The Anemia of Infection. I. Hypoferremia, Hypercupremia, and Alterations in Porphyrin Metabolism in Patients 1

Cartwright, G. E.; Lauritsen, Marjorie; Jones, Peter J H; Merrill, I. M.; Wintrobe, M. M.

doi:10.1172/jci101690

Cited by 148 publications

(73 citation statements)

References 35 publications

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“…The hypoferremia associated with infection was first noted over 70 years ago by Cartwright et al (101) and was hypothesized to sequester iron in tissues to prevent transfer to invading microbes. Based on the overwhelming weight of evidence, this response is primarily due to the up-regulation of hepcidin.…”

Section: Anemia Of Inflammation and Infectionmentioning

confidence: 99%

Regulation of Iron Metabolism by Hepcidin under Conditions of Inflammation

Schmidt

2015

Journal of Biological Chemistry

135

105

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Iron is a redox-active metal required as a cofactor in multiple metalloproteins essential for a host of life processes. The metal is highly toxic when present in excess and must be strictly regulated to prevent tissue and organ damage. Hepcidin, a molecule first characterized as an antimicrobial peptide, plays a critical role in the regulation of iron homeostasis. Multiple stimuli positively influence the expression of hepcidin, including iron, inflammation, and infection by pathogens. In this Minireview, I will discuss how inflammation regulates hepcidin transcription, allowing for sufficient concentrations of iron for organismal needs while sequestering the metal from infectious pathogens.Iron is crucial for many life functions in both eukaryotic hosts and prokaryotic pathogens. Due to its ability to readily accept or donate electrons, iron is a valuable cofactor in proteins essential in metabolic processes. However, when left unsupervised, iron can also react with oxygen to generate radical oxygen species that can damage all facets of a cell, leading to tissue damage and eventual organ failure. Therefore, it is crucial for organisms to maintain strict control over iron uptake and distribution to assure appropriate amounts for life requirements, yet regulate and sequester it tightly to prevent oxidative stress or microbial proliferation during infection. Herein, I will present an overview of how iron balance is maintained in vertebrate organisms and discuss the role of hepcidin, the master regulator of iron metabolism, in iron regulation during inflammation and infection. General Iron HomeostasisEach day the average human must absorb 1-2 mg of iron from the diet to offset unregulated losses from general bleeding, menstruation, or the sloughing of epithelial cells. Iron is a critical cofactor required for DNA synthesis, mitochondrial respiration, and various signaling pathways. Most crucially, almost 25 mg of iron per day is required for hemoglobin synthesis and the replacement of an estimated 200 billion RBCs. The vast majority of this iron pool is acquired through the recycling of senescent erythrocytes by macrophages of the reticuloendothelial compartment. Whole body iron homeostasis is thought to occur completely at the level of iron absorption, as no physiologically regulated means of iron excretion has been elucidated. Hence, influx of iron from the diet, and recycling of iron from aged or damaged RBCs, must be closely regulated to prevent iron-restricted erythropoiesis resulting in anemia or excess iron loading and subsequent tissue damage caused by the generation of radical oxygen species. Proper distribution of circulating iron to tissues such as the brain, heart, and skeletal muscle is crucial for the prevention of human disease states.Non-heme dietary reduced iron is admitted into the body through divalent metal transporter 1 (DMT1, Slc11a2) (1, 2), an iron transporter located on the apical membrane of duodenal enterocytes located in the first section of the small intestine ( Fig. 1). After uptake in...

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Section: Anemia Of Inflammation and Infectionmentioning

confidence: 99%

Regulation of Iron Metabolism by Hepcidin under Conditions of Inflammation

Schmidt

2015

Journal of Biological Chemistry

135

105

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“…In order to secure concentrated specimens of reticulocytes and of mature cells, after separating the plasma, the column of packed cells of various samples of blood was divided into three equal parts: the upper (u) and lower (1) parts were then suspended separately in 0.9 per cent NaCl to approximate the original volume. In both fractions the reticulocyte percentage was determined by the brilliant cresyl blue wet stain method (19).…”

Section: Methods and Calculationsmentioning

confidence: 99%

“…The following determinations were run on the whole (w) blood as well as on the upper (u) and lower (1) fractions: red blood cell counts using the bright line Spencer counting chamber and a standardized red cell pipette; volume of packed cells, using the Wintrobe hematocrit tube; hemoglobin, by the photoelectric oxyhemoglobin method, using an Evelyn photoelectric colorimeter. The instrument was standardized by the Van Slyke procedure as well as by the hemin method of Clegg and King (20).…”

Section: Significance Of Free Erythrocyte Protoporphyrinmentioning

confidence: 99%

The Anemia of Infection. Vii. The Significance of Free Erythrocyte Protoporphyrin, Together With Some Observations on the Meaning of the “Easily Split-Off” Iron 1

Grinstein¹,

Silva²,

Wintrobe³

1948

J. Clin. Invest.

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Studies in this laboratory (1) on the anemia accompanying infection have indicated that there is associated with such anemia a disturbance in the metabolism of porphyrins. The amount of free protoporphyrin in the erythrocytes has been found to be increased and the excretion of coproporphyrin in the urine is greater than normal. The present report deals with studies designed to investigate the significance of the free protoporphyrin in the erythrocytes.The presence of free protoporphyrin in the erythrocytes (EP) Watson and Clarke (6) observed upon centrifuging different samples of blood that the upper layer of the packed cells, which is richer in reticulocytes, showed a much higher content of proto-

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“…Previous studies (1)(2)(3)(4) have shown that, with the development of inflammation, hypoferremia occurs and a decrease takes place in the concentration of the metal binding protein in the plasma. When iron is given by mouth, there is little change in the level of plasma iron and, following the intravenous injection of iron, only a transient rise in the plasma iron develops.…”

mentioning

confidence: 99%

“…That reduced iron intake is not the limiting factor in the anemia associated with infection was suggested by the fact that the intravenous administration of relatively large amounts of iron failed to relieve it (1)(2)(3)(4)(5)(6)(7)(8). A defect in these studies, as carried out in human subjects, however, was that the administration of preparations such as iron ascorbate (10 to 300 mg.) was attended by local and systemic reactions and consequently the amounts of iron given were not as great as might have been desired.…”

mentioning

confidence: 99%