Chronic occlusive pulmonary disease (COPD) is a common, progressive condition associated with considerable symptom burden for patients, and cost implications for society. Current therapies are of limited benefit. This talk will highlight the rationale behind the novel use of an established therapy, intravenous iron. The pulmonary circulation as a therapeutic target Current COPD therapies have focused on the airways. Consideration of the pulmonary circulation remains a neglected area, despite the fact that in COPD pulmonary hypertension and increased pulmonary vascular resistance are associated with increased hospitalisation(Kessler, Faller et al. 1999) and mortality (Burrows, Kettel et al. 1972) and decreased exercise capacity (Sims, Margolis et al. 2009). Furthermore pulmonary hypertension with a mean pulmonary vascular pressure >20mmHg is common at around 1/3 at rest (Weitzenblum, Hirth et al. 1981; Doia, Nakanob et al. 2003) and 2/3 on exercise (Oswald-Mammosser, Apprill et al. 1991; Christensen, Ryg et al. 2004), and pulmonary vascular resistance is almost universally raised (Burrows, Kettel et al. 1972). Therapies to optimise the pulmonary circulation may therefore reduce morbidity and mortality in COPD. Candidates for pulmonary circulation optimisation As yet, drugs used with success in idiopathic pulmonary hypertension, such as the endothelin-1 antagonist, Bosentan, have not been effective in pulmonary hypertension of COPD (Stolz, Rasch et al. 2008). Furthermore, Bosentan worsens oxygenation in COPD, due to worsening ventilation: perfusion matching (Stolz, Rasch et al. 2008). In hypoxic COPD patients long term oxygen therapy is the only therapy that has been shown to reduce mortality (1980; 1981) and ameliorate pulmonary hypertension (1981; Weitzenblum, Sautegeau et al. 1985) and raised pulmonary vascular resistance(1980; 1981; Weitzenblum, Sautegeau et al. 1985). A limitation of long term oxygen therapy is that it is only associated with mild improvements in pulmonary haemodynamics in COPD (1980; 1981). This is because there is no reversal of pulmonary vascular remodeling (Wilkinson, Langhorne et al. 1988), which contributes to pulmonary hypertension through narrowing of small and precapillary arteries (Peinado, Pizarro et al. 2008). This difference may be in part because long term oxygen therapy is non-continuous, tending to be used for 15 hours a day. Alternative agents are therefore urgently sought. We propose iron could be an alternative effective therapy. Rationale for the use of intravenous iron We have recently demonstrated for the first time that the normal pulmonary vascular pressure rise in response to hypoxia is iron dependent; first, intravenous iron blunts the usual acute hypoxic pulmonary vasoconstriction after 8 hours (Smith, Balanos et al. 2008), and one week’s (Smith, Talbot et al. 2009) hypoxic exposure in healthy volunteers. Secondly, lowering iron availability using iron chelation over 8 hours (Smith, Balanos et al. 2008), or venesection of high altitude residents with chronic mountain sickness (Smith, Talbot et al. 2009) augments hypoxic pulmonary vasoconstriction. These effects of iron are plausible, as there is a strong biochemical rationale for interplay between oxygen and iron, potentially acting via the hypoxia inducible factor (HIF) pathway. HIF is a family of transcription factors that controls hundreds of genes involved in oxygen sensing and delivery. One of its effects is development of pulmonary hypertension, as observed by our group in patients with the rare genetic disorder, Chuvash polycythaemia, in which HIF-mediated gene activation is pathologically increased (Smith, Brooks et al. 2006). Control of HIF is by degradation of the HIF-alpha subunit by prolyl hydroxylases. This is an iron dependent process(Ivan, Kondo et al. 2001; Jaakkola, Mole et al. 2001; Yu, White et al. 2001), hence iron deficiency may up regulate but iron supplementation down regulate HIF activity. The future challenges Future challenges include optimal assessment techniques in COPD patients, in whom non-invasive pulmonary vascular measures are suboptimal and elucidating molecular mechanisms by which iron affects the pulmonary circulation.