a(CHEBI:"iron(2+)")
With respect to the absence of Hri, there were slightly greater serum iron concentrations, total splenic iron content, and hepatic hepcidin expression level in Hri-deficient mice, relative to those in Wt mice (Figure 8A−C). PubMed:25411909
However, Pb exposure induced hepatic hepcidin expression by nearly 2- fold in Ko + Pb mice with a resultant significant increase of total splenic iron, compared to that in Ko − Pb mice (Figure 8 B and C; P < 0.05). PubMed:25411909
Within cells, heme is catabolized by the activity of heme oxygenases (inducible HO-1 and constitutive HO-2) into iron, carbon monoxide, and biliverdin. PubMed:26675351
Iron was also detected in the macrophages of the red pulp of CEP mice, while almost no iron deposit was observed in the spleen of Hjv–/– mice (Figure 4B), confirming that Hb and “free” heme are the likely source of macrophage iron accumulation. PubMed:28143953
Under heme overload conditions, macrophages acquire an iron phenotype characterized by low intracellular iron and high ferroportin expression. PubMed:29212341
In subsequent reactions, metHb or metHb-derived heme participates in redox chain reactions that lead to the accumulation of modified lipids and proteins, as well as to heme degradation and to the release of free iron.19,25 PubMed:29610666
We showed that simulation of macrophages with LPS resulted in significant reduction in ferroportin mRNA and protein expression and enhanced intracellular iron deposition throughout all time points tested (Fig. 5A–D). PubMed:29212341
This dramatically contrasts the iron phenotype that develops in response to LPS, hallmarked by high intracellular iron levels and low ferroportin expression (10, 20, 48). PubMed:29212341
Concentrations of iron, conjugated dienes and lipid hydroperoxides were elevated by about 2- fold in ruptured complicated lesions, as compared to atheromatous lesions (0.433 ± 0.075 vs. 0.185 ± 0.096 nmol Fe/mg tissue; 0.047 ± 0.019 vs. 0.021 ± 0.003 A234 conjugated dienes/mg tissue and 0.465 ± 0.110 vs. 0.248 ± 0.106 nmol LOOH/mg tissue, respectively) and complicated lesions contained 5.6 times more TBARs than atheromatous lesions (0.028 ± 0.012 vs. 0.005 ± 0.001 nmol/mg tissue). PubMed:20378845
Stored RBCs undergo a complex structural and metabolic impairment that includes leakage of hemoglobin from the cells and hemolysis, reduced energy and NO production, formation of toxic products, such as lysophospholipids and free iron, phosphatidylserine exposure and shedding MPs [59]. PubMed:28458720
Fig 2 shows that free hemoglobin and free heme were higher 4 h after resuscitation with stored RBCs compared to fresh RBCs (n = 3±7 as indicated); NTBI level was also higher, but this difference did not reach statistical significance (p = 0.07). PubMed:29522519
In old blood-transfused animals, strong Hb and iron deposition was observed in the tubule lumen and epithelial cells, respectively. PubMed:26794659
Tissue iron staining revealed greater cortical iron accumulation in the kidneys of mice resuscitated with SRBCs, SRBCs combined with albumin and SRBCs combined with hemopexin than in the kidneys of mice transfused with FRBCs (Figure 6A and B). PubMed:27515135
Splenic iron content was greater in mice after resuscitation with SRBCs than in FRBC-transfused mice. PubMed:27515135
Taken together, these results indicate that haptoglobin co-transfusion prevented stored blood transfusion-associated renal iron uptake and led to increased weight and greater iron- accumulation in the spleens of mice. PubMed:27515135
There is a clear need for, and medical benefit from, blood transfusions; nonetheless, administration of red blood cells (RBCs) does result in exposure to toxicants specific to hemoglobin (Hb) and its degradation components, hemin and iron. PubMed:30281034
Differently from biliverdin and CO, which have anti-inflammatory effects (Otterbein et al., 2000; Baranano et al., 2002), free Fe is highly oxidative and can promote free radicals generation through the Fenton reaction, which catalyzes hydroxyl radicals from the reaction of Fe with H2O2 (Fenton, 1894). PubMed:24904418
