Lactoferrin. A natural glycoprotein involved in iron and inflammatory homeostasis

Human lactoferrin (hLf), an iron-binding multifunctional cationic glycoprotein secreted by exocrine glands and by neutrophils, is a key element of host defenses. HLf and bovine Lf (bLf), possessing high sequence homology and identical functions, inhibit bacterial growth and biofilm dependently from iron binding ability while, independently, bacterial adhesion to and the entry into cells. In infected/inflamed host cells, bLf exerts an anti-inflammatory activity against interleukin-6 (IL-6), thus up-regulating ferroportin (Fpn) and transferrin receptor 1 (TfR1) and down-regulating ferritin (Ftn), pivotal actors of iron and inflammatory homeostasis (IIH). Consequently, bLf inhibits intracellular iron overload, an unsafe condition enhancing in vivo susceptibility to infections, as well as anemia of inflammation (AI), re-establishing IIH. In pregnant women, affected by AI, bLf oral administration decreases IL-6 and increases hematological parameters. This surprising effect is unrelated to iron supplementation by bLf (80 µg instead of 1-2 mg/day), but to its role on IIH. AI is unrelated to the lack of iron, but to iron delocalization: cellular/tissue overload and blood deficiency. BLf cures AI by restoring iron from cells to blood through Fpn up-expression. Indeed, anti-inflammatory activity of oral and intravaginal bLf prevents preterm delivery. Promising bLf treatments can prevent/cure transitory inflammation/anemia/oral pathologies in athletes

Efficacy of lactoferrin oral administration in the treatment of anemia and anemia of inflammation in pregnant and non-pregnant women: an interventional study

The discovery of the ferroportin-hepcidin complex has led to a critical review on the treatment of anemia and anemia of inflammation (AI). Ferroportin, the only known mammalian iron exporter from cells to blood, is negatively regulated by hepcidin, a hormone peptide able to bind to ferroportin, leading to its degradation. Therefore, new efficient therapeutic interventions acting on hepcidin and ferroportin are imperative to manage anemia and AI. Bovine milk derivative lactoferrin (bLf), a glycoprotein able to chelate two ferric ions per molecule, is emerging as a natural anti-inflammatory substance able to modulate hepcidin and ferroportin synthesis through the down-regulation of interleukin-6 (IL-6). Here, an interventional study (ClinicalTrials.gov Identifier: NCT01221844) was conducted by orally administering 100 mg of 20-30% iron-saturated bLf (corresponding to 70-84 μg of elemental iron) twice a day. This treatment was compared with the Italian standard therapy, consisting in the oral administration of 329.7 mg of ferrous sulfate once a day (corresponding to 105 mg of elemental iron). Treatments were carried out on 29 anemic women with minor ß-thalassemia (20 pregnant and 9 non-pregnant), 149 women with hereditary thrombophilia (HT) (70 pregnant and 79 non-pregnant) affected by AI and 20 anemic pregnant women suffering from various pathologies. In anemic pregnant and non-pregnant women with minor ß-thalassemia, presenting undetectable hepcidin levels, differently from ferrous sulfate management, bLf decreased IL-6 (from 25 ± 8 to 6 ± 3 pg/ml) and increased total serum iron (TSI) (from 54 ± 17 to 80 ± 9 μg/dl). BLf was also more efficient than ferrous sulfate in AI treatment in HT pregnant and non-pregnant women by decreasing both serum IL-6 (from 89 ± 8 to 58 ± 6 pg/ml) and hepcidin (from 115 ± 23 to 65 ± 10 ng/ml), thus increasing hematological parameters, such as the number of red blood cells (RBCs), the concentration of hemoglobin, TSI and serum ferritin. BLf was also efficient in treating anemia in other pathological pregnancies. Taken together all the results, bLf, showing a greater benefit and efficacy than the standard ferrous sulfate management, can be considered as a promising compound in treating anemia and AI through its ability to down-regulate IL-6, thus restoring ferroportin-mediated iron export from cells to blood in a hepcidin-dependent or independent way

Effect of bovine lactoferrin on chlamydia trachomatis infection and inflammation.

