Emerging Roles of the Iron Chelators in Inflammation.

Iron is a crucial element for mammalian cells, considering its intervention in several physiologic processes. Its homeostasis is finely regulated, and its alteration could be responsible for the onset of several disorders. Iron is closely related to inflammation; indeed, during inflammation high levels of interleukin-6 cause an increased production of hepcidin which induces a degradation of ferroportin. Ferroportin degradation leads to decreased iron efflux that culminates in elevated intracellular iron concentration and consequently iron toxicity in cells and tissues. Therefore, iron chelation could be considered a novel and useful therapeutic strategy in order to counteract the inflammation in several autoimmune and inflammatory diseases. Several iron chelators are already known to have anti-inflammatory effects, among them deferiprone, deferoxamine, deferasirox, and Dp44mT are noteworthy. Recently, eltrombopag has been reported to have an important role in reducing inflammation, acting both directly by chelating iron, and indirectly by modulating iron efflux. This review offers an overview of the possible novel biological effects of the iron chelators in inflammation, suggesting them as novel anti-inflammatory molecules.

Anti-Inflammatory Effects of the Iron Chelator, DIBI, in Experimental Acute Lung Injury.

Iron plays a critical role in the immune response to inflammation and infection due to its role in the catalysis of reactive oxygen species (ROS) through the Haber-Weiss and Fenton reactions. However, ROS overproduction can be harmful and damage healthy cells. Therefore, iron chelation represents an innovative pharmacological approach to limit excess ROS formation and the related pro-inflammatory mediator cascades. The present study was designed to investigate the impact of the iron chelator, DIBI, in an experimental model of LPS-induced acute lung injury (ALI). DIBI was administered intraperitoneally in the early and later stages of lung inflammation as determined by histopathological evaluation. We found that lung tissues showed significant injury, as well as increased NF-κB p65 activation and significantly elevated levels of various inflammatory mediators (LIX, CXCL2, CCL5, CXCL10, IL-1𝛽, IL-6) 4 h post ALI induction by LPS. Mice treated with DIBI (80 mg/kg) in the early stages (0 to 2 h) after LPS administration demonstrated a significant reduction of the histopathological damage score, reduced levels of NF-κB p65 activation, and reduced levels of inflammatory mediators. Intravital microscopy of the pulmonary microcirculation also showed a reduced number of adhering leukocytes and improved capillary perfusion with DIBI administration. Our findings support the conclusion that the iron chelator, DIBI, has beneficial anti-inflammatory effects in experimental ALI.

What Can Cellular Redox, Iron, and Reactive Oxygen Species Suggest About the Mechanisms and Potential Therapy of COVID-19?

Accumulating evidence suggests that there are important contributions to coronavirus disease (COVID-19) from redox imbalance and improperly coordinated iron, which cause cellular oxidative damage and stress. Cells have developed elaborate redox-dependent processes to handle and store iron, and their disfunction leads to several serious diseases. Cellular reductants are important as reactive oxygen species (ROS) scavengers and to power enzymatic repair mechanisms, but they also may help generate toxic ROS. These complicated interrelationships are presented in terms of a cellular redox/iron/ROS triad, including ROS generation both at improperly coordinated iron and enzymatically, ROS interconvertibility, cellular signaling and damage, and reductant and iron chelator concentration-dependent effects. This perspective provides the rational necessary to strongly suggest that COVID-19 disrupts this interdependent triad, producing a substantial contribution to the ROS load, which causes direct ROS-induced protein and phospholipid damage, taxes cellular resources and repair mechanisms, and alters cellular signaling, especially in the more critical acute respiratory distress syndrome (ARDS) phase of the infection. Specific suggestions for therapeutic interventions using reductants and chelators that may help treat COVID-19 are discussed.