light chain phosphatase; PKA: protein kinase A; PKC, protein kinase C; PLC: phospholipase C; β₂-AR: β₂-adrenoceptor. Solid line, activation; dotted line, inhibition.

Fig. 2

Combined inhibition of phosphodiesterase (PDE)3 and PDE4 has additive and synergistic anti-inflammatory and bronchodilatory effects versus inhibition of either PDE3 or PDE4 alone. Furthermore, it increases mucociliary clearance. In red, the main PDE involved in the activity of the specific cell (Matera et al., 2021c). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 3

Schematic representation of the roles of phosphoinositide 3-kinase (PI3K)γ and PI3Kδ signaling in selected cells important or potentially important in COPD. PI(4,5)P₂: phosphatidylinositol (4,5)-bisphosphate; PI(3,4,5)P₃: phosphatidylinositol-3,4,5-triphosphate; TCR: T-cell receptor; ROS: reactive oxygen species; GC: glucocorticoid.

Fig. 4

The p38 MAPK pathway, which is activated by a wide variety of stimuli, is crucial in inflammation, cell death and cell proliferation, and therefore has been implicated in many cellular events relevant to COPD pathophysiology. In particular, p38 signaling pathway induces the release of proinflammatory cytokines and chemokines (IL-1β, IL-8, TNF-α), which together with other mediators (IL-17A and IL-17 ​F) produced by Th17 and ILC3 cells contribute to recruitment and activation of neutrophils. These findings support the pharmacological rationale for targeting p38 MAPK.

Fig. 5

Neutrophil elastase (NE) and metalloproteinases (MMP-9 and MMP-12) are implicated in COPD so that blocking a single enzyme with a NE inhibitor or a MMP inhibitor may not have a major therapeutic effect. Α1-Antitrypsin (AAT) inhibits NE and suppresses MMP-12 production by macrophages (Matera et al., 2021c).