humoruli homeostazis cvlilebebi antifosfolipiduri sindromis dros

Tbilisis saxelmwifo samedicino universiteti

xelnaweris uflebiT

elene jondos asuli JorJolaZe

humoruli homeostazis

cvlilebebi antifosfolipiduri sindromis dros

orsulTa preeklamfsiisas

14.00.36 - alergologia-imunologia

medicinis mecnierebaTa kandidatis samecniero xarisxis

mosapoveblad warmodgenili

d i s e r t a c i a

samecniero xelmZRvanelebi: jemal metreveli

med.Mmec. doqtori, profesori

Tamar sanikiZe

biologiis mec. doqtori, profesori

Tbilisi – 2006 w.

sarCevi

disertaciaSi gamoyenebuli Semoklebani da abreviaturebi --------- 4

Sesavali ------------------------------------------------------------------------------------------- 6

naSromis mecnieruli siaxle ---------------------------------------------------------- 10

naSromis praqtikuli Rirebuleba -------------------------------------------------- 11

praqtikaSi danergva ------------------------------------------------------------------------- 12

sadisertacio Sromis aprobacia ---------------------------------------------------- 12

naSromis irgvliv gamoqveynebuli publikaciebi -------------------------- 12

naSromis struqtura da moculoba ------------------------------------------------ 13

sajaro dacvaze gamosatani debulebebi ---------------------------------------- 13

Tavi 1. literaturis mimoxilva ------------------------------------------------------ 14

1.1 antifosfolipiduri sindromi ------------------------------------------- 14

1.2 imunuri sistemis roli orsulobis dros ----------------------- 20

1.3 Tavisufalradikaluri Jangva da misi roli

orsulobis paTogenezSi ----------------------------------------------------------

35

Tavi 2. kvlevis masala da meTodebi ---------------------------------------------- 49

2.1 klinikuri masalis mimoxilva (pacientebis SerCeva) 49

2.2 laboratoruli kvlevebi ------------------------------------------ 50

2.2.1 sisxlis imunologiuri maCveneblebis gansazRvra 50

2.2.1.1 pereferiul sisxlSi antifosfolipiduri

sxeulebis Semcvelobis gansazRvra --------------------------------

50

2.2.1.2 periferiul sisxlSi СMV da HSV mimarT

antisxeulebis Semcvelobis gansazRvra -------------------------

51

2.2.1.3 pereferiul sisxlSi steroiduli hormonebis

Semcvelobis gansazRvra ----------------------------------------------------

51

2.2.1.4 T- da B- limfocitebis raodenobrivi gansazRvra - 51

2.2.1.5 leikocitebis interferonuli reaqcia ------------------ 51

2.2.1.6 periferiuli sisxlis limfoiduri ujredebis

parametrebis gansazRvra ----------------------------------------------------

52

2.2.1.7 sisxlis neitrofilebis fagocituri aqtivobis

kvleva ---------------------------------------------------------------------------------

52

2

2.2.2 sisxlis bioqimiuri maCveneblebis gansazRvra

rezonansis (epr) speqtroskopuli meTodiT --------------------

52

2.3 masalis statistikuri damuSaveba -------------------------------------- 54

Tavi 3. gamokvlevis Sedegebi ----------------------------------------------------------- 55

3.1 orsulTa pereferiul sisxlSi antifosfolipiduri

sxeulebis Semcveloba -------------------------------------------------------

55

3.2 orsulTa pereferiul sisxlSi anti-CMV IgG da anti-

HSV IgGSemcveloba ------------------------------------------------------------------

56

3.3 orsulTa placentis paramagnituri centrebis

cvlilebebi antifosfolipiduri sxeulebis Tanaobisas

57

3.4 orsulTa pereferiul sisxlSi steroiduli

hormonebis Semcvelobis cvlilebebi -----------------------------------

62

3.5 orsulTa pereferiul sisxlSi Jangbadis

parcialuri wnevis (pO2) cvlilebebi -----------------------------------

65

3.6 orsulTa pereferiul sisxlSi Tavisufali azotis

Jangis Semcvelobis cvlilebebi----------------------------------------------

66

3.7 orsulTa pereferiul sisxlSi superoqsid- da

lipoperoqsid radikalebis Semcveloba -------------------------------

68

3.8 sisxlis imunologiuri maCveneblebis cvlilebebi ------- 70

Tavi 4. kvlevis Sedegebis ganxilva (gansja) --------------------------------- 74

daskvnebi -------------------------------------------------------------------------------------------- 90

praqtikuli rekomendaciebi ------------------------------------------------------------- 92

gamoyenebululi literatura --------------------------------------------------------- 93