Chlamydia trachomatis is an obligate, intracellular pathogen responsible for the most common sexually transmitted bacterial disease worldwide, causing acute and chronic infections. The acute infection is susceptible to antibiotics, whereas the chronic one needs prolonged therapies, thus increasing the risk of developing antibiotic resistance. Novel alternative therapies are needed. The intracellular development of C. trachomatis requires essential nutrients, including iron. Iron-chelating drugs inhibit C. trachomatis developmental cycle. Lactoferrin (Lf), a pleiotropic iron binding glycoprotein, could be a promising candidate against C. trachomatis infection. Similarly to the efficacy against other intracellular pathogens, bovine Lf (bLf) could both interfere with C. trachomatis entry into epithelial cells and exert an anti-inflammatory activity. In vitro and in vivo effects of bLf against C. trachomatis infectious and inflammatory process has been investigated. BLf inhibits C. trachomatis entry into host cells when incubated with cell monolayers before or at the moment of the infection and down-regulates IL-6/IL-8 synthesized by infected cells. Six out of 7 pregnant women asymptomatically infected by C. trachomatis, after 30 days of bLf intravaginal administration, were negative for C. trachomatis and showed a decrease of cervical IL-6 levels. This is the first time that the bLf protective effect against C. trachomatis infection has been demonstrated

On the psychological aspects of pregnancies with indications for early prenatal diagnosis

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The influence of lactoferrin, orally administered, on systemic iron homeostasis in pregnant women suffering of iron deficiency and iron deficiency anaemia

Iron is a fundamental element for humans as it represents an essential component of many proteins and enzymes. However, this element can also be toxic when present in excess because of its ability to generate reactive oxygen species. This dual nature imposes a tight regulation of iron concentration in the body. In humans, systemic iron homeostasis is mainly regulated at the level of intestinal absorption and, until now, no regulated pathways for the excretion of iron have been found. The regulation and maintenance of systemic iron homeostasis is critical to human health. Excessive iron absorption leads to iron-overload in parenchyma, while low iron absorption leads to plasma iron deficiency, which manifests as hypoferremia (iron deficiency, ID) and ID anaemia (IDA). ID and IDA are still a major health problem in pregnant women. To cure ID and IDA, iron supplements are routinely prescribed. The preferred treatment of ID/IDA, consisting in oral administration of iron as ferrous sulphate, often fails to exert significant effects on hypoferremia and may also cause adverse effects. Lactoferrin (Lf), an iron-binding glycoprotein abundantly found in exocrine secretions of mammals, is emerging as an important regulator of systemic iron homeostasis. Recent data suggest that this natural compound, capable of interacting with the most important components of iron homeostasis, may represent a valuable alternative to iron supplements in the prevention and cure of pregnancy-associated ID and IDA. In this review, recent advances in the molecular circuits involved in the complex cellular and systemic iron homeostasis will be summarised. The role of Lf in curing ID and IDA in pregnancy and in the maintenance of iron homeostasis will also be discussed. Understanding these mechanisms will provide the rationale for the development of novel therapeutic alternatives to ferrous sulphate oral administration in the prevention and cure of ID and IDA. (C) 2008 Elsevier Masson SAS. All rights reserved

La lattoferrina per os, un’importante alternativa priva di effetti indesiderati, nella prevenzione e trattamento dell’ipoferremia ed anemia da carenza di ferro in gravidanza

