A Role of Iron in the Pathogenesis of Idiopathic Pulmonary Fibrosis

Iron is a trace element indispensable for nearly all living organisms and participates in a variety of biological processes, including electron transport, oxygen transport, and DNA synthesis. On the other hand, excessive iron can result in tissue damage due to the formation of free radicals. Abnormal iron homeostasis causes a broad spectrum of human diseases. A number of studies suggest that iron is associated with pulmonary fibrosis. However, it is still unclear about molecular mechanisms of iron action in the pathogenesis of pulmonary fibrosis. In the present study, we aimed to investigate the effects of iron on fibroblast activation and global gene expression in pulmonary fibroblasts. LL29 lung fibroblasts were treated with desferrioxamine (DFX) to deplete iron in the cells. Real‐time PCR showed that iron depletion by DFX suppressed TGFβ‐induced mRNA expression of collagens (COL1A1, COL3A1, COL4A1), α‐smooth muscle actin, and fibronectin mRNA expression. To explore the molecular mechanisms of iron action on fibroblast activation, RNA sequencing was employed to study the effects of iron on gene expression profile in LL29 fibroblasts. The expression of 1,203 mRNAs and 198 lncRNAs were found to be significantly changed by DFX. Gene ontology and functional annotation analyses indicated that iron‐downregulated mRNAs were involved in TGFβ and HIF signaling pathways and iron‐upregulated mRNAs were involved in the regulation of cell cycle. Moreover, functional annotation analyses showed that iron‐dysregulated lncRNAs were involved in the regulation of cell proliferation. Iron‐controlled SMURF2, DBF4, and MCM6 genes which contain potential iron response elements were further verified by real‐time PCR. These results suggest that iron may control fibroblast activation by regulating TGFβ signaling pathway and fibroblast proliferation by regulating cell cycle genes. Support or Funding Information NIH R01HL116876, 1R01HL135152, and P20GM103648 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .