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Disruption of any stage of iron homeostasis, including uptake, utilization, efflux, and storage, can cause progressive damage to peripheral organs. The health hazards associated with occupational exposure to inhalation anesthetics (IA) in combination with chronic iron overload are not well documented. This study aimed to investigate changes in the concentration of essential metals in the peripheral organs of rats after iron overload in combination with IA. The aim was also to determine how iron overload in combination with IA affects tissue metal homeostasis, hepcidin–ferritin levels, and MMP levels according to physiological, functional, and tissue features. According to the obtained results, iron accumulation was most pronounced in the liver (19×), spleen (6.7×), lungs (3.1×), and kidneys (2.5×) compared to control. Iron accumulation is associated with elevated heavy metal levels and impaired essential metal concentrations due to oxidative stress (OS). Notably, the use of IA increases the iron overload toxicity, especially after Isoflurane exposure. The results show that the regulation of iron homeostasis is based on the interaction of hepcidin, ferritin, and other proteins regulated by inflammation, OS, free iron levels, erythropoiesis, and hypoxia. Long-term exposure to IA and iron leads to the development of numerous adaptation mechanisms in response to toxicity, OS, and inflammation. These adaptive mechanisms of iron regulation lead to the inhibition of MMP activity and reduction of oxidative stress, protecting the organism from possible damage.

Although iron is a first-line pro-oxidant that modulates clinical manifestations of various systemic diseases, including diabetes, the individual tissue damage generated by active oxidant insults has not been demonstrated in current animal models of diabetes. We tested the hypothesis that oxidative stress is involved in the severity of the tissues injury when iron supplementation is administered in a model of type 1 diabetes. Streptozotocin (Stz)-induced diabetic and non-diabetic Fischer rats were maintained with or without a treatment consisting of iron dextran ip at 0.1 mL day −1 doses administered for 4 days at intervals of 5 days. After 3 weeks, an extensive increase ( p  < 0.001) in the production of reactive oxygen species (ROS) in neutrophils of the diabetic animals on iron overload was observed. Histological analysis revealed that this treatment also resulted in higher ( p  < 0.05) tissue iron deposits, a higher ( p  < 0.001) number of inflammatory cells in the pancreas, and apparent cardiac fibrosis, as shown by an increase ( p  < 0.05) in type III collagen levels, which result in dysfunctional myocardial. Carbonyl protein modification, a marker of oxidative stress, was consistently higher ( p  < 0.01) in the tissues of the iron-treated rats with diabetes. Moreover, a significant positive correlation was found between ROS production and iron pancreas stores ( r  = 0.42, p  < 0.04), iron heart stores ( r  = 0.54, p  < 0.04), and change of the carbonyl protein content in pancreas ( r  = 0.49, p  < 0.009), and heart ( r  = 0.48, p  < 0.02). A negative correlation was still found between ROS production and total glutathione content in pancreas ( r  = −0.50, p  < 0.03) and heart ( r  = −0.45, p  < 0.04). In conclusion, our results suggest that amplified toxicity in pancreatic and cardiac tissues in rats with diabetes on iron overload might be attributed to increased oxidative stress.

Background/Aims: Iron overload (IO) is accompanied by hepatic inflammation. The chemokine (C-C motif) ligand 2 (CCL2) mediates inflammation, and its overexpression is associated with IO. However, whether IO results in CCL2 overexpression in the liver and the underlying mechanisms are unclear. Methods: We subjected mice to IO by administering intraperitoneal injections of dextran-iron or by feeding mice a 3% dextran-iron diet to observe the effects of IO on miR-122/CCL2 expression through real-time qPCR and Western blot analysis. We also used indicators, including the expression of the inflammatory cytokine, the inflammation score based on H&E staining and the serum content of ALT and AST to evaluate the effects of IO on hepatic inflammation. Meanwhile, we observed the effects of vitamin E on IO-induced hepatic inflammation. In cells, we used 100 µΜ FeSO 4 or 30 µΜ Holo-Tf to produce IO and observed the roles of miR-122 in regulating CCL2 expression by using miR-122 mimics or inhibitors to overexpress or inhibit miR-122. Then, we used a dual-luciferase reporter assay to prove that miR-122 regulates CCL2 expression through direct binding to its complementary sequence in the CCL2 mRNA 3’UTR. Results: IO induces the downregulation of miR-122 and the upregulation of CCL2, as well as inflammatory responses both in vitro and in vivo. Although IO-induced oxidative stress is eliminated by the antioxidant vitamin E, IO-induced hepatic inflammation still exists, which probably can be explained by the fact that vitamin E has no effects on the miR-122/CCL2 pathway. In in vitro experiments, the overexpression and inhibition of miR-122 significantly reduced and increased CCL2 expression, respectively. The dual-luciferase reporter assay indicates that miR-122 binds CCL2 mRNA 3’UTR. Conclusion: We propose the roles of miR-122/CCL2 in IO-induced hepatic inflammation. Our studies should provide a new clue for developing clinical strategies for patients with IO.

