Iron chelation is a potential treatment for cigarette smoke-induced COPD [PreClinical]

1. IRP2, a gene overexpressed in patients with chronic obstructive pulmonary disease (COPD), promoted mitochondrial dysfunction and increased iron loading in mice exposed to cigarette smoke (CS).

2. Deferiprone, an iron chelator, was effective both prophylactically and therapeutically in decreasing COPD pathology in mice exposed to CS.

Evidence Rating Level: 1 (Excellent)

Study Rundown: The pathogenesis of CS-induced COPD and its contributing genetic factors have not been fully characterized, therefore making it difficult to find effective treatments. In previous work, the authors performed a genome-wide association study on a cohort of COPD patients and found that IRP2 was overexpressed in the patients. This study used a variety of mouse models to determine the influence of IRP2 on COPD pathogenesis and to test a potential therapeutic approach based on IRP2’s mechanism of action.

First, the authors confirmed that IRP2 was also overexpressed in CS-induced COPD mouse models. After genetically knocking out IRP2 in mice, the animals were protected from lung damage induced by CS. These mice also developed significantly less mitochondrial damage when introduced to CS as compared with wild type (WT) mice. This damage, stimulated by IRP2 expression, was due to an increase of iron entering the mitochondria. Following this finding, the iron chelator deferiprone was administered to determine its effects on lung pathology. This drug had similar effects as genetically knocking out IRP2, providing protection from CS-induced lung damage and inflammation. Notably, deferiprone was also effective in treating established CS-induced COPD symptoms. In addition to elucidating a mechanism contributing to lung damage, this study also suggests iron chelation as a potential therapy for CS-induced COPD.

Click to read the study in Nature Medicine

Relevant reading: The role of iron in pulmonary pathology

In-Depth [animal study]: When WT mice were exposed to CS over 6 months, they showed significantly increased levels of IRP2 expression compared to animals exposed to room air (p<0.05). The authors then compared WT and Irp2^-/- mice (with the IRP2 gene knocked out) when both were exposed to CS for 1-6 months. The Irp2^-/- mice showed a decrease in IL-6 (not significant) and IL-33 (p<0.01), cytokines associated with the severity of acute COPD, along with a protection from decreased mucociliary clearance (p<0.05). The Irp2^-/- mice also showed a decrease in expression of caspase 3, MMP9, and other CS-induced injury markers.

To identify the mechanism of action of IRP2, a microarray was used to compare the transcriptomes of WT and Irp2^-/- mouse lungs. There was significant differential expression of genes related to mitochondrial function (p=1.08×10^-8). When WT and Ipr2^-/- mice were exposed to CS, cytochrome c, a marker of mitochondrial damage, was only measured in WT mice. Compared to unexposed mice, CS-exposed WT mice showed more iron deposits (p<0.01) and elevated mitoferrin 2 levels (p<0.005), a protein involved in iron transport in the mitochondria. The Irp2^-/- mice, however, were protected from both of these changes upon CS exposure.

Because of these findings, mitochondrial iron was targeted using deferiprone, an iron chelator that prevents mitochondrial iron loading. Deferiprone was administered via drinking water at 1 mg/mL. When prophylactic treatment was given concurrently alongside CS exposure, WT mice were protected from mucociliary clearance impairment (p<0.05). Therapeutic treatment for mice with established CS exposure symptoms significantly improved mucociliary impairment (p<0.01). Therapeutic treatment also reduced pulmonary inflammation as demonstrated by decreased IL-6, IL-33, and leukocyte levels.

Image: PD

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