Because of large exposures to iron that occur in both disorders following transfusion, patients are inevitably prescribed small molecule iron chelation and the concomitant monitoring that is required. PubMed:30281034
Once inside the cells, heme is catabolized by HO enzymes, generating equimolar amounts of biliverdin, carbon monoxide (CO), and Fe (Tenhunen et al., 1968). PubMed:24904418
Importantly, protoporphyrin did not induce TNFα, suggesting a critical proinflammatory role for iron within the heme moiety (supplemental Figure 8). PubMed:26675351
Likewise, NAC was able to prevent iron-induced M1 polarization in M0, M1, and M2 BMDMs (supplemental Figure 13), indicating that the alteration of macrophage plasticity in response to iron is mostly explained by its pro-oxidant properties. PubMed:26675351
Thus, by participating in Fenton chemistry, non-transferrin-bound iron (i.e., iron not bound to the physiological iron transport protein, transferrin) causes oxidative damage, cytotoxicity and enhanced endothelial expression of adhesion molecules, thereby enhancing thrombotic risk (Hershko, 2007). PubMed:25307023
This engenders the release of iron, which can promote further the oxidation of plaque lipids through redox cycling reactions. The result of these chemical reactions is the formation of deleterious oxidized ‘gruel’ which, among other things, leads to endothelial oxidative stress and ultimately to cytotoxicity. PubMed:20378845
Thus, by participating in Fenton chemistry, non-transferrin-bound iron (i.e., iron not bound to the physiological iron transport protein, transferrin) causes oxidative damage, cytotoxicity and enhanced endothelial expression of adhesion molecules, thereby enhancing thrombotic risk (Hershko, 2007). PubMed:25307023
Extracellular hemoglobin and its degradation products, free heme and iron, are highly toxic due to oxidative stress induction and decrease in nitric oxide availability. PubMed:28088643
Hb and its degradation products – free heme and iron - perpetuate oxidative stress, and together with decreased NO availability promote many SCD complications. PubMed:28088643
There are in vitro and animal model data linking increased free Hb, heme, and iron to inflammation, 6 infection,7 platelet (PLT) activation,8,9 vasculopathy, 10 and thrombosis. PubMed:29603246
The causes for RBC-based toxicant exposures are multifactorial; however, following acute transfusion, the most common occurs during the processes of extravascular hemolysis, which includes macrophage erythrophagocytosis followed by macrophage death [1&&], release of iron, transferrin (Tf) saturation and, finally, accumulation of labile plasma iron (LPI) [2]. PubMed:30281034
Extracellular hemoglobin and its degradation products, free heme and iron, are highly toxic due to oxidative stress induction and decrease in nitric oxide availability. PubMed:28088643
Iron was also detected in the macrophages of the red pulp of CEP mice, while almost no iron deposit was observed in the spleen of Hjv–/– mice (Figure 4B), confirming that Hb and “free” heme are the likely source of macrophage iron accumulation. PubMed:28143953
Another pathogenic mechanism involves the release of iron from cell-free hemoglobin with consecutive radical formation, which in turn can modify lipids, proteins, and DNA, leading to inflammation [39]. PubMed:29956069
Tissue iron staining revealed greater cortical iron accumulation in the kidneys of mice resuscitated with SRBCs, SRBCs combined with albumin and SRBCs combined with hemopexin than in the kidneys of mice transfused with FRBCs (Figure 6A and B). PubMed:27515135
Only transfusion of SRBCs and haptoglobin prevented SRBC-induced renal iron accumulation (Figure 6A and B). PubMed:27515135
In comparison to mice transfused with SRBCs alone, the spleens of mice resuscitated with SRBCs and haptoglobin contained more iron (Figure 6D). PubMed:27515135