Periodic blood transfusion can lead to secondary iron overload in patients with hematologic and oncologic diseases. Iron overload can result in iron deposition in heart tissue, which decreases cardiac function and can ultimately lead to death due to dilated cardiomyopathy and cardiac failure. In this study, we established murine model of secondary iron overload, studied the changes in cardiac function with echocardiography, and examined the histopathologic changes. Three experimental groups of the six week-old C57/BL mice (H-2 b ) were injected intraperitoneally with 10 mg of iron dextran daily 5 days a week for 2, 4, and 6 weeks. Cumulative doses of iron for the three experimental groups were 100, 200, and 300 mg, while the control groups were injected with the same amounts of phosphate-buffered saline. We studied the cardiac function under anesthesia with echocardiography using a GE Vivid7 Dimension system. Plasma iron levels and liver iron contents were measured. The hearts and livers were harvested and stained with H&E and Perls Prussian blue for iron, and the levels of iron deposit were examined. We assessed the cardiac measurements after adjustment for weight. On echocardiography, thicknesses of the interventricular septum and posterior ventricular wall (PS) during diastole showed correlation with the amount of iron deposit ( P  < 0.01). End-diastolic volume showed dilatation of the left ventricle in the 300 mg group ( P  < 0.01). Changes in the fractional shortening were not statistically significant ( P  = 0.07). Plasma iron levels and liver iron contents were increased proportionally according to the amount of iron loaded. The histopathologic findings of PS and liver showed higher grade of iron deposit proportional to the cumulated iron dose. In this study, we present an animal model which helps understand the cardiac function changes in patients with secondary iron overload due to repeated blood transfusions. Our results may help characterize the pathophysiologic features of cardiomyopathy in patients with secondary iron overload, and our model may be applied to in vivo iron-chelating therapy studies.

The effects of iron dextran on the oxidative stress in cardiovascular tissues of rats with chronic renal failure. Redox-active iron can promote oxidative stress and tissue injury by catalyzing hydroxyl radical generation and lipid peroxidation. Intravenous iron preparations are routinely administered in conjunction with erythropoietin to treat anemia in patients with chronic renal failure (CRF), a condition that is marked by oxidative stress and inflammation. This treatment frequently elevates iron burden, which can potentially intensify oxidative stress and, thus, cardiovascular disease in this population. We studied renal function and oxidative stress parameters in the cardiovascular tissues of CRF (5/6 nephrectomized) and sham-operated control rats 3months after a single intravenous infusion of iron dextran (500mg/kg). Arterial pressure was equally elevated and creatinine clearance was equally reduced in both iron-treated and -untreated CRF groups. Iron administration significantly raised the blood hemoglobin, serum iron concentration, and transferrin saturation in both CRF and control groups. Iron administration resulted in a significant rise in plasma concentration of lipid peroxidation product, malondialdehyde in the CRF rats, and an insignificant rise in the control group. Plasma oxidized low-density lipoprotein (LDL) concentration was increased in the CRF groups, and was not affected by iron administrations. Iron administration raised nitrotyrosine abundance in the aorta of CRF but not in the control group. Left ventricular tissue abundance of p22phox subunit of NAD(P)H oxidase was elevated in CRF group and was not affected, whereas p67phox subunit abundance was raised by prior iron administration. Iron administration insignificantly lowered aorta p22phox, but had no effect on p67phox subunit abundance in the treated CRF group. Previous iron administration significantly lowered superoxide dismutase and catalase abundance in the aorta and glutathione peroxidase in the left ventricle of CRF animals, but did not significantly change these parameters in the iron-treated control animals. A single intravenous injection of iron dextran increased oxidative stress in the cardiovascular tissues in the CRF group, but not the control rats, pointing to heightened susceptibility to iron-mediated toxicity in CRF. However, administration of iron dextran did not adversely affect kidney function, and favorably affected hemoglobin concentration in rats with CRF induced by renal mass reduction. Further studies are needed to explore the effects of other parenteral iron preparations, repeated intravenous iron administration, and presence of comorbid conditions such as diabetes.

Background Infections in hemodialysis (HD) patients lead to high morbidity and mortality rates and are associated with early cardiovascular mortality, possibly related to chronic inflammation. Intravenous (IV) iron is widely administered to HD patients and has been associated with increased oxidative stress and dysfunctional cellular immunity. The purpose of this study was to examine the effect of three commercially available IV iron preparations on intracellular reactive oxygen species generation and lymphocyte subpopulation survival. Methods Peripheral blood mononuclear cells (PBMC) were isolated from healthy donor buffy coat. PBMC were cultured and incubated with 100 μg/mL of sodium ferric gluconate (SFG), iron sucrose (IS) or iron dextran (ID) for 24 hours. Cells were then probed for reactive oxygen species (ROS) with dichlorofluorescein-diacetate. In separate studies, isolated PBMCs were incubated with the 25, 50 or 100 μg/mL iron concentrations for 72 hours and then stained with fluorescein conjugated monoclonal antibodies for lymphocyte subpopulation identification. Untreated PBMCs at 24 hours and 72 hours served as controls for each experiment. Results All three IV iron preparations induced time dependent increases in intracellular ROS with SFG and IS having a greater maximal effect than ID. The CD4+ lymphocytes were most affected by IV iron exposure, with statistically significant reduction in survival after incubation with all three doses (10, 25 and 100 μg/mL) of SFG, IS and ID. Conclusion These data indicate IV iron products induce differential deleterious effects on CD4+ and CD16+ human lymphocytes cell populations that may be mediated by intracellular reactive oxygen species generation. Further studies are warranted to determine the potential clinical relevance of these findings.