I ron is an essential element for humans. The body iron, about 3 g in women and 4 g in men, is mainly incorporated in the haemoglobin, myoglobin and cytocromes (2-2.7 g). In bone marrow, every day, 20 mg of iron deriving from lyses of senescent erythrocytes, are utilized for the synthesis of the new erythrocyte heme. The non-hemic iron store in cells and blood is guaranteed by ferritin, a protein able to sequestrate more than 4500 iron atoms per molecule. I ron deficiency is the most common nutritional deficiency, and an important nutritional disorder afflicting about two billion of people in the world. Iron deficiency has been identified by World Health Organization as one of the ten risk factors for illness, disability and death in the world. Moreover, iron deficiency in pregnant women as a consequence of an increased iron requirement, due to enhanced blood volume and development of foetal-placenta unit, represents a high risk for maternal and infant health: preterm delivery, foetal growth retardation, low birth weight, inferior neonatal health. There are three possible ways to prevent and control the development of iron deficiency and iron deficiency anaemia. These encompass dietary diversification, food fortification, and individual supplementation. Anyway, the preferred treatment of these pathologies consists in oral administration of iron as ferrous sulphate. However, the large quantity of ferrous sulphate to be administer to subjects, suffering of iron deficiency and iron deficiency anaemia, is related to the poor bio-availability of inorganic iron. Moreover, ferrous sulphate oral administration often fails to exert significant effects on iron deficiency and iron deficiency anaemia, and frequently causes many problems, including gastrointestinal discomfort, nausea, vomiting, diarrhoea, constipation, and sometimes may increase the susceptibility to infections. Lactoferrin, a glycoprotein synthesised by exocrine glands and neutrophils, able to chelate two ferrric ions per molecule, can be an interesting alternative to ferrous sulphate in preventing and curing iron deficiency and iron deficiency anaemia in pregnant women. The idea to orally administer lactoferrin is very fashionable, by the light of the recent knowledge on the role of inflammation in iron homeostasis. A s matter of fact, recent clinical studies have clearly demonstrated the efficacy of lactoferrin in rescuing iron homeostasis, in the absence of any side effect. Lactoferrin, orally administered, restores the physiological levels of iron in the blood, thus preventing a cell damage induced by iron overload in the tissues

Bovine lactoferrin in preventing preterm delivery associated with sterile inflammation

Preterm delivery (PTD) occurs before the 37th week of gestation. Iron deficiency anemia and inflammatory processes either related to infection or sterile inflammatory response represent risk factors for PTD. Bovine lactoferrin (bLf), an emerging important regulator of iron and inflammatory homeostasis, can represent a new therapeutic approach for PTD treatment. Here an open-label cohort and subcohort study is reported. The cohort was designed to assess the effect of bLf oral administration on iron and inflammatory homeostasis in anemic pregnant women. The subcohort including women of the cohort with PTD threat was additionally treated with bLf intravaginal administration. A significant improvement of hematological parameters was observed in the women's cohort together with a consistent decrease of serum interleukin-6 (IL-6) levels. Combined administration of oral and intravaginal bLf to the women's subcohort with PTD threat decreased IL-6 in both serum and cervicovaginal fluids, cervicovaginal prostaglandin F-2 alpha, and suppressed uterine contractility. BLf administration blocked further shortening of cervical length and the increase of fetal fibronectin thus prolonging the length of pregnancy. The deliveries occurred between the 37th and 38th week of gestation. These results provide strong evidence for a role of bLf in PTD treatment, thus extending the therapeutic potential of this multifunctional natural protein

Importanza dell'attività antinfiammatoria della lattoferrina nell'omeostasi sistemica del ferro.

