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bases of a pathogenesis of an anaemia at chronic illnesses

Cytokines and cells of reticuloendothelial system cause changes in a homeostasis of iron, a proliferation of erythroidal cells-precursors, production of erythropoetin, life expectancy of erythrocytes, each of which brings the contribution to a pathogenesis of an anaemia [131,248,252].

The typical representative of "an inflammation anaemia», caused by action exclusively cytokines is the anaemia, assotsiirovannaja with rhematoid
The arthritis, known as a rhematoid anaemia [149]. In the absence of effective treatment an anaemia widespread among patients with a pseudorheumatism (according to various researches from 33,3 to 59,1 %) [185].

Disturbance of regulation of a homeostasis of iron in an organism

Distinctive feature AHB is development of disturbances of a homeostasis of iron with the raised consumption and iron accumulation in cells of reticuloendothelial system. It leads to a redirection of iron from circulation in storehouse in reticuloendothelial system. With the subsequent restriction of availability of iron for erythroidal cells-precursors and, as consequence, to an iron deficiency erythrogenesis [43,245].

In 2001 data about allocation from urine of the person of a new peptide which as believed, possesses antimicrobial properties as it is rich with Cysteinum for the first time have been published. The fiber name gepsidin (hepcidin) has been formed from: hepar (an armour. - a liver - a place of synthesis of a peptide) and cidin (an armour. - unichtozhitel - underlines antimicrobial properties of a peptide) (a drawing 1.1.) [97]. Later it has been shown, that synthesis gepsidina occurs and in the tubular apparatus of kidneys, and in other cells, tissues and organs, including macrophages, adipotsity and brain cells that can speak about the important role gepsidina in autocrine and parakrinnom the control of an exchange of iron at local level [73,1б2,221,255]. Allocation gepsidina - ostrofaznogo fiber-regulator of an exchange of the iron consisting of 25 amino acids - has helped to throw light on communication of the immune answer and a homeostasis of iron and AHB [240].


Gepsidin it is coded as 84-amino-acid prepropeptid [237]. The mature hormone circulates in plasma and is bound to a2-macroglobulin [98]. While activating action of this communication has been described, deducing mechanisms gepsidina are up to the end unknown till now. The basic way of deducing gepsidina - its egestion with urine. When function of kidneys is not broken, concentration gepsidina in urine correlates with level circulating gepsidina, without visible regulation of process of an egestion. However, being based on comparison between concentration gepsidina in blood serum and urine, only 5 % gepsidina plasmas filtered by kidneys, are deduced in not changed kind with urine. It means that gepsidin it can not freely be filtered in glomuluses and-or filtered gepsidin reabsorbiruetsja and degrades in proximal canaliculuses, it is similar to another small peptidnym to hormones [109,231]. Gepsidin the receptor-mediated endocytosis in the tissues expressing its receptor - ferroportin also can be deduced, that shows accumulation labelled gepsidina in tissues rich ferroportinom and destruction by complex endocytosis gepsidin-ferroportin in cultivated tissues [213].

On the structure gepsidin reminds the bent hairpin for the hair, linked among themselves four disulfide ponticuluses. Last data show, that for communication gepsidina with a receptor participation of one of disulfide communications is required. Excision of one of disulfide communications does not lead to significant depression of activity gepsidina in vitro, it testifies that plural disulfide communications can promote formation of contact with ferroportinom [223].

Amfipatichesky structure gepsidina and its plural disulfide communications usually characterise antimicrobial and antifungoid peptides. However gepsidin shows only modest antimicrobial properties in vitro and only in the big concentration (10 - 30 іі), the importance of its antimicrobial possibilities in vivo is not defined. At patients with the hereditary
The hemochromatosis bound to deficiency gepsidina, describes development of the infections caused by atypical microorganisms (Vibrio, Yersinia and Listeria). But this susceptibility can be bound to the advantages received by bacteria, in connection with the raised level of iron, more than with loss of immediately antibacterial effect gepsidina [162]. The structure gepsidina is presented in a drawing 1.2.

Drawing 1.2. A structure gepsidina [162]

Gepsidin is the main regulator of concentration of iron in plasma. The injection gepsidina to mice leads to appreciable depression of serumal iron within an hour. In spite of the fact that gepsidin it is quickly deduced from plasma, the effect from introduction of one dose remains till 72 o'clock. Possibly, this time is required for a resynthesis of enough of a receptor gepsidina - ferroportina [94,213].