Tissue iron staining revealed greater cortical iron accumulation in the kidneys of mice resuscitated with SRBCs, SRBCs combined with albumin and SRBCs combined with hemopexin than in the kidneys of mice transfused with FRBCs (Figure 6A and B). PubMed:27515135
These data suggested that during severe hemolysis, heme mediated ferroportin induction and low hepcidin in HbS mice (11) served to elevate systemic iron availability, required to sustain high erythropoietic demands in these mice. PubMed:29212341
Cells deficient on FtH are more susceptible to oxidative damage, while increased amounts of FtH protects cells from death induced by challenges such as Fe, tumor necrosis factor (TNF), heme, heme plus TNF, or oxidized low-density lipoprotein (LDL; Juckett et al., 1995; Pham et al., 2004; Gozzelino et al., 2012). PubMed:24904418
These studies do begin to suggest that apo-Tf administration could attenuate acute iron overload and hemochromatosis progression following chronic RBC transfusions. PubMed:30281034
In addition, iron and ferritin deposition are found in ependymal or subependymal location after neonatal IVH.7–9 PubMed:24667910
Interestingly elevated levels of body iron stores are associated with an increased risk of myocardial infarction, and carriers of the hemochromatosis gene have an increased risk of myocardial infarction and cardiovascular death (20, 21). PubMed:19276082
Earlier chemical investigations of gruel from advanced lesions revealed that it contains ceroid-like insoluble material composed mainly of hydoxyapatite, iron and calcium. PubMed:20378845
Using isolated duodenal loops to measure the transepithelial iron transport, we found that CEP mice presented a higher rate of iron absorption than the WT mice, although the differences between the area under the curves did not reach statistical significance (Figure 3D). PubMed:28143953
Serum iron was also increased in CEP mice, but this did not lead to elevated Tf saturation because Tf was also significantly increased, which is reminiscent of iron deficiency anemia and facilitates iron delivery to a larger number of erythroblasts (Table 1 and Figure 3G). PubMed:28143953
Iron was also detected in the macrophages of the red pulp of CEP mice, while almost no iron deposit was observed in the spleen of Hjv–/– mice (Figure 4B), confirming that Hb and “free” heme are the likely source of macrophage iron accumulation. PubMed:28143953
As expected, Perl’s staining of CEP kidneys showed significant accumulation of iron in the renal cortical part, particularly in the proximal tubules (Figure 6A). PubMed:28143953
There are in vitro and animal model data linking increased free Hb, heme, and iron to inflammation, 6 infection,7 platelet (PLT) activation,8,9 vasculopathy, 10 and thrombosis. PubMed:29603246
Twenty-four hours after injection, T2 MRI showed a significant bilateral ventricular enlargement in the iron-injected group (17.9±5.7mm3) compared with salineinjected rats (9.2±5.7mm3, Po0.01, Figure 4). PubMed:24667910
The major findings of this study are (1) intraventricular injection of lysed RBCs but not packed RBCs resulted in hydrocephalus; (2) lysed RBCs upregulated brain HO-1 and ferritin levels; (3) intraventricular injection of iron also caused hydrocephalus; and (4) iron chelation with deferoxamine reduced lysed RBC-induced hydrocephalus. PubMed:24667910
There are in vitro and animal model data linking increased free Hb, heme, and iron to inflammation, 6 infection,7 platelet (PLT) activation,8,9 vasculopathy, 10 and thrombosis. PubMed:29603246
There are in vitro and animal model data linking increased free Hb, heme, and iron to inflammation, 6 infection,7 platelet (PLT) activation,8,9 vasculopathy, 10 and thrombosis. PubMed:29603246
ROS generation by haem is at least partially dependent on the Fenton reaction, in which iron catalyses the production of toxic ROS (Wagener et al, 2003). PubMed:25307023
Interestingly elevated levels of body iron stores are associated with an increased risk of myocardial infarction, and carriers of the hemochromatosis gene have an increased risk of myocardial infarction and cardiovascular death (20, 21). PubMed:19276082