3

disertaciaSi gamoyenebuli Semoklebani da abreviaturebi

ADP - adenozindifosfati

APG - antigen prezentirebul ujredebTan

ATP - adenozintrifosfati

ACA- antikardiolipinuri antisxeulebi

APA- antifosfatidilserinis antisxeulebi

AAb- asimetruli antisxeulebi

β2GP1- β2-glikoproteini-1

cNOS - konstituciuri NO sinTaza

COX - ciklooqsigenaza

CTL- citotoqsiuri T limfocitebi

CMV- citomegalo virusi

DETC- dieTildiTiokarbomati

epr – eleqtronulparamagnituri rezonansi

HLA – adamianis autoantigeni

HO•- hidroqsilradikali

HSV- herpes virusi

INFα interferon-α

IFN-γ - interferon-γ

Ig - imunoglobulinebis ojaxi

ii- imunoregulaciis indeqsi

IL – interleikinebis ojaxi

INF _ interferoni

iNOS - inducibeluri NO sinTaza

LOO. – lipidebis peroqsiradikalebi

Lupus index- mgluras antikoagulanti

LIF- leikimia mainhibirebeli faqtori

MAP - mitogen gamaaqtivebeli proteini

Me – cvalebadvalentovani metalis ioni

HLA- dakavSirebuli polimorfuli antigeni

4

MIP-1α _ makrofagis anTebis proteini-1α

NK – naturaluri kileri

N- terminaluri kinaza

nNOS - neironuli NO sinTaza

eNOS - endoTeluri NO sinTaza

NO – azotis Jangi

NOS - NO sinTazas ojaxi

O2- - superoqsidi

ONOO- peroqsinitriti

P-53 – ujredul ciklSi transkrifciis faqtori

P-450- citoqromi

PAP-1- placentis antikoagulanturi antigeni

PKC - proteinkinaza C

RNS - azotis reaqciuli naerTebi

ROS – Jangbadis reaqtiuli SenaerTebi

SOD _ superoqsiddismutaza

TCR - antigenis gamocnobaze pasuxismgebeli receptorebi

TGF-α - matransformirebeli zrdis faqtori

Th - T helperi

Ts - T supresori

TIMP - specifiuri qsovilovani inhibitori

TNF-α - simsivnis manekrozirebeli faqtori

hCG- qorionaluri gonadotropini

5

S e s a v a l i

perinataluri sikvdilianoba, orsulobis dromde

miutanloba da neonataluri ganviTarebis SezRudvis maRali

maCveneblebi Tanamedrove medicinis aqtualuri problemaa.

cnobilia, rom orsulobis garTulebebis ganviTarebaSi

mniSvnelovan rols TamaSobs placentis humoruli

metabolizmisa da fetoplacentaruli sisxlis mimoqcevis

darRveva.

miCneulia, rom orsulTa paTologiebis

ganviTarebaSiGgenetikur darRvevebTan erTad mniSvnelovani

roli eniWeba iSemiuri procesebis ganviTarebas, lipidur

metabolizmis cvlilebebs, agreTve organizmis

imunoadaptaciuri Tvisebebis daqveiTebas [Cooper et al., 1993,

Jauniaux E. et al 2000, Sugino N. et al 2000, Kankofer M. 2001, Haddan

E,F. et al. 1997, Hung T. – H. et al. 2001, Chwalisz K. et al 1996., Huberl

C.A. 1999].

bolo wlebis klinikurma kvlevebma cxadyo, rom

orsulobis paTologiur mimdinareobas Tan axlavs ujreduli

da humoruli imunitetis disfunqcia, citokinebisa da

sxvadasxva autoantigenebis mimarT autoantisxeulebis

gaZlierebuli warmoqmna [Taylor, 1997]. imis miuxedavad, rom

humoruli darRvevebi ar warmoadgenen am sindromis ZiriTad

gamomwvev faqtors, araadekvaturi pasuxis SemTxvevaSi maT

SeuZliaT orsulobis mimdinareobaze zemoqmedeba [Vinaiter et al.,

1995].

