How inhaled corticosteroids target inflammation in COPD

Abstract

Inhaled corticosteroids (ICS) are the most commonly used anti-inflammatory drugs for the treatment of COPD. COPD has been previously described as a “corticosteroid-resistant” condition, but current clinical trial evidence shows that selected COPD patients, namely those with increased exacerbation risk plus higher blood eosinophil count (BEC), can benefit from ICS treatment. This review describes the components of inflammation modulated by ICS in COPD and the reasons for the variation in response to ICS between individuals. There are corticosteroid-insensitive inflammatory pathways in COPD, such as bacteria-induced macrophage interleukin-8 production and resultant neutrophil recruitment, but also corticosteroid-sensitive pathways including the reduction of type 2 markers and mast cell numbers. The review also describes the mechanisms whereby ICS can skew the lung microbiome, with reduced diversity and increased relative abundance, towards an excess of proteobacteria. BEC is a biomarker used to enable the selective use of ICS in COPD, but the clinical outcome in an individual is decided by a complex interacting network involving the microbiome and airway inflammation.

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.…”

“…Inhaled corticosteroids, which are the most commonly used anti-inflammatory treatment in COPD, have proven to be beneficial for the prevention of exacerbations in select patients when combined with a long-acting β-agonist (LABA) or a LABA and a long-acting muscarinic antagonist (LAMA) [12]. However, corticosteroids, by virtue of their mechanism of action, do not target all inflammatory pathways active in COPD (figure 3) [103,104]. Indeed, even at high doses, inhaled corticosteroids do not reduce neutrophil counts in the sputum of patients with COPD [105].…”

Inhaled Corticosteroids in Subjects with Chronic Obstructive Pulmonary Disease: An Old, Unfinished History

“…It is increasingly recognized that COPD progression and exacerbation frequency, even in the early phases, are linked to the composition of the lung microbiome [52,53]. In addition, COPD subjects can modify the lung microbiome and acquire neutrophilic or eosinophilic inflammatory predominant patterns during exacerbations [52][53][54][55][56]. The lung microbiome may also influence the sensitivity to ICS.…”

Eosinophils and therapeutic responses to steroids and biologics in COPD: a complex relationship

“…There is also speculation that the benefits of IL-33 blockade might be influenced by a complex interacting network involving the microbiome and airway inflammation. 29 Eosinophilia observed in blood (or even in sputum) may not always be a pathological process but could also be a reflection of airway microbial dysbiosis 30 that could also be modulated by inhaled or oral corticosteroids. The association between airway eosinophilia in COPD and mixed viral and bacterial infections was demonstrated almost two decades ago, 31 and this may not be critically dependent on IL-5.…”

“…Também há especulações de que os benefícios do bloqueio da IL-33 possam ser influenciados por uma complexa rede de interação entre o microbioma e a inflamação das vias aéreas. (29) A eosinofilia observada no sangue (ou mesmo no escarro) pode nem sempre ser um processo patológico, mas pode também ser um reflexo da disbiose microbiana das vias aéreas (30) que pode também ser modulada por corticosteroides inalatórios ou orais. A associação entre eosinofilia das vias aéreas na DPOC e infecções mistas virais e bacterianas foi demonstrada há quase duas décadas, (31) e isso pode não ser criticamente dependente da IL-5.…”