Abstract

The current definition of COPD as a single disease entity associated with old age and a focus on smoking has resulted in knowledge gaps that may have prevented the development of novel drug therapies. Gaps include the different disease trajectories and probable mechanisms of different COPD subtypes. Excess inflammation and altered immunity is observed in most types of inflammation but despite this knowledge we still have no good anti-inflammatory drugs in the COPD armamentarium. Inhaled corticosteroids are effective in a subset of COPD although the characteristics that identify these patients is unclear although there may be a link with IL-33-stimulated mast cells which supports Phase II clinical data. Type 2 (T2) inflammation-directed antibody therapy that successfully treat many patients with severe asthma have proved ineffective in COPD studies but preclinical data supports a role for IL-13 and IL-22 and also common downstream signalling pathways including JAK-STAT as potential novel therapies in COPD. There is a plethora of preclinical and human cell data supporting a key role the involvement of various epigenetic factors in COPD pathophysiology. Animal models of COPD demonstrate the potential of bromodomain mimics, particularly if delivered via the inhaled route for future development. Cellular senescence is a characteristic of diseases of premature ageing as seen in COPD. Recent preclinical evidence in mouse models and in COPD primary cell models indicate the potential for repurposing drugs used to treat pulmonary hypertension as well as novel targets such as the lymphytoxin beta receptor. Further refinement of the current disease models, greater use of human primary cells and testing of drugs in selected patient subtypes will improve success in clinical trials.