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1.4. A role of glucocorticoid hormones at diseases of lungs

Glucocorticoids possess powerful antiinflammatory dejstviyoem which is bound to their influence on microvessels, cells and production cells of mediators of an inflammation.

One of the basic components of inflammatory process in bronchuses and lungs is rising of permeability of vessels microvascular rusyola, a transuding of a liquid part of plasma in intercellular space and foryomirovanie an inflammatory edema.

Experimental researches on gryyozunah have shown, that entered intravenously or mestno glucocorticoids inhibit caused by inflammation mediators raised pronitsaeyomost microvessels (Boschctto P., Rogers D. F., Fabbri L. M.ct. al., 1991). This effect is caused as direct stabilising action gljukokorti-koidov on an endothelium of vessels, and sensitivity rising sosudiyostoj walls to pressornym to agents, for example kateholamiiam (permissivnoe action of glucocorticoids). Glucocorticoids oppress also rising of permeability of the vessels, caused iejrogennym with an inflammation in bronchuses. It is supposed, that it occurs thanks to activity rising nejyotralnoj eidopeptidazy which oppresses liberation tahikininov from the sensitive nervous terminations (Barnes P. J., 1991).

gljuyokokortikoidov it is possible to carry their influence on quantity and activity to number of the basic mechanisms of antiinflammatory action kleyotok, participating in inflammation realisation in bronchuses and lungs, and their this influence is rather various. So, it is shown, that kortikostsroidy sniyozhajut quantity circulating in blood bazofilov, monocytes and limfoyotsitov. Partly this effect is bound to oppression of factors iigibirujushchih graiulotsitopoez, such as graiulotsity - macrophages koloniestimuliruju-shchy the factor (GMKSF). Besides, kortikostsroidy stimulate an exit of eosinocytes and, probably, lymphocytes from a blood channel and depot in perifeyoricheskie tissues, including in bronho-pulmonary, leading, thus, to reduction of their quantity in blood. In this connection eozinopeiichesky and limfopenpchesky effects of glucocorticoids bind recently, basically, not with destruction of cells in blood, and their redistribution in organism tissues (Barnes P. J., 1991).

The quantity of mast cells in mucous bronchuses again decreases under the influence of glucocorticoids that bind with ingibitsiej them vysvoyobozhdenija factors of growth of a mast cell, such as intsrlejkin-3 and GMKSF.

Further under the influence of glucocorticoids the exit of the majority of leucocytes from a vascular bed in peripheric tissues and oryogany in a consequence ingibitsii liberation hsmoattraktantov and the cytokines activating an endothelium of vessels, such as intsrlsikin-1, the factor of a necrosis of a tumour (Doc R is oppressed. P., Lohrenz F., River G. et. al., 1982). At the same time gljukoyokortikoidy stimulate synthesis of neutrophils in an osteal brain, that privoyodit to augmentation of the maintenance of neutrophils in peripheric blood.

Besides, glucocorticoids operate not only on mobility of leucocytes, but also also on their various functions. It is established, that they poyovyshajut synthesis V-adrsnortseptorov owing to what the V-Adrenergichesky answer amplifies, adenylatecyclase is activated, synthesis ts-AmF (Doe R amplifies. P., Lohrcnz F., River G. et. al., 1982). Glucocorticoids also inhibit degranulate of macrophages, bazofilov and mast cells, that doyokazano while in experiments on animals.

Anyway, depression quantity of receptors kompleyomenta and activity of monocytes of the person under the influence of glucocorticoids is shown. They reduce also proliferation T-limfotsitov, reduce them aktivyonost at the expense of production oppression intsrlsjkina-2 (Doe R. P., Lohrcnz F., River G. et. al., 1982).

Last years it is established, that glucocorticoids reduce koliyochestvo and reduce activity of dendritic cells in mucous bronchuses, that oppresses activity of an inflammation in reply to such stimulus, as allergen (Howarth J., Huszr E, Barath E, Kollai M, 1996).

