Novel Anti-Inflammatory Approaches to COPD

Abstract

Airway inflammation, driven by different types of inflammatory cells and mediators, plays a fundamental role in COPD and its progression. Neutrophils, eosinophils, macrophages, and CD4 + and CD8 + T lymphocytes are key players in this process, although the extent of their participation varies according to the patient's endotype. Anti-inflammatory medications may modify the natural history and progression of COPD. However, since airway inflammation in COPD is relatively resistant to corticosteroid therapy, innovative pharmacological anti-inflammatory approaches are required. The heterogeneity of inflammatory cells and mediators in annethe different COPD endo-phenotypes requires the development of specific pharmacologic agents. Indeed, over the past two decades, several mechanisms that influence the influx and/or activity of inflammatory cells in the airways and lung parenchyma have been identified. Several of these molecules have been tested in vitro models and in vivo in laboratory animals, but only a few have been studied in humans. Although early studies have not been encouraging, useful information emerged suggesting that some of these agents may need to be further tested in specific subgroups of patients, hopefully leading to a more personalized approach to treating COPD.

What every clinician should know about inflammation in COPD

“…IL, interleukin; ILC3, type 3 innate lymphoid cells; LTB4, leukotriene B4; MAPK, mitogen-activated protein kinase; MCP-1, monocyte chemoattractant protein-1; MIP-1α, macrophage inflammatory protein-1α; MMPs, matrix metalloproteinases; MPO, myeloperoxidase; NE, neutrophil elastase; PGP, proline-glycine-proline; TGF-β, transforming growth factor-β; TNF-α, tumour necrosis factor-α. [103,104,111,112,114,119]. ICS, inhaled corticosteroids; IL, interleukin; ILC2, type 2 innate lymphoid cell; LAMA, longacting muscarinic antagonist; PDE, phosphodiesterase; TSLP, thymic stromal lymphopoietin.…”

“…There are, however, several biologic therapies in development for COPD. In this section, we will discuss those that have reached phase 3 clinical development, including mepolizumab, benralizumab, dupilumab, itepekimab, and tozorakimab [114]. As with asthma, the majority of therapies in late-stage development target elements known to be involved in type 2 inflammation, such as IL-5, IL-4, and IL-13.…”

“…Overall, the results of clinical trials have been mixed. The monoclonal antibodies mepolizumab and benralizumab reduce or deplete eosinophils by inhibiting IL-5 signalling (figure 3) [114,119], a major player in the recruitment, proliferation, maturation, and activation of eosinophils [67].Although increases in IL-5 have been observed in patients with COPD and eosinophilia [89], mepolizumab and benralizumab have not been effective in treating COPD. Two phase 3, randomized, double-blind, placebo-controlled clinical trials (METREX and METREO) have been conducted with mepolizumab as an add-on therapy in a total of 837 patients with COPD and a history of moderate or severe exacerbations while receiving triple therapy that included a high-dose inhaled corticosteroid [115].…”

“…The reproducibility of these findings is being evaluated in a second phase 3 study of dupilumab in COPD, which is due for completion in 2024 (NOTUS; NCT04456673). Two biologic therapies that target type 1 and type 2 inflammation are currently in development, itepekimab and tozorakimab, both of which target IL-33 (figure 3) [114]. A phase 2a, randomized, double-blind, placebo-controlled, proof-of-concept study of itepekimab in patients with moderate-to-severe COPD failed to meet its primary endpoint, reduction in the annualized rate of moderate to severe exacerbations in patients treated with itepekimab versus placebo [125].…”

“…PDE inhibitors exert their effects by preventing the hydrolysis of cyclic adenosine monophosphate (cAMP) to AMP or cyclic guanosine monophosphate (cGMP) to GMP [114]. cAMP serves as a second messenger involved in multiple pathways that regulate inflammation [130].…”