Does Pathological Iron Overload Impair the Function of Human Lungs?

The concentration of iron in plasma, the total amount of iron in the body and the systemic distribution of iron to various tissues are subject to close homeostatic regulation by the hepatic hormone hepcidin and its receptor, the cellular iron exporter ferroportin (Ganz, 2013). In response to the low bioavailability of iron in the environment, the trace metal is highly conserved in the human organism and in laboratory animal models. Compared to the total amount of iron in the human body (2–5 g) only a small amount of dietary iron needs to be absorbed (1–2 mg/day) to compensate for very small and essentially unregulated losses. Genetic disruption of the homeostatic system that regulates dietary iron absorption, or nonphysiologic administration of exogenous iron, usually in the form of blood (~ 200 mg/unit), can lead to total body iron overload. Unchaperoned excess iron is highly reactive and catalyzes the formation of various reactive oxygen species that can injure tissues. The usual targets of iron toxicity are tissues that readily accumulate iron, including the liver, endocrine glands and the heart. Until now, the lungs appeared to be exempt from iron-mediated toxicity but this may have to be reconsidered based on the work of Neves et al. in this issue of EBioMedicine (Neves et al., 2017).

Neves et al. used a previously characterized mouse model of severe iron overload (Altamura et al., 2014), wherein ferroportin is mutated so as to abolish hepcidin binding and the regulation of dietary iron absorption. In this model, excessive iron absorption causes very severe iron overload in the liver and many other tissues. In the current study, Neves et al. show iron accumulation in several types of lung cells, including alveolar macrophages, epithelial cells lining the lung parenchyma and conducting airways, and vascular smooth muscle cells. Compared to humans, mice seem to be remarkably resistant to the toxic effects of iron, for reasons that are not well understood. Surprisingly, iron overload in the lungs appears to have measurable functional consequences including increased rigidity of the lungs and decreased blood oxygen saturation (hypoxemia). Even more surprisingly, the functional changes are not accompanied by the expected histopathological abnormalities, such as inflammation, fibrosis or vascular changes.

The finding of restrictive lung disease without readily visible microstructural abnormalities is unusual. In this context, increased lung rigidity could be caused by abnormal surfactant (Whitsett et al., 2015), the material that is secreted by type 2 alveolar cells to decrease the surface tension in the alveoli. The concomitant hypoxemia may have a more complex causation. Thinking of the lung as a highly folded-membrane separating flowing blood from flowing air, optimal oxygenation of blood in the lungs depends on close local matching of air flow and blood perfusion throughout the lung (Macintyre, 2014). The gas exchange units function in parallel. If blood flow locally exceeds air flow, not enough oxygen will be transferred across the membrane to completely saturate blood with oxygen, and overall blood oxygenation will be compromised. If local airflow is excessive compared to blood flow, ventilation needed in another part of the lung is wasted by a malfunctioning exchange unit. Thus hypoxemia without structural changes could be caused by alveoli in which ventilation by air and perfusion by blood are dynamically mismatched. Impairment of smooth muscle function in bronchioles and/or arterioles, that control air and blood flow, respectively, could cause such a mismatch between gas exchange and blood perfusion (V/Q mismatch). It is not yet known whether iron overload of smooth muscle can cause such malfunction. Alternatively, low cardiac output or the shunting of unoxygenated blood across the lungs through abnormal vascular connections could also cause hypoxemia.

What can this model teach us about human disease? Abnormal lung function has not been reported in humans with pure iron overload from genetic disorders of iron regulation. However, restrictive lung disease is common in iron-loading anemias such as β-thalassemia, whether or not the affected patients require regular blood transfusions (Piatti et al., 2006). In β-thalassemia and other hemoglobinopathies, additional factors such as hemolysis and the release of hemoglobin into blood plasma (Kato et al., 2017), may sensitize the human lungs to the effect of iron overload. The possible contribution of pulmonary iron overload to lung disease in humans with β-thalassemia may have been missed and is worth reexamining. Other diseases where similar pathogenic mechanisms could operate include sickle cell anemia and chronic hemolytic anemias. The findings by Neves et al. therefore highlight the need to reappraise lung function and pathology in a variety of diseases stemming from iron overload.

Disclosure

The author has no conflict of interest relative to the subject matter of this commentary.