The inflammation at gepsidin-scarce mice does not lead to depression of iron of Serum [53,107]. The induction gipoferremii interlejkinom-6 and gepsidinom develops within several hours and it does not become perceptible at mice with switched off
Expression interlejkina-6, processed by turpentine (as inflammation model) [107].

The chronic hyperproduction gepsidina leads to development zhelezoyoogranichennoj to an anaemia at mice and the person [204]. On the contrary, deficiency gepsidina leads to an overload iron with iron accumulation in a liver and other organs. Full absence gepsidina leads to development juvenilnogo a hemochromatosis, the most serious form of a hereditary hemochromatosis [138,145,222].

Excess and deficiency implications gepsidina show, that gepsidin inhibits an iron absorption in an intestine and representation of iron from the macrophages utilising old erythrocytes [71]. At a hyperproduction gepsidina in embryonal development in a foetus the iron deficiency anaemia develops and many die at a birth, it testifies that gepsidin inhibits transplacental transport of iron [204]. Gepsidin, probably, also blocks, at least partially, export of stocks of iron from hepatocytes, in it specifies iron accumulation in a liver at the mice suffering gepsidinprodutsirujushchimi by tumours [90]. Gepsidin, made out of a liver, can carry out the control over a local exchange of iron in tissues in which it is produced. For example, the central nervous system is separated from plasma by a hematoencephalic barrier and circulating gepsidin cannot be transported through this barrier. However it has been described, that brain tissues can produce gepsidin, keeping possibility to regulate a local metabolism of iron irrespective of the system control [196,253].

Gepsidin operates, modulating export of cellular iron to plasma and an extracellular liquid, means ferroportina. Ferroportin is simultaneously both a receptor gepsidina and unique known the exporter of cellular iron at pozvonochnyh. Ferroportin expresses on the cells which are professional output agents of iron in an organism: the enterocytes of a duodenum absorbing alimentary iron,
Macrophages of a liver and the lien, utilising old erythrocytes, the hepatocytes reserving iron and trophoblasts, transporting iron to a foetus during pregnancy [220]. Ferroportin also expresses on erythroidal cells predecessors, it allows to assume, that its presence allows to raise sensitivity of cells-predecessors to system level of iron and helps to define a direction of their growth and a differentiation [7]. It has been shown, that full absence of an expression ferroportina at mice led to mors of embryoses, in connection with impossibility of embryonal trophoblasts to transport iron from mother to a foetus. At mice with selective interlocking of production ferroportina (with kept placental ferroportinom) the newborn mice deprived ferroportina, had a serious iron deficiency anaemia, owing to a low absorption of alimentary iron in 12 perstnoj to an intestine, and also the broken representation of iron from hepatic stocks and the macrophages utilising iron [220].

posttransljatsionnnyj the level control ferroportina it ligandom gepsidinom - a leading way of regulation ferroportina. Linkage gepsidina with ferroportinom starts internalization and complex degradation ligand - a receptor [94]. Linkage, most likely, includes a disulfide exchange between one of disulfide communications gepsidina and external tiolnym rest Cys326 ferroportina. At patients with mutation Cys326S the taped overload iron develops early, mutant ferroportin loses ability to contact gepsidinom in vitro. As soon as there was an internalization, a complex gepsidin-ferroportin degrades in lysosomes and transport of cellular iron stops. The expression gepsidina can be regulated also irrespective of gepsidina, the cellular maintenance of iron. The mechanism of transport of iron ferroportinom remains not investigated [7].

Gepsidin gomeostaticheski it is regulated by level of iron, hemopoietic activity and a hypoxia. Excess of iron stimulates production gepsidina and
Hormone rising, in turn, blocks an iron absorption in an intestine, preventing the further load iron. On the contrary, production gepsidina is oppressed at deficiency of iron, allowing to raise an absorption of alimentary iron and replenishment of stocks of iron. Rising of erythropoietic activity also renders supressivnyj effect on production gepsidina. Besides rising of an absorption of iron it allows to give quickly stocks of iron from macrophages and hepatocytes and to enlarge delivery of iron for an erythrogenesis. Besides, the hypoxia reduces production gepsidina, causing the effects described above. The molecular mechanism underlying regulation of level gepsidina by means of level of iron and activity of an erythrogenesis, is area of intensive researches, but still is not completely understood. Level gepsidina also is enlarged at an inflammation and an infection, and it assumes, that the given mechanism is the answer of immune system for the purpose of restriction of availability of iron for microorganisms. It is considered, that the inflammation is the most powerful regulator of production gepsidina and suppresses action of other mechanisms [33,68,93,116,147,227,254].

