The utility of iron chelators in the management of inflammatory disorders

Abstract

Since iron can contribute to detrimental radical generating processes through the Fenton and Haber-Weiss reactions, it seems to be a reasonable approach to modulate iron-related pathways in inflammation. In the human organism a counterregulatory reduction in iron availability is observed during inflammatory diseases. Under pathological conditions with reduced or increased baseline iron levels different consequences regarding protection or susceptibility to inflammation have to be considered. Given the role of iron in development of inflammatory diseases, pharmaceutical agents targeting this pathway promise to improve the clinical outcome. The objective of this review is to highlight the mechanisms of iron regulation and iron chelation, and to demonstrate the potential impact of this strategy in the management of several acute and chronic inflammatory diseases, including cancer.

Figure 1

Role of iron in the development of disease.

Figure 2

Putative involvement of iron in inflammation. Inflammation induces the production of proinflammatory cytokines which can induce the sequestration of iron within cells through the modulation of iron regulatory protein expression (e.g., divalent metal transporter 1 (DMT1), hepcidin (HAMP), ferritin, and ferroportin1 (FPN)). Increased iron levels, especially in macrophages, may lead to ROS production via the Fenton and Haber-Weiss reactions. ROS in return can increase levels of labile iron and induce oxidative damage of DNA, proteins, and lipids. Additionally, ROS can activate redox-sensitive transcription factors whose targets include proinflammatory cytokines.