Il ferro, elemento essenziale per gli esseri viventi a causa della sua caratteristica di acquisire e cedere elettroni, può, se presente in eccesso, essere tossico a causa della sua capacità di promuovere la formazione di specie reattive dell'ossigeno e la moltiplicazione microbica. Questa doppia natura impone una sottile regolazione dell'omeostasi sistemica del ferro che, nell'uomo, è regolata dall'assorbimento intestinale e dal trasporto del ferro dalle cellule al circolo. In condizioni patologiche, l'inibizione del trasporto del ferro dalle cellule al circolo porta ad anemia da carenza di ferro associata ad un dannoso accumulo di ferro nei tessuti e nelle secrezioni, che favorisce le infezioni e le infiammazioni. La regolazione ed il mantenimento dell'omeostasi sistemica del ferro sono fattori chiave per la salute dell'uomo. Nei tessuti e nelle secrezioni, in situazioni fisiologiche, la concentrazione di ferro disponibile non deve superare 10 -18 M ed è garantita dalla lattoferrina (Lf), una glicoproteina in grado di chelare due ioni ferrici per molecola. Lf è sintetizzata dalle ghiandole esocrine e dai neutrofili nei siti di infezione e d'infiammazione e differentemente dalla transferrina, tipica proteina di trasporto del ferro che rilascia questo ione già a pH 6.5, Lf è in grado di tenere legato lo ione ferrico fino a pH inferiori a 4, tipici dei siti d'infezione ed infiammazione. Alla Lf fu primariamente attribuita un'azione antimicrobica dipendente dalla sua capacità di legare, con alta affinità, il ferro necessario alla replicazione dei microorganismi. Successivamente, le furono attribuite numerose altre funzioni indipendenti dalla capacità di chelare il ferro, come, recentemente, quella di diminuire la sintesi delle citochine pro-infiammatorie, inclusa l'interleuchina 6 (IL-6). Infatti, in alcune situazioni patologiche, la quantità di ferro è così elevata da rimanere ancora in eccesso dopo la saturazione completa della lattoferrina. L'eccesso di ferro disponibile attiva un processo infiammatorio che richiama i neutrofili che, a loro volta, secernono la lattoferrina nel sito d'infezione/infiammazione, contribuendo alla diminuzione sia del ferro disponibile che della sintesi delle citochine pro-infiammatorie. Le nuove acquisizioni sui disordini dell'omeostasi sistemica del ferro, dipendenti dal sovraccarico di ferro nei tessuti e dalle citochine proinfiammatorie, unitamente ai nostri recenti risultati sull'attività antiinfiammatoria della lattoferrina ottenuti in vitro ed in vivo, ci hanno permesso di scoprire il ruolo chiave di questa proteina naturale, estratta dal latte bovino, nella regolazione dell'omeostasi sistemica del ferro attraverso la diminuzione dell'infiammazione, ed il conseguente ripristino dell'espressione della ferroportina e dell'epcidina, principali fattori dell'omeostasi sistemica del ferro

Body iron delocalization: the serious drawback in iron disorders in both developing and developed countries

Over 2 billion people in both developing as well as developed countries - over 30% of the world's population - are anaemic. With the classical preconception that oral iron administration or the intake of foods rich in iron increase haemoglobin concentration and reduce the prevalence of anaemia, specific programs have been designed, but iron supplementations have been less effective than expected. Of note, this hazardous simplification on iron status neglects its distribution in the body. The correct balance of iron, defined iron homeostasis, involves a physiological ratio of iron between tissues/secretions and blood, thus avoiding its delocalization as iron accumulation in tissues/secretions and iron deficiency in blood. Changes in iron status can affect the inflammatory response in multiple ways, particularly in the context of infection, an idea that is worth remembering when considering the value of iron supplementation in areas of the world where infections are highly prevalent. The enhanced availability of free iron can increase susceptibility and severity of microbial and parasitic infections. The discovery of the hepcidin-ferroportin (Fpn) complex, which greatly clarified the enigmatic mechanism that supervises the iron homeostasis, should prompt to a critical review on iron supplementation, ineffective on the expression of the most important proteins of iron metabolism. Therefore, it is imperative to consider new safe and efficient therapeutic interventions to cure iron deficiency (ID) and ID anaemia (IDA) associated or not to the inflammation. In this respect, lactoferrin (Lf) is emerging as an important regulator of both iron and inflammatory homeostasis. Oral administration of Lf in subjects suffering of ID and IDA is safe and effective in significantly increasing haematological parameters and contemporary decreasing serum IL-6 levels, thus restoring iron localization through the direct or indirect modulation of hepcidin and ferroportin synthesis. Of note, the nuclear localization of Lf suggests that this molecule may be involved in the transcriptional regulation of some genes of host inflammatory response. We recently also reported that combined administration of oral and intravaginal Lf on ID and IDA pregnant women with preterm delivery threat, significantly increased haematological parameters, reduced IL-6 levels in both serum and cervicovaginal fluid, cervicovaginal prostaglandin PGF2 alpha, and suppressed uterine contractility. Moreover, Lf combined administration blocked further the shortening of cervical length and the increase of foetal fibronectin, thus prolonging the length of pregnancy until the 37th-38th week of gestation. These new Lf functions effective in curing ID and IDA through the restoring of iron and inflammatory homeostasis and in preventing preterm delivery, could have a great relevance in developing countries, where ID and IDA and inflammation-associated anaemia represent the major risk factors of preterm delivery and maternal and neonatal death