Background. Elevated mean pulmonary artery pressure (mPAP) and mild-to-moderate pulmonary hypertension (PH) are typical features of COPD. However, a subset of patients develops severe pre-capillary PH with a very poor prognosis. The factors driving different PH endotypes in COPD remain unclear. Although COPD lungs exhibit a higher iron content compared to healthy controls, up to 50% of patients develop systemic iron deficiency associated with more severe PH. The role of iron and iron-associated genes and proteins (ironome) in COPD-PH is not yet understood.

Objective. We aimed to characterize the ironomes of COPD patients with moderate and severe PH.

Methods. Iron and iron-associated factors were measured in the blood and explanted lungs of healthy donors, COPD patients without PH (mPAP<20 mmHg), with moderate PH (mPAP=20-35 mmHg) and severe PH (mPAP>35 mmHg) (n=30). Microarray analysis was performed to assess the bronchial gene expression in donor and COPD lungs with moderate and severe PH (n=15).

Results. Soluble transferrin receptor-1 in the blood was correlated with mPAP only in COPD with severe PH, corresponding to the levels of transferrin receptor-1 in the lungs. Number of iron-loaded cells in COPD lungs was correlated with NT-proBNP, but did not differ between severe and moderate PH. Two distinctive patterns of iron distribution were identified in COPD lungs with severe PH: those with and without intramural iron accumulation in small vessels. Bronchial genes involved in ferrous iron binding were downregulated in COPD with severe PH compared to controls, which was not observed in those with moderate PH.

Conclusion. Ironome-based approach may better distinguish PH endotypes in COPD.