Critical role for iron accumulation in the pathogenesis of fibrotic lung disease

Abstract

Increased iron levels and dysregulated iron homeostasis, or both, occur in several lung diseases. Here, the effects of iron accumulation on the pathogenesis of pulmonary fibrosis and associated lung function decline was investigated using a combination of murine models of iron overload and bleomycin-induced pulmonary fibrosis, primary human lung fibroblasts treated with iron, and histological samples from patients with or without idiopathic pulmonary fibrosis (IPF). Iron levels are significantly increased in iron overloaded transferrin receptor 2 (Tfr2) mutant mice and homeostatic iron regulator (Hfe) gene-deficient mice and this is associated with increases in airway fibrosis and reduced lung function. Furthermore, fibrosis and lung function decline are associated with pulmonary iron accumulation in bleomycin-induced pulmonary fibrosis. In addition, we show that iron accumulation is increased in lung sections from patients with IPF and that human lung fibroblasts show greater proliferation and cytokine and extracellular matrix responses when exposed to increased iron levels. Significantly, we show that intranasal treatment with the iron chelator, deferoxamine (DFO), from the time when pulmonary iron levels accumulate, prevents airway fibrosis and decline in lung function in experimental pulmonary fibrosis. Pulmonary fibrosis is associated with an increase in Tfr1 + macrophages that display altered phenotype in disease, and DFO treatment modified the abundance of these cells. These experimental and clinical data demonstrate that increased accumulation of pulmonary iron plays a key role in the pathogenesis of pulmonary fibrosis and lung function decline. Furthermore, these data highlight the potential for the therapeutic targeting of increased pulmonary iron in the treatment of fibrotic lung diseases such as IPF.

Animal and translational models of SARS-CoV-2 infection and COVID-19

“…Multiple sections can be obtained from a single lung, including human, 227 Rhesus Macaques, 228 marmosets 229 and mice. 230 – 232 SARS-CoV-2 replication in PCLS has not been established, but other viruses such as Adenovirus Type-7 can replicate in human, 233 swine IAV can replicate in pig 234 and respiratory syncytial virus can replicate in mouse PCLS. 235 The complexity of PCLS maintaining all cell types in their in vivo configuration is an advantage other culture techniques and the ability to directly compare between species is translational.…”

Study of Antioxidant Properties of Agents from the Perspective of Their Action Mechanisms

“…Thus, the study of the chelating properties of biocompounds can also serve as a good approach in the study of antioxidant properties. This is confirmed by numerous studies of the relationship between increased levels of free iron ions in humans and animals with increased risk of various diseases, such as vascular diseases, cancer, and some neurological conditions [ 144 , 145 , 146 , 147 , 148 ].…”

COVID-19 and iron dysregulation: distant sequence similarity between hepcidin and the novel coronavirus spike glycoprotein

“…It may also be important to point to a number of circumstantial but perhaps important findings in the literature pertaining to lung disease. These include (i) a link between SARS and liver function abnormalities [ 74 ], (ii) the association of pulmonary iron overload and restrictive lung disease [ 49 , 90 , 91 ], (iii) the role of iron in pulmonary fibrosis [ 3 ], (iv) hepcidin’s modulation of the proliferation of pulmonary artery smooth muscle cells [ 107 ], and (v) the vital role of hepcidin in alveolar macrophage function [ 98 ]. Furthermore, (vi) hepcidin upregulation along with serum iron reduction has been reported in influenza infections [ 10 , 45 ].…”