Increased release of ferritin and iron by iron-loaded alveolar macrophages in cigarette smokers

The lower respiratory tract of cigarette smokers contains an increased amount of iron that is predominantly sequestered within alveolar macrophages (AM), but is also present in alveolar epithelial fluid. Extracellular ferritin-bound iron could potentially be released by reductants present in cigarette smoke and catalyze generation of highly reactive hydroxyl radicals capable of causing oxidant injury. To determine whether AM are a source of alveolar extracellular ferritin and iron, we assessed in vitro release of iron, ferritin, and transferrin by AM recovered by bronchoalveolar lavage (BAL) of 27 healthy subjects including nine nonsmokers (NS), nine light smokers (LS), and nine heavy smokers (HS). Release of iron in vitro over 20 h was increased in AM recovered from LS (2.24 ± 0.21 nmol/10⁶ AM/20 h, p < 0.001) and HS (3.11 ± 0.32 nmol/10⁶ AM, p < 0.001) compared with NS (1.28 ± 0.08 nmol/10⁶ AM). Release of ferritin in vitro over 20 h was also increased in AM recovered from LS (71 ± 24 ng/10⁶ AM, p < 0.05) and HS (176 ± 35 ng/10⁶, p < 0.001) compared with NS (18 ± 3 ng/10⁶ AM). AM recovered from 12 smokers (8 HS, 4 LS) contained greater than 10 nmol of iron per 10⁶ cells. These iron-loaded AM released a greater percentage of cell ferritin stores in vitro over 4 h (8.4% ± 1.1, p < 0.01) than did AM from NS (3.2% ± 0.6). Release of lactate dehydrogenase (LDH) over 4 h was substantially less (2.9% ± 0.3, p < 0.001) than ferritin release. Ferritin release by AM in vitro over 20 h correlated with concentrations of ferritin present in BAL fluid (r = 0.80, p < 0.001) for all subjects. Transferrin release in vitro by AM from each group was similar. These data suggest that high concentrations of extracellular ferritin and iron in alveolar structures of some cigarette smokers may be derived, in part, from release of ferritin and iron by iron- loaded AM.