The action mechanism gljukokoryotikoidov speaks subcellular and molecular level their influence on the genetic apparatus of a cell. schitayoetsja, that owing to the lipofilnosti steroids freely pass cheyorez a cellular membrane and get in a cell where contact tsi-toplazmaticheskimi glucocorticoid receptors. Further the complex a glucocorticoid-receptor gets into a cell kernel in which it operates as the transcription factor, being bound with areas of DNA specific to it. This interaction leads to activation or gene-target oppression (Ray A., Siegel M, D., Prefontaine to. E, Ray R, 1995). As a result of this interaction decreases or synthesis matrix RNK (m-rnk) is enlarged, that, in turn, leads to production rising nekoyotoryh mediators, enzymes and other fibers, including lipokortin-1, endoyo

nuklsazy, neutral epdoneptiazu, V-adrenorepsptory and to depression of production of other mediators, first of all cytokines. Now it is established, that cytokines play the leading part in formation and about-gresenrovaiii inflammatory process at acute and chronic nespe-pificheskih diseases of lungs, such as a bronchial asthma and hronicheyoskaja obstruktnvnaja illness of lungs (Barnes P. J., 1995). Therefore it is active veyodetsja search of new ways of the therapy based on influence on cytokines. However yet it was not possible to frame specific the CYTOKINE-ingibitory, kotoyorye would appear in treatment of an inflammation by more effective, than gljukokor-tikoidy (Barnes P. J., 1995).

Last years new mechanisms of interaction of glucocorticoids with tsitokpnami have been found out. It is known, that cytokines operate on cells by change of a transcription of genes. Their interactions with retseptoyorami the pas of a surface of a cell leads to activation of factors of a transcription, such, as the protein-1 activator (АП-1) and the nuclear factor kappa-in (JAFkB) (Barnes P. J., 1995; Ray L, Sicgcl M, D., Prefontaine To. E, Ray R, 1995). These factors then are referred to a cell kernel where contact DNA (in prinyotsipe, same by, as well as a complex a glucocorticoid-receptor) and influence, thus, synthesis m-rnk and production of proinflammatory proteins (cytokines) in a cell. It has appeared, that the complex a glucocorticoid-receptor can co-operate immediately both with АП-1, and with JAFkB in a kernel, warning, thus, their action as factor of a transcription of DNA and effectively blocking influence of cytokines on a cell. It is a protein - proteiyonovoe interaction - more authentically, according to some authors, explains very important mechanism of antiinflammatory action gljukoyokortikoidov (Ray A., Siegel M, D., Prefontaine to. E, Ray R, 1995; Rutgers S. R., Postma D. S., van der Mcrk Th. W., Kocter G. H., 1996). As JAFkB and АП-1 mediate hronnzatsiju inflammatory effects, their inactivation leads to oppression of this process.

Recently also it has been shown, that deksamstazon would stimulate produkyotsiju 1, the squirrel who contacts JAFkB in a cytoplasma and warns sju a translocation in a cell kernel (Ray A., Siegel M, D., Prefon­taine to. E, Ray R, 1995). Oppression of translocation JAFkB also conducts to reyoduktsii liberation of cytokines and to expression reduction vospaliyotelnoj reactions.

Except cytokines, the important role in formation inflammatory proyotsessa in the bronho-pulmonary apparatus, at such diseases as bronhialyonaja the asthma and a chronic obstructive bronchitis, is taken away to eicosanoids which are synthesised from membranous fosfolipidov by activation kasyokada enzimov, known as the cascade arahidoiovoj acids. Such biologically active substances concern eicosanoids, as lejkotrisny, about-staglandiny, tromboksan and lipoksiny. Lejkotrisny are among naiyobolee the powerful inflammatory mediators participating in a pathogenesis razyolichnyh of diseases of bronchuses and lungs. It is known, that glucocorticoids ii-gibirujut liberation lejkotrienov from inflammation cells. The mechanism of their action explain stimulation of synthesis of fiber lipokortina-1 which blocks enzyme fosfolipazu Ag, a "starting" metabolism arahidoioyovoj acids (Barnes P. J., 1991;. Honvath J., Huszr E, Barath E, Kollai M, 1996).

