Inflammation in COPD

COPD is associated with a chronic inflammation of the airways and lung parenchyma, characterised by increased numbers of neutrophils, activated macrophages and activated T-lymphocytes (Tc1 and Th1 cells). The inflammation in COPD lungs is amplified compared with that seen in normal smokers and the molecular basis for this amplification are now better understood, providing novel targets for future therapies. Macrophages are markedly increased in COPD and these cells play a key role in recruiting other inflammatory cells and in releasing mediators and proteases. Macrophages in the lung are recruited from circulating monocytes by chemotactic factors, such as CXCL1 and CCL2. The inflammatory changes in COPD are due to the release of multiple inflammatory mediators, including lipid mediators, cytokines and chemokines. Activated macrophages and neutrophils release elastolytic enzymes, particularly MMP-9, that result in emphysema. In addition, Tc1 cells may induce the destruction of alveolar cells to promote emphysema. Small airway narrowing and fibrosis appear to be the major mechanism contributing to airflow limitation and air trapping, but the mechanisms of fibrosis are poorly understood. In sharp contrast to asthma, the inflammation in COPD shows little response to corticosteroids. This steroid resistance may be explained by reduced activity of a key nuclear enzyme histone deacetylase-2 (HDAC2), which also accounts for the amplified inflammation in COPD. HDAC2 is reduced by oxidative stress through the activation of phosphoinisitide-3-kinase-δ (PI3K-δ). Low concentrations of theophylline restore the low levels of HDAC2 levels in COPD macrophages to normal and reverse steroid resistance in vitro and in vivo by blocking PI3K-δ. These studies may lead to new therapeutic approaches with the use of low dose theophylline and in the future PI3K-δ selective inhibitors to reverse corticosteroid resistance.