orsulobis garTulebebis paTogenezSi sxvadasxva

faqtoris rolis Seswavlis dros gansakuTrebul

6

mniSvnelobas iZens autoimunuri reaqciebis (zogierTi

sakuTari fosfolipidebis mimarT antisxeulebis warmoqmnis)

zemoqmedebis Seswavla implantaciis, embrionis zrda-

ganviTarebis procesebze, agreTve orsulobis mimdinareobasa

da mSobiarobis gamosavalze.

vinaidanFfosfolipidebi ujreduli da subujreduli

membranebis universaluri komponentebia, antifosfolipiduri

sindromis gamovlineba sistemur xasiaTs atarebs.

antifosfolipiduri sindromi orsulobis garTulebebis

paTogenezSi (preeklamfsia, placentaruli ukmarisoba, nayofis

hipotrofia da a. S.) gvxvdeba orsuli qalebis 27-45%-Si, xolo

mkurnalobis Cautareblobisas orsulTa 90-95%-Si embrionis

sikvdils ganapirobebs (Агаджанова А.А., 1999).

miCneulia, rom antifosfolipiduri antisxeulebi

warmoadgens imuno-qimiuri specifiurobiT gansxvavebul

autoantisxeulebis heterogenul jgufs. maT miekuTvneba

antisxeulebi ujredul membranebze lokalizirebuli

sxvadasxva fosfolipiduri antigenebis (fosfatidilqolini,

fosfatidi-linozitolamini, fosfatidilserini, fosfati-

dilinozitoli), G, A da M klasebis imunoglobulinebis (lupus

koagulanti), kardiolipinis (difosfatidilgliceroli) da

sxv. mimarT.

orsulobis dros antifosfolipiduri antisxeulebis

arseboba ganapirobebs Trombocitebis funqciuri aqtivobis

gaZlierebas, Trombebis warmoqmnas, placentaSi qronikul

ukmarisobasa da hipoqsias, placentis cilis masinTezirebeli,

hormonmaproducirebeli unaris daqveiTebas, dedis organizmSi

hipertenziasa da SeSupebis ganviTarebas. Aam darRvevebis

7

ganviTarebis meqanizmebi dResdReobiT bolomde dadgenili ar

aris.

Larsebuli monacemebis Tanaxmad (Prafico D., et al., 1999, Vega-

Ostertag, M., et al., 2005), autoantifosfolipiduri antisxeulebis

warmoqmnis erT-erTi mizezia lipidebis Tavisufalradikaluri

Jangvis intensifikacia da lipoperoqsiduli radikalebis

gaZlierebuli warmoqmna. antifosfolipiduri antisxeulebi

Tavis mxriv Jangbadis reaqciuli naerTebis generatorebis,

membranaSekavSirebuli fermentebis (Simoncini S., et al., 2005), МАР-

kinazebis, maT mier regulirebadi transkripciuli faqtorebis

(Kyriakis J.M., Avruch J., 2001) saSualebiT xels uwyoben

proanTebiTi ujredebis aqtivacias da am ujredebis mier

Jangbadis da azotis reaqciuli naerTebis

Tavisufalradikaluri formebis generacias.

antifosfolipiduri sindromis dros orsulTa

placentaSi gamovlenilia proanTebiTi ujredebis da

makrofagebis maRali Semcveloba (Stone S., 2005). placentaSi

Aaqtivirebuli makrofagebis infiltracia da anTebis

ganviTareba mniSvnelovan rols asrulebs trofoblastebis

invaziis, spiraluri arteriebis transformaciis darRvevis,

apoptozis iniciaciisa da placentis disfunqciis

ganviTarebaSi (Mor G., Abrahams V.M.. 2003). maSasadame, rogorc

Cans, antifosfolipiduri sindromiT garTulebuli

orsulobis dros placenta axdens Jangbadis reaqciuli

naerTebis didi raodenobiT generacias.

antifosfolipiduri sindromiT garTulebuli

orsulobisaTvis damaxasiaTebeli placentis JangviTi

metabolizmis darRvevas SeuZlia gamoiwvios imunuri sistemis

8

aqtivobis cvlilebebi, rac, Tavis mxriv zemoqmedebas axdens

orsulobis mimdinareobaze da xels uwyobs sxvadasxva

garTulebebis ganviTarebas (preeklamfsiis, orsulobis

dromde miutanlobis da a.S.).