Concentrations of iron, conjugated dienes and lipid hydroperoxides were elevated by about 2- fold in ruptured complicated lesions, as compared to atheromatous lesions (0.433 ± 0.075 vs. 0.185 ± 0.096 nmol Fe/mg tissue; 0.047 ± 0.019 vs. 0.021 ± 0.003 A234 conjugated dienes/mg tissue and 0.465 ± 0.110 vs. 0.248 ± 0.106 nmol LOOH/mg tissue, respectively) and complicated lesions contained 5.6 times more TBARs than atheromatous lesions (0.028 ± 0.012 vs. 0.005 ± 0.001 nmol/mg tissue). PubMed:20378845
Thus, the antioxidant, anticoagulant, anti-proliferative and vasodilating effects of the HMOX1 and biliverdin reductase systems probably compensate for the nitric oxide (NO) scavenging, vasoconstrictive, proliferative, inflammatory and pro-oxidant effects of circulating free haemoglobin, haem and haem-iron, which are discussed below (Rother et al, 2005). PubMed:25307023
This engenders the release of iron, which can promote further the oxidation of plaque lipids through redox cycling reactions. The result of these chemical reactions is the formation of deleterious oxidized ‘gruel’ which, among other things, leads to endothelial oxidative stress and ultimately to cytotoxicity. PubMed:20378845
Thus, by participating in Fenton chemistry, non-transferrin-bound iron (i.e., iron not bound to the physiological iron transport protein, transferrin) causes oxidative damage, cytotoxicity and enhanced endothelial expression of adhesion molecules, thereby enhancing thrombotic risk (Hershko, 2007). PubMed:25307023
Extracellular hemoglobin and its degradation products, free heme and iron, are highly toxic due to oxidative stress induction and decrease in nitric oxide availability. PubMed:28088643
Hb and its degradation products – free heme and iron - perpetuate oxidative stress, and together with decreased NO availability promote many SCD complications. PubMed:28088643
Earlier chemical investigations of gruel from advanced lesions revealed that it contains ceroid-like insoluble material composed mainly of hydoxyapatite, iron and calcium. PubMed:20378845
In addition, iron and ferritin deposition are found in ependymal or subependymal location after neonatal IVH.7–9 PubMed:24667910
Twenty-four hours after injection, T2 MRI showed a significant bilateral ventricular enlargement in the iron-injected group (17.9±5.7mm3) compared with salineinjected rats (9.2±5.7mm3, Po0.01, Figure 4). PubMed:24667910
The major findings of this study are (1) intraventricular injection of lysed RBCs but not packed RBCs resulted in hydrocephalus; (2) lysed RBCs upregulated brain HO-1 and ferritin levels; (3) intraventricular injection of iron also caused hydrocephalus; and (4) iron chelation with deferoxamine reduced lysed RBC-induced hydrocephalus. PubMed:24667910
Differently from biliverdin and CO, which have anti-inflammatory effects (Otterbein et al., 2000; Baranano et al., 2002), free Fe is highly oxidative and can promote free radicals generation through the Fenton reaction, which catalyzes hydroxyl radicals from the reaction of Fe with H2O2 (Fenton, 1894). PubMed:24904418
These concepts challenged the idea that the cytotoxic and inflammatory effects of heme were exclusively mediated by the oxidative capability of the Fe associated with the amphipathic property of the porphyrin ring. PubMed:24904418
Thus, the antioxidant, anticoagulant, anti-proliferative and vasodilating effects of the HMOX1 and biliverdin reductase systems probably compensate for the nitric oxide (NO) scavenging, vasoconstrictive, proliferative, inflammatory and pro-oxidant effects of circulating free haemoglobin, haem and haem-iron, which are discussed below (Rother et al, 2005). PubMed:25307023
There are in vitro and animal model data linking increased free Hb, heme, and iron to inflammation, 6 infection,7 platelet (PLT) activation,8,9 vasculopathy, 10 and thrombosis. PubMed:29603246
Thus, the antioxidant, anticoagulant, anti-proliferative and vasodilating effects of the HMOX1 and biliverdin reductase systems probably compensate for the nitric oxide (NO) scavenging, vasoconstrictive, proliferative, inflammatory and pro-oxidant effects of circulating free haemoglobin, haem and haem-iron, which are discussed below (Rother et al, 2005). PubMed:25307023