It has appeared also, that glucocorticoids reduce production okisi the nitrogen, one of aggressive factors of an inflammation who is found out in exhaled air at diseases top and bottom respiratory puyotej (Baraldi E, Azzolin N., Zanconuto S. et al., 1996; Tokuyama K., Lotvall J. O., Lofdahl C. G., Barnes P. L., Chang K., 1990). okis nitrogen it is formed of a L-arginine bazaliymi by epithelial cells under influence indutsirueyomoj nitro-oksid-sintazy (Horwath R, 1997). Glucocorticoids inhibit activity of this enzyme at the expense of blockade of cytokines (intsrlsjkina-1-bsta and the factor, nskrotizirujushchego a tumour-alpha) which induce eksyopressiju nitro-oksid-sintazy (Mosonyi L., 1976).

Thus, glucocorticoids possess powerful ish ibirujushchim effect on inflammatory process thanks to width and variety meyohanizmov actions at cellular, subcellular and molecular levels.

Therefore the deficiency of an endogenous hydrocortisone appearing at patients, especially with fixing or chronic forms of an inflammation in bronchuses and lungs, promotes development and advance inflammatory proyotsessa. Mechanisms of development of glucocorticoid insufficiency can be various, bound both with disturbance of function of adrenals, and with extraadrenal factors.

The adrenal glucocorticoid insufficiency caused nayorusheniem of synthesis of glucocorticoid hormones by cells of a cortex nadpochechyonikov, is caused by long hormonal therapy (Chuchalin F.G., Shmushkovich B.I., Mavrasv D.E., 1984 more often; Pederson S., 0, Byrnc P., 1997), attrition of reserve possibilities of a cortex of adrenals owing to long stress, an intoxication and a hypoxia, meeting at dliyotelno current chronic diseases, including bronchial astyome (Pytsky Century I, Andrianova N.V., Artomasova A.V., 1995; Trofimov V. I, SHaporova II.Л., Lebedeva D.P., 1991). Other, more rare variant razyovitija adrenal glucocorticoid insufficiency, is nayorushenie parities between the basic hormones synthesised by a cortex of adrenals (Pytsky Century I, Sjusjunin J.P., Hodakova I.A., etc., 1988). It was found out, that under the influence of a number of factors (the chronic hypoxia, metayobolicheskie disturbances) occurs reduction of synthesis of a hydrocortisone (osnovyonogo a glucocorticoid hormone of the person) at simultaneous uvelicheyonii synthesis of Corticosteronum possessing considerably smaller protivoyovospalitelnym and antiallergenic action.

To the factors promoting depression of steroid function of a cortex of adrenals, it is necessary to carry interaction disturbance in system reguyoljatsii a hypothalamus-pituitary body-bark of adrenals. Well-known, that reyoguljatsija synthesis of glucocorticoids in norm is carried out, basically, by a principle of a negative feedback, that is depression of level of a hydrocortisone in a blood plasma conducts to augmentation of synthesis of a kortikotropin-rilizing-hormone (kortikoliberina) a hypothalamus and the AKTG-HYPOPHYSIS. Spent on chair of hospital therapy SPBGMU it. akad. I.P.Pavlova obsledoyovanie 56 sick bronchial asthma with use small dsksameta-zonovogo the test disturbance funktsionirovayonija has allowed to tap at 80 % from them systems a hypothalamus-pituitary body-bark of adrenals which was svjazayono, apparently, with rising of a threshold of sensitivity of cells gipotalayomusa and a pituitary body to inhibiting action of glucocorticoids (Trofimov V. I, Shaporova P. L, Lebedeva D.P., 1991; Trofimov V. I, 1992). And it priyovodit to stimulation of synthesis of glucocorticoids by a cortex of adrenals on nayochalnyh stages of formation of a bronchial asthma with the subsequent istoshcheyoniem reserve possibilities of a cortex of adrenals or progressed!! Diseases.

