What Does the Future Hold for the Therapy of COPD?

Current therapies for COPD fail to prevent disease progression or mortality. The mainstay of current drug therapy is long-acting bronchodilators; several longer-acting inhaled β2-agonists and muscarinic antagonists (and combinations) are now in development. No treatments have so far been shown to suppress chronic inflammation in COPD lungs. With better understanding of the inflammatory and destructive process in the pathophysiology of COPD, several new therapeutic targets have been identified. Several mediator antagonists tested in COPD have so far been disappointing, but CXCR2 antagonists that block pulmonary neutrophil and monocyte recruitment may be more promising. Broad-spectrum anti-inflammatory drugs may be more effective and include inhibitors of the enzymes phosphodiesterase-4, p38 mitogen-activated protein kinase, NF-κB kinase and PI3 kinase-γ and PI3 kinase-δ, but side effects will be a major limitation with systemic administration, so that inhaled delivery may be necessary. Perhaps the most promising approach is reversal of corticosteroid resistance through increasing histone deacetylase-2 (HDAC2) activity. This might be achieved by theophylline-like drugs, selective PI3 kinase-δ inhibitors, more effective antioxidants and nonantibiotic macrolides.