Cveni kvlevis mizani iyo antifosfolipiduri sindromiT

garTulebuli orsulobis dros humoruli da JangviTi

homeostazis cvlilebebis Seswavla da preeklamfsiis

ganviTarebaSi am cvlilebebis rolis dadgena.

dasaxuli miznis misaRwevad davisaxeT Semdegi amocanebi:

saWiro iyo antifosfolipiduri sindromis fonze

mimdinare orsulTa preeklamfsiis dros gamogvekvlia:

1. sisxlSi antifosfolipiduri antisxeulebi;

2. sisxlSi Jangbadis parcialuri wneva (pO2);

3. orsulTa placentaSi energo- da steroidogenezSi

monawile paramagnituri centrebi;

4. sisxlis hormonuli statusis Sefasebis mizniT

steroiduli hormonebis, progesteronis, estradiolis da

testosteronis Semcveloba.

5. redoqs homeostazis Sefasebis mizniT:

_ sisxlis prooqsidanturi sistemis (spinmoniSnuli

Jangbadis (O2-) da lipidebis (LOO.) Tavisufali radikalebis)

aqtivoba;

_ placentis prooqsidanturi sistemis (spinmoniSnuli

lipidebis Tavisufali radikalebis (LOO.), Mn2+-ionebis)

Semcveloba;

9

_ sisxlsa da placentaSi Tavisufali NO-s Semcveloba;

6. organizmis imunologiuri rezistentobis donis

Sefasebis mizniT periferiuli sisxlis limfoiduri

ujredebis funqciuri da raodenobrivi cvlilebebis

gansazRvra, kerZod:

- periferiul sisxlSi B- da T- limfocitebisa da maTi

subpopulaciebis (T - aqtiuri, T- helperebi, T- supresorebi)

procentuli Semcveloba da imunoregulaciis indeqsi;

- sisxlis neitrofilebis fagocituri aqtivobis

maCveneblebi (fagocituri ricxvi da indeqsi, monelebis

procenti);

- α da γ interferonebis aqtivoba (sisxlis leikocitebis

mier maTi in vitro produqciis mixedviT).

naSromis mecnieruli siaxle

naSromSi antifosfolipiduri sindromiT garTulebuli

preeklamfsiis kompleqsuri kvlevis Sedegad pirvelad

gamovlenilia:

• dadebiTi korelacia orsulTa organizmSi

antifosfolipiduri antisxeulebis gamoCenas,

oqsidaciuri stresis intensifikaciasa da preeklamfsiis

sindromis ganviTarebas Soris;

• placentaSi oqsidaciuri stresi da NO-inducirebuli

steroidogenezis darRveva ganapirobebs dedis organizmSi

imunuri balansis darRvevas, rac Tavis mxriv kodev ufro

aRrmavebs hormonuli statusis cvlilebebs

(progesteronis da estradiols Semcvelobis daqveiTeba);

10

• sisxlZarRvebis vazomotoruli funqciis daqveiTebisa da

hipertenziis ganviTarebis meqanizmebSi Tavisufali NO-sa

da steroidogenezis intensivobis redoqs-damokidebuli

cvlilebebis mniSvnelovani roli;

• organizmis imunologiuri rezistentobis donis

daqveiTeba (ganpirobebuli sisxlSi limfoiduri

ujredebis subpopulaciis funqciuri aqtivobis

SemcirebaiT, B-limfocitebis raodenobis mkveTri

daqveiTebiTa daG T- limfocitebis supresoruli

populaciis raodenobrivi zrdiT).

naSromis praqtikuli Rirebuleba

1. naSromSi dadgenili pozitiuri korelaciuri kavSiri

orsulTa organizmSi antifosfolipiduri antisxeulebis

gamoCenas, oqsidaciuri stresis ganviTarebasa da

preeklamfsiis sindromis ganviTarebas Soris saSualebas

iZleva pirveli ori maCvenebeli preeklamfsiis

ganviTarebis risk-faqtorTa ricxvs mivakuTvnoT, rac,

Tavis mxriv, dRis wesrigSi ayenebs simtomuri

medikamentozuri mkurnalobis aucileblobas.

2. antifosfolipiduri sindromis Camoyalibebisa da

Semdgom ganviTarebuli preeklamfsiis dros,

Tavisufalradikaluri Jangvis intensifikaciis

mniSvnelovani rolis gamovlineba orsul qalebSi

antifosfolipiduri antisxeulebis gamoCenisas

antioqsidanturi preparatebis gamoyenebis aucileblobaze

miuTiTebs.