Iron chloride injections into the rat SNc can cause chronic decreases in striatal dopamine (DA) levels. However, changes in striatal DA content after iron-dextran injection into rat SNc have not been completely elucidated. The aim of this work was to measure striatal DA concentrations after iron-dextran injection into the SNc. We divided 40 male Wistar rats into five groups, including control, saline injected then sacrificed 7 days or 30 days later, and iron-dextran injected then sacrificed 7 days or 30 days later. Striatal DA content was measured in control animals and in all animals sacrificed 7 days or 30 days after injection, and motor performance was assessed in iron-dextran and saline injected groups 30 days after injection. The striatal DA levels were determined using HPLC. There were significant (P < 0.05) decreases in DA concentrations in the striatum ipsilateral to the injection site in the iron-dextran treated rats compared to control and saline-injected rats. There were no significant differences in DA concentration between the sham-operated (i.e., saline-injected) and control rats. We also observed motor deficits in the iron-dextran injected rats. The striatal DA reduction observed after iron-dextran injection may be attributable to iron-induced oxidative injury in the SNc. Motor deficits, in turn, may be explained by subsequent disturbances in striatal and cortical dopaminergic neuromodulation.

One hypothesis for the etiology of cell damage arising from iron overload is that its excess selectively affects mitochondria. Here we tested the effects of acute iron overload on liver mitochondria isolated from rats subjected to a single dose of i.p. 500 mg/kg iron-dextran. The treatment increased the levels of iron in mitochondria (from 21 ± 4 to 130 ± 7 nmol/mg protein) and caused both lipid peroxidation and glutathione oxidation. The mitochondria of iron-treated rats showed lower respiratory control ratio in association with higher resting respiration. The mitochondrial uncoupling elicited by iron-treatment did not affect the phosphorylation efficiency or the ATP levels, suggesting that uncoupling is a mitochondrial protective mechanism against acute iron overload. Therefore, the reactive oxygen species (ROS)/H⁺ leak couple, functioning as a mitochondrial redox homeostatic mechanism could play a protective role in the acutely iron-loaded mitochondria.

Iron overload was induced by iron dextran i.v. in clinically healthy adult pigeons, Columbia livia, (n = 8). Hemosiderosis was induced in all treated birds. Two control pigeons received no iron injections. Pigeons did not show clinical signs of iron overload during the 6-wk study. Ultrasound examination of the liver in the pigeons receiving iron dextran was performed on days 0, 13, 28, and 42. No ultrasound images were collected on the control pigeons. Magnetic resonance imaging was performed on days 0, 13, 28, and 42 on all study pigeons and imaging sequences were collected in three different imaging formats: T1, T2, and gradient-recalled echo (GRE). Surgical liver biopsies were performed on pigeons receiving iron dextran on days 2, 16, and 45 (at necropsy). A single liver sample was collected at necropsy from the control birds. Histologic examination, quantitative image analysis, and tissue iron analysis by thin-layer chromatography were performed on each liver sample and compared to the imaging studies. Although hemosiderosis was confirmed histologically in each experimental pigeon, no significant change in pixel intensity of the ultrasound images was seen at any point in the study. Signal intensity, in all magnetic resonance imaging formats, significantly decreased in a linear fashion as the accumulation of iron increased.

Skin chemical carcinogenesis has been divided into the process of initiation, promotion and progression. Earlier, we showed the role of iron overload in the promotion stage of skin carcinogenesis. In this communication, we report that iron overload does not augment croton oil-mediated tumor promotion in 7,12-dimethylbenz(a)anthracene (DMBA)-initiated pregnant mice skin tumorigenesis. Virgin female Swiss mice were given 1 mg iron/mouse/day parenterally for 2 weeks to induce iron overload. After the last injection, a group of mice was left with male mice for 10 days. These animals showed an increase in cutaneous iron concentration as compared to normal mice. Papillomas were induced in mice skin by a single topical application of DMBA as initiator. A week after the initiation, promoting agent, croton oil was applied twice per week for 20 weeks. The appearance of the first tumor (papilloma), number of tumors/mouse and percentage incidence were recorded. When compared to the iron unloaded control and iron overload pregnant groups, the iron overload virgin animals showed an increased incidence of tumors. In iron overload virgin animals, tumors appeared earlier and also the numbers of tumors/mouse were significantly higher. However, in iron overload pregnant animals, diminished tumor incidence was observed and the numbers of tumors matched the result of normal pregnant animals. Our results show that iron overload in pregnant mice does not participate in the augmentation of DMBA and croton oil-induced skin tumorigenesis.