Thus, the antioxidant, anticoagulant, anti-proliferative and vasodilating effects of the HMOX1 and biliverdin reductase systems probably compensate for the nitric oxide (NO) scavenging, vasoconstrictive, proliferative, inflammatory and pro-oxidant effects of circulating free haemoglobin, haem and haem-iron, which are discussed below (Rother et al, 2005). PubMed:25307023
We confirmed that the redox active iron, which is derived from heme catabolism in macrophages, is capable of catalyzing ROS formation (Fig. 7A) (19). PubMed:29212341
Finally, ferrous iron, through Fenton-derived hydroxyl radical species production and protein kinase C function, activates platelets (Iuliano et al, 1994). PubMed:25307023
There are in vitro and animal model data linking increased free Hb, heme, and iron to inflammation, 6 infection,7 platelet (PLT) activation,8,9 vasculopathy, 10 and thrombosis. PubMed:29603246
Thus, by participating in Fenton chemistry, non-transferrin-bound iron (i.e., iron not bound to the physiological iron transport protein, transferrin) causes oxidative damage, cytotoxicity and enhanced endothelial expression of adhesion molecules, thereby enhancing thrombotic risk (Hershko, 2007). PubMed:25307023
Thus, by participating in Fenton chemistry, non-transferrin-bound iron (i.e., iron not bound to the physiological iron transport protein, transferrin) causes oxidative damage, cytotoxicity and enhanced endothelial expression of adhesion molecules, thereby enhancing thrombotic risk (Hershko, 2007). PubMed:25307023
Thus, by participating in Fenton chemistry, non-transferrin-bound iron (i.e., iron not bound to the physiological iron transport protein, transferrin) causes oxidative damage, cytotoxicity and enhanced endothelial expression of adhesion molecules, thereby enhancing thrombotic risk (Hershko, 2007). PubMed:25307023
There are in vitro and animal model data linking increased free Hb, heme, and iron to inflammation, 6 infection,7 platelet (PLT) activation,8,9 vasculopathy, 10 and thrombosis. PubMed:29603246
With respect to the absence of Hri, there were slightly greater serum iron concentrations, total splenic iron content, and hepatic hepcidin expression level in Hri-deficient mice, relative to those in Wt mice (Figure 8A−C). PubMed:25411909
However, Pb exposure induced hepatic hepcidin expression by nearly 2- fold in Ko + Pb mice with a resultant significant increase of total splenic iron, compared to that in Ko − Pb mice (Figure 8 B and C; P < 0.05). PubMed:25411909
Within cells, heme is catabolized by the activity of heme oxygenases (inducible HO-1 and constitutive HO-2) into iron, carbon monoxide, and biliverdin. PubMed:26675351
Under heme overload conditions, macrophages acquire an iron phenotype characterized by low intracellular iron and high ferroportin expression. PubMed:29212341
Importantly, protoporphyrin did not induce TNFα, suggesting a critical proinflammatory role for iron within the heme moiety (supplemental Figure 8). PubMed:26675351
Another pathogenic mechanism involves the release of iron from cell-free hemoglobin with consecutive radical formation, which in turn can modify lipids, proteins, and DNA, leading to inflammation [39]. PubMed:29956069
Likewise, NAC was able to prevent iron-induced M1 polarization in M0, M1, and M2 BMDMs (supplemental Figure 13), indicating that the alteration of macrophage plasticity in response to iron is mostly explained by its pro-oxidant properties. PubMed:26675351
In old blood-transfused animals, strong Hb and iron deposition was observed in the tubule lumen and epithelial cells, respectively. PubMed:26794659
Tissue iron staining revealed greater cortical iron accumulation in the kidneys of mice resuscitated with SRBCs, SRBCs combined with albumin and SRBCs combined with hemopexin than in the kidneys of mice transfused with FRBCs (Figure 6A and B). PubMed:27515135
