iron signature in pulmonary hypertension associated with chronic obstructive pulmonary disease

Oleh MYRONENKO1, Vasile FORIS1,3, Pero CURCIC2, Andrea OLSCHEWSKI3,4, Horst OLSCHEWSKI1,3

1Division of Pulmonology, Medical University of Graz, Graz, Austria
2Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
3Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria
4Department of Anaesthesiology and Intensive Care Medicine, Medical University of Graz, Graz, Austria

Introduction. Chronic obstructive pulmonary disease (COPD) is a leading cause of high morbidity and mortality worldwide. Pulmonary hypertension (PH) is prevalent in the majority of COPD patients and can lead to right heart failure with a very poor prognosis. While COPD lungs exhibit a higher iron content in the epithelium and alveolar macrophages (AMs) compared to healthy controls, the mechanisms behind local iron overload and involvement of the pulmonary vasculature in this process are not yet clear. Moreover, up to 50% of COPD patients develop systemic iron deficiency associated with more severe PH, and IREB2 has been identified as a COPD susceptibilty gene. Conflicting results exist regarding the impact of iron on the development of experimental COPD and PH in animal models.

Objectives. We aimed to characterize circulating iron-associted factors, gender- and lung compartment-specific iron distribution, as well as presence of an "iron signature" in the transcriptomic profile of severe PH in COPD lungs. 

Results. High levels of circulating soluble transferrin receptor-1 were associated with severe PH in COPD, corresponding to the levels of transferrin receptor in the lungs. Ferric iron-loaded cells in lung sections were negatively correlated with NT-proBNP and were significantly enriched in COPD patients with moderate PH, but not severe PH. Distinctive patterns of iron distribution in COPD lungs with severe PH were identified. Transcriptomic profiling of bronchi revealed down-regulated ferrous iron binding (GO “Molecular function”), and upregulated pulmonary artery morphogenesis (GO “Biological process”) signatures in COPD with severe PH compared to controls.