11

praqtikaSi danergva

1. antifosfolipiduri sindromis gamovlenis SemTxvevaSi

garTulebebis Tavidan asacileblad aucilebelia pacientis

monitoringi 21-dan 36 kv. orsulobis vadaze;

doplerografiuli, ultrabgeriTi gamokvleva, imunuri da

homeostazis sistemis kontroli.

2. gestaciis 21-dan 36 kvira antifosfolipiduri sindromis

gamovlenis SemTxvevaSi orsulisaTvis iTvleba kritikul

periodad. amitom saWiroa medikamenturi koreqcia, rac

gulisxmobs antikoagulantur mkurnalobas

imunoproteqtantebis CarTviT.

sadisertacio naSromis aprobacia

sadisertacio naSromis aprobacia Catarda Tbilisis

saxelmwifo samedicino universitetis meanobisa da

ginekologiis #1 kaTedris gafarToebul sxdomaze (6 aprili,

2006 w., oqmi #6a).@

naSromis irgvliv gamoqveynebuli publikaciebi

sadisertacio naSromis irgvliv gamoqveynebulia …4

samecniero naSromi:

1. ”Успехи в лечении аутоиммунных нарушений у женщин с антифосфолипидным синдромом. Опыт применения ЭВЛТ в процеcсе подготовки к беременности” INTERNATIONAL JOURNAL ON IMMUNOREHABILITATION (June,2001 v. 3, n. 3, p.161-163) 2. ”Диагностика и тактика регулирования иммунной системы при лечении внутриутробных инфекций ТОRH ”

12

INTERNATIONAL JOURNAL ON IMMUNOREHABILITATION (June,2001 v. 3, n. 3, p. 163-164) 3. “Роль нарушения гормонального гомеостаза в патогенезе развития эндотелиальной дисфункции при прэклампсии” Georgian Medical News, January 2006, N.3, (130) p.104-107 4. ”Антифосфолипидные антитела при преэклампсии” eqsperimentuli da klinikuri medicina, 2006w. #2 (27), gv. 18-21

naSromis struqtura da moculoba

naSromi warmodgenilia qarTul enaze, kompiuterze

nabeWdi teqstis 115 gverdze. igi Sedgeba Sesavlis,

literaturis mimoxilvis, masalisa da kvlevis meTodebis

aRweris, sakuTari kvlevis Sedegebisa da maTi ganxilvis,

daskvnebis, praqtikuli rekomendaciebis da disertaciaSi

gamoyenebuli aRniSvnebisagan. bibliografiaSi gamoyenebulia

211 literaturuli wyaro. disertacia ilustrirebulia 6

diagramiT, 8 cxriliT da 5 imunogramiT.

sajaro dacvaze gamosatani debulebebi

1. antifosfolipiduri antisxeulebis gamoCena orsulTa

organizmSi qmnis preeklamfsiis sindromis ganviTarebis

saSiSroebas.

2. orsulTa antifosfolipiduri sindromiT inducirebuli

peeklamfsiis paTogenezSi Tavisufalradikaluri Jangvis

intensifikacia erT-erT sakvanZo rgols warmoadgens _ xels

uwyobs steroidgenezis darRvevas, humoruli homeostazis

moSlas, sisxlZarRvebis vazoreaqtiulobis momatebas da

hipertenziis ganviTarebas.

13

Tavi 1. literaturis mimoxilva

1.1. antifosfolipiduri sindromi

Oorsulobis dromde miutanlobis paTogenezis

imunopaTologiuri procesebis Seswavlisas didi mniSvneloba

eniWeba autoimunuri reaqciebis (antisxeulebis warmoqmna

sakuTari fosfolipidebis mimarT) zemoqmedebas implantaciis,

embrionis zrdisa da ganviTaebis procesebze, orsulobis

mimdinareobaze da mSobiarobis gamosavalze.Ffosfolipidebi –

ujreduli da subujreduli membranebis universaluri

komponentia. maTi universaloba ganapirobebs antifosfo-

lipiduri sindromis gamovlinebis sistemur xaiaTs.