One of the important reasons of development extraadrenal gljukokortiko-idnoj failures is the raised linkage of hormones by fibers of plasma by Transcortinum and an albumin. Synthetic steroids are bound by Transcortinum a little bit more weakly, than Hidrocortizonum that causes their easier penetration into organism tissues (Sergeev P. V, 1984).

The given literatures and results of the researches spent on kafedyore hospital therapy of SPb GMU by it. akad. I.P.Pavlova, testify to the raised linkage of glucocorticoids trapkortinov and depression of level of free, biologically active fraction of hormones at a part bolyonyh a bronchial asthma (Landyshsv J.S., Marihina N.S., Shavilova A.N., etc., 1986; Trofimov V. I, Shaporova N.L., Lebedeva D.P., 1991). The reasons of rising of activity traiskortina are insufficiently studied (one of them is augmentations of level of estrogens in a blood plasma), however, abundantly clear, that this factor can serve one of development mechanisms otyonositelnoj gljukokortikoidioj to insufficiency at kept or dayozhe to the raised steroid function of a cortex of adrenals.

Certain value in a biological inactivation of Hidrocortizonum has also its linkage with blood cells, first of all, erythrocytes (Sergeev P. V, 1984).

Except the described mechanisms of development glucocorticoid nedostayotochnosti, at sick of a bronchial asthma takes place fabric or kletochyonyj the mechanism se formations. According to V.I.Pytskogo (1988) and issledoyovany, spent on chair of hospital therapy of SPb GMU it. akad. I.P.Pavlova, almost at 60 % surveyed sick of a bronchial asthma the authentic augmentation of number of the lymphocytes steady to dejstyoviju physiological and pharmacological concentration of a hydrocortisone (TroYofimov V. I, Shaporova N.L., Lebedeva D.P., 1991) became perceptible. Researches, provedenyonye on chair of hospital therapy of ST.-P. GMU it. akad. I.P.Pavlova, poyozvolili to tap authentic depression of absorption of a hydrocortisone by lymphocytes at sick of a bronchial asthma in comparison with healthy faces. NaiYObolee considerably a hydrocortisone-absorption of lymphocytes it has been broken at patients infectious dependent and dishormonal variants zaboleyovanija (Trofimov V. I, Shaporova N.L., Lebedeva D.P., 1991; Shaporova N.L., 1990). Apparently, reduction kortizolpogloshchenija lymphocytes is bound to depression of number of membranous receptors of glucocorticoids to which belongs, on modern representations, the important role in proniknoveyonii a hormone in a cell and, realisations of its biological effects (SQUARE GoYolikov, 1988).

Apparently, the cellular mechanism of development glucocorticoid neyodostatochnosti at sick of a bronchial asthma is shown before other mechanisms as disturbances of absorption of a hydrocortisone by lymphocytes byyoli are found out in patients with a preasthma and persons with development threat bronhialyonoj asthmas (Fedoseyev G. B, Trofimov V. I, Sinitsina T.M., 1989;. Trofimov V. I, 1992).

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Scientific source Yefimova Olga Aleksandrovna. ESTIMATION of EFFICIENCY of TREATMENT GLJUKOKORTIKOSTEROIDNYMI PREPARATIONS of LUNGS SICK of CHRONIC OBSTRUCTIVE ILLNESS. The DISSERTATION on competition of a scientific degree of the candidate of medical sciences. St.-Petersburg - 2007. 2007

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  2. THE LITERATURE LIST
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