Splenic iron content was greater in mice after resuscitation with SRBCs than in FRBC-transfused mice. PubMed:27515135
Taken together, these results indicate that haptoglobin co-transfusion prevented stored blood transfusion-associated renal iron uptake and led to increased weight and greater iron- accumulation in the spleens of mice. PubMed:27515135
Tissue iron staining revealed greater cortical iron accumulation in the kidneys of mice resuscitated with SRBCs, SRBCs combined with albumin and SRBCs combined with hemopexin than in the kidneys of mice transfused with FRBCs (Figure 6A and B). PubMed:27515135
Tissue iron staining revealed greater cortical iron accumulation in the kidneys of mice resuscitated with SRBCs, SRBCs combined with albumin and SRBCs combined with hemopexin than in the kidneys of mice transfused with FRBCs (Figure 6A and B). PubMed:27515135
Only transfusion of SRBCs and haptoglobin prevented SRBC-induced renal iron accumulation (Figure 6A and B). PubMed:27515135
In comparison to mice transfused with SRBCs alone, the spleens of mice resuscitated with SRBCs and haptoglobin contained more iron (Figure 6D). PubMed:27515135
Extracellular hemoglobin and its degradation products, free heme and iron, are highly toxic due to oxidative stress induction and decrease in nitric oxide availability. PubMed:28088643
Hb and its degradation products – free heme and iron - perpetuate oxidative stress, and together with decreased NO availability promote many SCD complications. PubMed:28088643
Using isolated duodenal loops to measure the transepithelial iron transport, we found that CEP mice presented a higher rate of iron absorption than the WT mice, although the differences between the area under the curves did not reach statistical significance (Figure 3D). PubMed:28143953
Serum iron was also increased in CEP mice, but this did not lead to elevated Tf saturation because Tf was also significantly increased, which is reminiscent of iron deficiency anemia and facilitates iron delivery to a larger number of erythroblasts (Table 1 and Figure 3G). PubMed:28143953
There are in vitro and animal model data linking increased free Hb, heme, and iron to inflammation, 6 infection,7 platelet (PLT) activation,8,9 vasculopathy, 10 and thrombosis. PubMed:29603246
Iron was also detected in the macrophages of the red pulp of CEP mice, while almost no iron deposit was observed in the spleen of Hjv–/– mice (Figure 4B), confirming that Hb and “free” heme are the likely source of macrophage iron accumulation. PubMed:28143953
As expected, Perl’s staining of CEP kidneys showed significant accumulation of iron in the renal cortical part, particularly in the proximal tubules (Figure 6A). PubMed:28143953
These data suggested that during severe hemolysis, heme mediated ferroportin induction and low hepcidin in HbS mice (11) served to elevate systemic iron availability, required to sustain high erythropoietic demands in these mice. PubMed:29212341
We showed that simulation of macrophages with LPS resulted in significant reduction in ferroportin mRNA and protein expression and enhanced intracellular iron deposition throughout all time points tested (Fig. 5A–D). PubMed:29212341
This dramatically contrasts the iron phenotype that develops in response to LPS, hallmarked by high intracellular iron levels and low ferroportin expression (10, 20, 48). PubMed:29212341
Fig 2 shows that free hemoglobin and free heme were higher 4 h after resuscitation with stored RBCs compared to fresh RBCs (n = 3±7 as indicated); NTBI level was also higher, but this difference did not reach statistical significance (p = 0.07). PubMed:29522519
BEL Commons is developed and maintained in an academic capacity by Charles Tapley Hoyt and Daniel Domingo-Fernández at the Fraunhofer SCAI Department of Bioinformatics with support from the IMI project, AETIONOMY. It is built on top of PyBEL, an open source project. Please feel free to contact us here to give us feedback or report any issues. Also, see our Publishing Notes and Data Protection information.
If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.