Production regulation gepsidina mediated by iron is carried out, most likely, by in common circulating iron bound to a transferrin (FeTf), and cellular stocks of iron. Besides, zhelezoyosensornye molecules for extracellular and intracellular iron, probably, different, but they, most likely, use a way of a medullar morphogenetic protein (BMP) for expression rising gepsidina. The given way has arisen as the extremely necessary regulator of an expression gepsidina [9]. Usually, koretseptorom in the given process is gemojuvelin (HJV). At people with a mutation blasting HJV the overload iron bound to excision gepsidina, without other visible disturbances [158,165] develops. The second way of regulation of production gepsidina includes transferrinovye receptors 2 (TfR2) and HFE. TfR2 are gomologami TfR1 - the receptors necessary for capture of iron by enterocytes, also expresses on many other things types of cells [80,226]. HFE - a protein similar MHC 1 class. It does not bind
Iron, but influences an iron metabolism oposredovanno through zhelezoyosvjazyvajushchie fibers - TfR1 and TfR2. In researches it has been shown, that interaction HFE and TfR2 is necessary for an induction gepsidina in reply to FeTf [118]. Mutations HFE and TfR2 are described at the adult form of a hereditary hemochromatosis. Also interaction HFE and TfR2 with HJV has been described and is possible, that linkage FeTf with TfR1 and TfR2 initiates formation of a supercomplex consisting of HFE, TfR2, HJV and BMP receptors [133]. Besides FeTf, gepsidin it can be regulated also by the iron stocks, presumably some forms of intracellular iron. The mechanism of participation of intracellular iron in regulation gepsidina while remains obscure, however recently on the first positions in this process left BMP6 which operates, being bound immediately with HJV. However still it is necessary to define, how production BMP6 is regulated by iron [32]. Also presence of the molecules co-operating with HJV and changing its expression on a surface of cells has been described. It is a protease - matriptaza-2 (matriptase-2) which codes gene TMPRSS6, and the big multifunctional transmembrane protein neogenin (neogenin). neogenin regulates a homeostasis of iron by the oppression of secretion HJV inhibiting alarm system BMP, that, in turn, leads to expression rising gepsidina. Матриптаза-2 negative impact on production gepsidina, by splitting gemojuvelina [60,129,163,221,256] is transmembrane serinovoj a protease, making.

Erythropoietic activity plays the important role in production regulation gepsidina. Level gepsidina decreases at an iron deficiency anaemia, hemolitic anemias and anemias with a noneffective erythrogenesis. However the mechanism of depression of production gepsidina at these conditions can be various. These mechanisms can include the soluble proteins developed in an osteal brain by erythroblasts, depression of circulating iron or its stocks and a hypoxia. The molecular bases involved in given mechanisms while remain are obscure. Erythropoetin (EPO) induced by a hypoxia can operate as the intermediary and to oppress production gepsidina
Through EpO-stimulirovannuju a proliferation of erythroblasts, products of secretion of precursors of erythrocytes and, finally, rising of recycling of iron for synthesis of haemoglobin [99,195,210].

The inflammation plays the leading part in synthesis regulation gepsidina. The expression gepsidina is induced lipopolisaharidami and interlejkinom-6, and inhibited FNO [12,107]. Synthesis gepsidina quickly raises at an infection and an inflammation. ИЛ-6 is the basic inductor gepsidina and operates through STAT3-dependent transkriptsionnyj the mechanism. At volunteers by whom has been entered ИЛ-6, the egestion gepsidina with urine was enlarged several times in 2 hours after infusion (the Drawing 1.3.) [89,92,95,106,213,239].

