Dysregulated iron metabolism associates with neutrophilic airway inflammation in COPD

Pulmonary iron levels are increased in chronic obstructive pulmonary disease (COPD), possibly due to increased red blood cell leakage from the microvasculature. Neutrophils cause endothelial cell damage which may cause vascular dysfunction and iron dysregulation in COPD. We investigate the relationships between neutrophilic inflammation, iron metabolism and vascular dysfunction in COPD. Using gene and protein analysis, associations between neutrophilic inflammation, iron dysregulation and vascular dysfunction were investigated in two COPD bronchoscopy cohorts: EvA (n=51) and Manchester (n=33). Patients were sub-grouped based on bronchoalveolar lavage (BAL) neutrophil percentage (neutrophilhigh≥3% and neutrophillow<3%). Heme was measured in BAL by LC-MS. BAL cell gene expression of neutrophilic inflammation markers such as C-X-C Motif Chemokine Ligand 8 (CXCL8) and interleukin 6 receptor (IL6R) were significantly increased in neutrophilhigh compared with neutrophillow patients in both cohorts; fold change (FC) differences 1.06-17. We found increased markers of iron and iron trafficking including lactoferrin (LTF), lipocalin-2 (LCN2) and myoglobin (MB) in neutrophilhigh patients in both cohorts. BAL cell gene expression and BAL fluid protein levels of the vascular dysfunction marker, vascular endothelial growth factor (VEGF), were significantly higher in neutrophilhigh compared with neutrophillow patients. Fibrinogen and heme were significantly increased in neutrophilhigh BAL fluid. In vitro experiments revealed that blood neutrophils had significantly increased expression of LTF and VEGFA following LPS-stimulation and heme induces endothelial dysfunction. COPD patients with distal lung neutrophilic inflammation have dysregulated iron metabolism which may be a consequence of increased vascular leakage into the airways.