Smoking-induced iron dysregulation in the lung

Abstract

Iron is one of the most abundant transition elements and is indispensable for almost all organisms. While the ability of iron to participate in redox chemistry is an essential requirement for participation in a range of vital enzymatic reactions, this same feature of iron also makes it dangerous in the generation of hydroxyl radicals and superoxide anions. Given the high local oxygen tensions in the lung, the regulation of iron acquisition, utilization, and storage therefore becomes vitally important, perhaps more so than in any other biological system. Iron plays a critical role in the biology of essentially every cell type in the lung, and in particular, changes in iron levels have important ramifications on immune function and the local lung microenvironment. There is substantial evidence that cigarette smoke causes iron dysregulation, with the implication that iron may be the link between smoking and smoking-related lung diseases. A better understanding of the connection between cigarette smoke, iron, and respiratory diseases will help to elucidate pathogenic mechanisms and aid in the identification of novel therapeutic targets.

Keywords: Cigarette smoke; Iron; Lung disease.

Figure 1.

In eukaryotes, iron acquisition is mediated through metal or metal-siderophore transporters transferrin receptor, Solute Carrier Family 39 Member 8 (SLC39A8 or ZIP8), Solute Carrier Family 39 Member 14 (SLC39A14 or ZIP14), Solute Carrier Family 11 Member 2 (SLC11A2 or DMT1), the heme receptors/transporters LDL receptor-related protein 1 (LRP1), Solute Carrier Family 48 Member 1 (SLC48A1 or HRG1) and Feline Leukemia Virus Subgroup C Cellular Receptor Family (FLVCR2). Once inside the cell, iron must be transported to sites of utilization such as the mitochondria (heme and Fe-S cluster synthesis), storage into the iron storage protein ferritin or into the lysosome to protect cells against iron toxicity. Poly C binding proteins (PCBP) act as iron chaperones that assists in the mineralization of ferritin. Nuclear receptor coactivator 4 (NCOA4) protein assists in the release of iron from ferritin through an autophagy-mediated mechanism. Iron is exported from the cell by ferroportin1 (FPN1).

Figure 2.. Iron import and export in the lung and disruption upon smoke exposure.

The lung obtains its iron from the microenvironment along with the pulmonary vasculature. Both alveolar macrophages and the bronchial and alveolar epithelia are able to sequester iron through transferrin receptor 1 (TFRC1), divalent metal transporter 1 (DMT1, also known as SLC11A2), and in macrophages and neutrophils by natural resistance-associated macrophage protein 1 (NRAMP1, also known as SLC11A1). Lung cells also express other iron uptake molecules including ZIP-14 (also known as SLC39A14), and the lactoferrin receptor, low-density lipoprotein receptor-related protein 1 (LRP1). Lung epithelial cells, alveolar macrophages and endothelial cells transport iron out of the cell via the transmembrane iron transporter ferroportin (also known as SLC40A1). Cigarette smoking alters many molecules involved in iron metabolism on lung epithelial cells, alveolar macrophages and possibly endothelial cells.