Iron in Lung Pathology

Abstract

The lung presents a unique challenge for iron homeostasis. The entire airway is in direct contact with the environment and its iron particulate matter and iron-utilizing microbes. However, the homeostatic and adaptive mechanisms of pulmonary iron regulation are poorly understood. This review provides an overview of systemic and local lung iron regulation, as well as the roles of iron in the development of lung infections, airway disease, and lung injury. These mechanisms provide an important foundation for the ongoing development of therapeutic applications.

Keywords: COPD; acute lung injury; cystic fibrosis; hepcidin; iron; lung; lung infection.

Figure 1

Proposed scheme of lung iron homeostasis. Iron is taken up into the alveolar epithelial cells through transferrin receptor (TfR1) and DMT1, and exported through ferroportin (Fpn), which was reported to be localized on the apical/airway facing layer of the epithelium. Within the cells, iron is stored in a non-reactive state in ferritin. Though hepcidin is mostly produced in the liver for systemic circulation, local production of hepcidin has also been suggested to play a role in lung iron homeostasis. Zip8 is highly expressed in the lung and facilitates iron intake, though its specific distribution remains unknown. Inset depicts an alveolar macrophage. Macrophages phagocytose airway red blood cells to recycle iron from heme. Solid arrows indicate direction of iron transport.

Figure 2

Proposed scheme of lung iron regulation during infection and inflammation. Bacteria secrete siderophores to capture host iron. The host combats this by increasing import of iron (lactoferrin (Lfn), DMT1), decreasing export of iron through ferroportin (Fpn), and increasing iron stores through ferritin. Secreted Lfn and NGAL bind free iron and siderophore-bound iron in the airway to prevent bacterial iron uptake. Inset shows an alveolar macrophage during infection. Alveolar macrophages phagocytose bacteria as a host defense response. NRAMP1 is expressed in macrophage phagosomes and transports iron out of the phagosome to limit iron availability to pathogens. Solid arrows indicate direction of iron transport.