Drawing 1.3. An inflammation role in synthesis regulation gepsidina [89]

At mice by which proinflammatory cytokines - interlejkin-1 and the factor of a necrosis of tumours were entered and (FNO) have developed depression of the maintenance of iron in Serum and an anaemia [114]; the combination of these conditions has been bound about a cytokine - by the induced synthesis of a ferritin - the main fiber, assotsiirovannogo to storage of iron by macrophages and hepatocytes [225]. At a chronic inflammation absorption of iron by macrophages occurs by eritrofagotsitoza and transmembrane import to fiber participation - divalent metallotransportera 1 (ДМТ1) [13,130].


ИФН-y, lipopolisaharidy, FNO raise expression ДМТ1 which in turn raises iron absorption by the activated macrophages [13]. These proinflammatory stimulus also induce expression depression ferroportina, thus, blocking an exit of iron from macrophages and its accumulation in them [43]. Ferroportin - transmembrane the exporter of iron as believe responsible for transport of the adsorbed "alimentary" iron from enterocytes in circulation [179]. Moreover, antiinflammatory cytokines, such as ИЛ-10, can cause an anaemia, through stimulation a transferrin - of the induced absorption of iron macrophages and transmitting stimulation of an expression of a ferritin [197].

Depression of production of erythropoetin

Erythropoetin on-line regulates a proliferation of erythroidal cells. The erythropoetin expression back depends on oxygenation of tissues and haemoglobin level. Production of erythropoetin at patients with AHB mismatches anaemia degree in the majority, but not in all cases [46,47].

Cytokines - ИЛ-1 and FNO directly inhibit an erythropoetin expression in vitro - that possibly speaks, at least partially, the CYTOKINE - the induced formation of active forms of oxygen which in turn lead to damage erythropoetin-producing of cells. Though the convincing data received in researches in public not enough, injections lipopolisaharidov to mice lead to an expression reduction mrnk erythropoetin in kidneys and to depression of level of circulating erythropoetin [134].

Sensitivity of cells-precursors to erythropoetin, possibly, is back bound to principal causes of chronic disease and quantity of cytokines circulating in blood. Concentration of interferon-Y or FNO it is ready above quantity of the erythropoetin necessary for restoration of formation E-fight [8,150].

Sensitivity to erythropoetin decreases by means of ingibitornyh effects of the proinflammatory cytokines referred on a proliferation of erythroidal cells-predecessors even more. In parallel depression of receptors of erythropoetin and restriction of availability of iron bring the contribution to retardation of a proliferation and haemoglobin synthesis. At last, raised eritrofagotsitoz leads to depression of life expectancy of erythrocytes, along with prospective damage of erythrocytes by cytokines and free radicals [31,207].

Retardation of a proliferation of erythroidal cells-precursors

At patients with AHB the proliferation and a differentiation of erythroidal precursors - erythroidal burstobrazujushchih units (E-fight) and erythroidal kolonieobrazujushchih units (E) - is slowed down and bound with ingibitornym effect of interferon,-in and, FNO, interlejkina-1 which influence growth E-fight and E [151]. Интерферон-Y sees the most powerful inhibitor that is reflected by return correlation between its level in blood and concentration of haemoglobin and number of reticulocytes [241]. The basic mechanism can include a cytokine-mediated an induction of an apoptosis which, probably, is partially bound to formation tseramida and depression of an expression of receptors of erythropoetin on cells-predecessors, oppression of formation of erythropoetin and depression of an expression of other prohemopoietic factors, such as the factor stvolovyh cells [151,119,241]. Besides, cytokines precursors have direct toxic influence on cells - causing formation of labile free radicals, such as okis nitrogen or superoksid anion, nearby macrophages [167].

It has been besides, described, that gepsidin oppresses an erythrogenesis (in vitro) at the lowered concentration of erythropoetin [44]. And disturbance of a homeostasis of iron, owing to a hyperproduction gepsidina, leading to availability restriction
The gland for erythroidal cells-precursors leads to retardation of their division owing to negative influence on biosynthesis gemma [245].

1.2.2.

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Scientific source EGOROV Andrey Sergeevich. THE GEPSIDIN-INTERLEUKIN-6 SYSTEM AS A FACTOR FOR MANAGING THE COURSE OF ANEMIA IN CHRONIC ARTHRITIS IN CHILDREN DISSERTATION for the degree of candidate of medical sciences. St. Petersburg - 2016. 2016

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