Dysregulated iron metabolism in remodeling of aging asthmatic human airways

Iron is essential for cellular function, and lung cells are no exception. Previous studies have demonstrated an association between increased level of iron in the lung and aging and age-related lung diseases, including pulmonary fibrosis and asthma in the elderly (AIE). However, the mechanisms underlying the accumulation of iron with aging or AIE, or the cell types involved, remain understudied. In the context of asthma, airway smooth muscle is a key cell type contributing to contractility as well as airway remodeling (proliferation, fibrosis). In this study, we characterized iron levels and regulation in human airway smooth muscle cells (hASMs) from young (<45 yr), old (≥65 yr), and AIE (≥65 yr) male/female patients, and investigated the contribution of iron overload in hASM to airway remodeling. Cells were treated with ferric ammonium citrate (FAC; 100 μM; 72 h) or iron chelator deferoxamine (DFO; 100 µM; 72 h). Basal levels of intracellular ferrous iron (Fe²⁺) were determined using the fluorescent dye FerroOrange. Cell lysates were analyzed for iron accumulation, antioxidant, lipid peroxidation, and extracellular matrix (ECM) markers, and cell proliferation was assessed. We found that iron accumulates with aging, but surprisingly decreases with AIE. hASM from AIE patients showed activated antioxidant pathways and lipid peroxidation, whereas FAC exposure impaired iron metabolism and enhanced ECM deposition. Iron depletion mitigated the antioxidant response, lipid peroxidation, cell proliferation, and ECM production. These findings suggest that iron metabolism in hASM contributes to cell hyperplasia and ECM remodeling, whereas in aging and particularly AIE, counter-regulatory changes in iron metabolism and antioxidant pathways occur, overall promoting airway remodeling.NEW & NOTEWORTHY Iron is an essential element for cellular homeostasis and functionality. Increased iron in the lung is associated with aging and asthma in the elderly (AIE). Using human airway smooth muscle cells from young versus elderly versus AIE patients, we found that dysregulated iron metabolism (more than iron accumulation), resulting in activation of antioxidant systems and increased susceptibility to ferroptosis, occurs in AIE, contributing to cell hyperplasia and matrix remodeling of aging and AIE.