Beyond corticosteroids: future prospects in the management of inflammation in COPD

Abstract

Inflammation plays a central role in the pathophysiology of chronic obstructive pulmonary disease (COPD). Exposure to cigarette smoke induces the recruitment of inflammatory cells in the airways and stimulates innate and adaptive immune mechanisms. Airway inflammation is involved in increased bronchial wall thickness, increased bronchial smooth muscle tone, mucus hypersecretion and loss of parenchymal elastic structures. Oxidative stress impairs tissue integrity, accelerates lung ageing and reduces the efficacy of corticosteroids by decreasing levels of histone deacetylase-2. Protease-antiprotease imbalance impairs tissues and is involved in inflammatory processes. Inflammation is also present in the pulmonary artery wall and at the systemic level in COPD patients, and may be involved in COPD-associated comorbidities. Proximal airways inflammation contributes to symptoms of chronic bronchitis while distal and parenchymal inflammation relates to airflow obstruction, emphysema and hyperinflation. Basal levels of airways and systemic inflammation are increased in frequent exacerbators. Inhaled corticosteroids are much less effective in COPD than in asthma, which relates to the intrinsically poor reversibility of COPD-related airflow obstruction and to molecular mechanisms of resistance relating to oxidative stress. Ongoing research aims at developing new drugs targeting more intimately COPD-specific mechanisms of inflammation, hypersecretion and tissue destruction and repair. Among new anti-inflammatory agents, phosphodiesterase-4 inhibitors have been the first to emerge.

Figure 1.

The four main pathophysiological mechanisms involved in the alteration of bronchial structure–function relationships in chronic obstructive pulmonary disease patients. Modified from [13] with permission from the publisher.

Figure 2.

Oxidative stress and corticoresistance. Stimulation of alveolar macrophages by pro-inflammatory stimuli activates nuclear factor (NF)-κB and other transcription factors to switch on histone acetyltransferase, leading to histone acetylation and, subsequently, transcription of genes encoding pro-inflammatory chemokines. Corticosteroids reverse this by binding to glucocorticoid receptors and recruiting histone deacetylase (HDAC)2. In chronic obstructive pulmonary disease patients, cigarette smoke generates oxidative stress (acting through the formation of peroxynitrite). This impairs the activity of HDAC2. Consequently, the inflammatory response to NF-κB activation is amplified, and the anti-inflammatory effect of corticosteroids is reduced. ROS: reactive oxygen species. Modified from [17] with permission from the publisher.