Neves et al used a previously characterized mouse model

Neves et al. used a previously characterized mouse model of severe iron overload (), wherein ferroportin is mutated so as to abolish hepcidin binding and the regulation of dietary iron absorption. In this model, excessive iron AG 013736 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 (), 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 (). 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 (). In β-thalassemia and other hemoglobinopathies, additional factors such as hemolysis and the release of hemoglobin into blood plasma (), 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
Krüppel-like factors (KLFs) belong to the family of 17 transcription factors that contain conserved zinc finger domains involved in binding to target DNA sequences. Many of these proteins are expressed in different tissues and have distinct tissue-specific activities and functions (). KLFs regulate many physiological processes such as growth, development, differentiation, proliferation, and embryogenesis.