What is the central question of this study? The aim was to explore the role and hitherto unclear mechanisms of action of
iron proteins in protecting the lung against the harmful effects of
iron accumulation and the ability of pulmonary cells to mobilize
iron in
iron deficiency. What is the main finding and its importance? We show that pulmonary
hepcidin appears not to modify cellular
iron mobilization in the lung. We propose pathways for supplying
iron to the lung in
iron deficiency and for protecting the lung against
iron excess in
iron overload, mediated by the co-ordinated action of
iron proteins, such as divalent
metal transporter 1, ZRT-IRE-like-
protein 14,
transferrin receptor,
ferritin,
haemochromatosis-associated
protein and
ferroportin.
Iron dyshomeostasis is associated with several forms of chronic
lung disease, but its mechanisms of action remain to be elucidated. The aim of the present study was to determine the role of the lung in whole-animal models with
iron deficiency and
iron overload, studying the divalent
metal transporter 1 (DMT1), ZRT-IRE-like
protein 14 (ZIP14),
transferrin receptor (TfR),
haemochromatosis-associated
protein (HFE),
hepcidin,
ferritin and
ferroportin (FPN) expression. In each model, adult CF1 mice were divided into the following groups (six mice per group): (i)
iron-overload model,
iron saccharate i.p. and control group (
iron adequate),
0.9% NaCl i.p.; and (ii)
iron-deficiency model, induced by repeated
bleeding, and control group (
sham operated).
Proteins were assessed by immunohistochemistry and Western blot. In control mice, DMT1 was localized in the cytoplasm of airway cells, and in
iron deficiency and overload it was in the apical membrane. Divalent
metal transporter 1 and TfR increased in
iron deficiency, without changes in
iron overload. ZRT-IRE-like
protein 14 decreased in airway cells in
iron deficiency and increased in
iron overload. In
iron deficiency, HFE and FPN were immunolocalized close to the apical membrane.
Ferroportin increased in
iron overload.
Prohepcidin was present in control groups, with no changes in
iron deficiency and
iron overload. In
iron overload,
ferritin showed intracytoplasmic localization close to the apical membrane of airway cells and intense immunostaining in macrophage-like cells. The results show that pulmonary
hepcidin does not appear to modify cellular
iron mobilization in the lung. We propose the following two novel pathways in the lung: (i) for supplying
iron in
iron deficiency, mediated principally by DMT1 and TfR and regulated by the action of FPN and HFE; and (ii) for
iron detoxification in order to protect the lung against
iron overload, facilitated by the action of DMT1, ZIP14, FPN and
ferritin.