Iron Homeostasis and Oxidative Balance in the Context of Endotoxemia

PILONI, N.E.; PUNTARULO, S.

Advances in Medicine and Biology

Nova Science Publishers

Lugar: Barcelona; Año: 2021;

This chapter intends to contribute to a deeper understanding of the main pathways playing a role in the complex mechanisms triggered in Fe-treated organisms. It has been shown that Fe overload causes an increase, as compared to values in control animals, in serum Fe content, and in hepatic ferritin (Ft) content, Fe content in Ft, labile Fe pool (LIP), and protein carbonyl content. High levels of LIP are harmful in tissues, especially through redox damage that can lead to fibrosis. High levels of Ft can occur in several diseases including hemophagocytic lymphohistiocytosis, macrophage activation syndrome, adult-onset Still?s disease, catastrophic antiphospholipid syndrome and septic shock. Lipopolysaccharide (LPS) treatment by itself significantly decreased Fe content in serum, and increased blood NO content. Numerous studies have demonstrated the immunomodulatory effects of Ft and its association with mortality and sustained inflammatory process. A pathogenic role of Ft and Fe has even been described during SARS-CoV-2 infection. Inflammatory responses involving microglia and astrocytes contribute to the pathogenesis of neurodegenerative diseases (NDs). Ferroptosis is a Reactive Oxygen Species (ROS)-and Fe-dependent form of regulated cell death, playing a critical role in organ injury. Ferroptosis participates in the development of cardiomyopathy including cardiac hypertrophy, diabetic cardiomyopathy and doxorubicin-induced cardiotoxicity. However, the role of ferroptosis in sepsis-induced injury remains unclear. Even though inflammation is tightly linked to Fe metabolism dysregulation, it is not clear whether the dysregulation of Fe metabolism induced by brain inflammation contributes to the pathogenesis of NDs or, depending on the doses and duration of the exposure, if it leads to hormesis (beneficial effects). The protective strategy against endotoxemia of sequestering serum Fe content is not fully operative under Fe-overload conditions, even though endogenous mechanisms are able to regulate the amount of catalytically active Fe. Information linked to these aspects of LPS exposure in several organs is updated here, but further studies are necessary to wholly identify the mechanisms involved.