Pfeffer-Kleemann, Daniel A.

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.

Iron is an important metal element regulating biological processes such as gene expression, electron transport, cell proliferation, differentiation and division, and cellular respiration. Regulation of iron levels is therefore critical, with excess iron accumulation leading to iron-dependent lipid peroxidation and cell death (ferroptosis). Factors such as aging and environmental exposures (e.g., high/low oxygen, particulate iron) can disrupt iron homeostasis. Iron-dependent processes influence downstream pathways such as inflammation, mitochondrial energetics, and remodeling (proliferation, fibrosis), pathways involved in lung diseases particularly at the extremes of age, from hyperoxic lung injury in neonates to chronic diseases such as asthma, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis (PF) that increase with age. Although these diseases involve structural and functional changes in bronchial versus alveolar compartments, including airway hyperreactivity, altered mucus production, cell proliferation and migration, increased extracellular matrix (ECM) remodeling, senescence, and metabolic dysregulation, the casual or consequential links between iron dysregulation and disease pathology, particularly with aging, are still being investigated. The aim of this topical review is to 1) highlight current knowledge regarding iron regulation in normal lung versus lung diseases, 2) identify known roles of iron in lung homeostasis and the contribution of iron dysregulation in lung diseases with aging, and 3) explore the potential benefit of targeting iron regulation and/or ferroptosis in lung diseases.

ABSTRACT Supplemental oxygen (hyperoxia), often provided to premature infants, can disrupt lung growth and contribute to development of neonatal and pediatric lung diseases, necessitating understanding of underlying mechanisms. We previously showed that even moderate hyperoxia (< 60% O 2 ) induces detrimental cellular senescence in 18–22 weeks human fetal airway smooth muscle (fASM), a key cell type in airway contractility and remodeling. In this study, we examined the ability of senotherapeutics Fucoidan and Dasatinib (D) + Quercetin (Q) (D + Q) to mitigate adverse effects of hyperoxia and assessed the preventive effect of mitochondrial antioxidants (MitoQ). fASM cells exposed to normoxia (21% O 2 ) or hyperoxia (50% O 2 ) were treated with Fucoidan [100 μg/mL], D + Q [250 nM + 375 nM] or MitoQ [100 nM] and assessed for senescence markers, senescence‐associated secretory profile (SASP), extracellular matrix (ECM) deposition, and cell viability. Our results showed that moderate hyperoxia increases senescence markers and SASP. Fucoidan decreased p21 expression and inhibited SASP release without inducing cell death, while D + Q decreased β‐galactosidase (β‐Gal) activity, p21 and plasminogen activator inhibitor‐1 (PAI‐1) expression, and caused cell death without affecting SASP in hyperoxia‐induced senescent fASM. MitoQ prevented increases in senescence markers and SASP in hyperoxia‐exposed fASM. These findings demonstrate distinct and viable strategies to counter hyperoxia‐induced fASM senescence. Fucoidan (senomorphic), D + Q (senolytic), and MitoQ (prophylactic antioxidant) represent promising, mechanistically different approaches to alleviate detrimental effects of moderate hyperoxia in developing airways towards limiting perinatal lung disease.