A antifosfolipiduri sindromi, romelic pirvelad

aRweril iqna sistemuri mgluras koagulantis gamovlinebis

dros 1986 wels Hughes G.R.V. da Tanaavtorebis mier, klinikuri

simptomatikis mravalferovnobiT, xangrZlivi persistenturi

mimdinareobiT, drouli diagnostikisa da ganviTarebuli

darRvevbis koreqciis aucileblobiT xasiaTdeba.

dReisaTvis ganasxvaveben pirvelad da meorad

antifosfolipidur sindroms. meoradi antifosfolipiduri

sindromis (APS) ganviTareba asociirebs autoimunur,

onkologiur, infeqciur daavadebebTan da, agreTve, sxvadasxva

samkurnalo preparatebis da toqsiuri nivTierebebis

zemoqmedebasTan. pirveladi APS-s adgili aqvs, roca APS-is

antisxeulebis warmoqmnas ar axlavs Tan zemoT CamoTvlili

daavadebebis da mdgomareobebis ganviTareba. APS-is

diagnostkis sayovelTaod aRiarebul kriteriumebs

miekuTvneba:

14

• venur sisxlSi minimum orjer mainc mgluras koagulantis

gamovlineba, 6-8 kviris intervaliT;

• axalgazrda asakSi (45 wlamde) venuri an arteriuli

Trombozebis (Tavis tvinis infarqtebis, insultebis, sisxlis

mimoqcevis darRvevebis, filtvis arteriis Tromboemboliis,

baduras sisxlZarRvebis Trombozis) ganviTareba;

• usimptomo, an kinikurad gamovlenili Trombocitopenia;

• qalebis anamnezSi orsulobis sxvadasxva vadebSi

(gansakuTrebiT 10 kvirsa da 10 kviris zemoT ors. vadaze,

rodesac nayofis daRupva genetikuri mizezebis gamo naklebad

savaraudoa) nayofis dakargva.

APS-is damatebiT kriteriumebs miekuTvneba nevrologiuri

gamovlinebebi (qorea, migreni), kidurebis qronikuli

wylulebi, endokarditi.

antifosfolipiduri sindromi qalebSi gvxdeba 2-5jer

ufro xSirad, vidre mamakacebSi. amasTan, pirveladi APS-is

SemTxvevaSi es Sefardeba 4:1 tolia, xolo daavadebis meoradi

formis SemTxvevaSi aRwevs 7:1, rac ganpirobebuli unda iyos

qalebis midrekilebiT SemaerTebeli qsovilis sitemuri

daavadebebis mimarT. HLA (human leucocites antigen) sistemis

antigenebis Seswavlam gviCvena, rom APS-iT daavadebulebSi

ufro xSirad, vidre mTel populaciaSi gvxvdeba HLA (DR4, DR7,

DRw53), rac daavadebis mimarT genetikuri midrekilibis

SesaZleblobaze metyvelebs.

avtorebis rigi aRniSnavs e.w. katastroful

antifosfolipidur sindroms, romelic, rogorc wesi,

xasiaTdeba swrafad ganviTarebadi poliorganuli ukmarisobiT

maprovocirebeli faqtorebis (infeqcuri daavadebebi,

15

operaciuli Carevebi) sapasuxod da vlindeba mwvave

respiraciuli distress-sindromiT, Tavis tvinis da

koronaruli sisxlis mimoqcevis moSliT, stuporiT,

dezorientaciiT, mwvave Tirkmlisa da Tirkmlelzeda

jirkvlis ukmarisobiT, msxvili sisxlZarRvebis tromboziT.

Ddroulad Catarebuli mkurnalobis gareSe letaloba aRwevs

60%-s.

dReisaTvis sayovelTaod aRiarebulia, rom

antifosfolipiduri antisxeulebi warmoadgenen

autoantisxeulebis geterogenur jgufs, romlebic

gansxvavdebian imuoqimiuri specifiurobiT. es garemoeba

ganpirobebulia, gansxvavebuli struqturisa da imunogenobis

ramodenime klasis antisxeulebis arsebobiT. APS-is mqone

pacintebis sisxlis SrtSi arsebuli antsxeulebi reagireben

ujredul membranebze lokalizirebul sxvadasxva

fosfolipidur antigenebTan: fosfatidilserinTan,

fosfatidilqolinTan, fosfatidileTanolaminTan,

fosfatidil-inozitolTan. zogierTi avtoris azriT

antigenebi warmoadgenilia uaryofiTad damuxtul (anionur)

fosfolipidebiT - fosfatidilseriniT, fosfatidil-

gliceroliT da neitraluri fosfolipidiT -

fosfatidileTanolaminiT heqsonalur fazaSi.

APS-is dros gamovlenilia agreTve antisxeulebi

fosfatidilinozitolis, fosfatidilqolonis mimarT.

auoantisxeulis aRniSnuli speqtri warmodgnilia G, M da A

klasis imunoglobulinebis saxiT, cnobili mgluras

koagulantis saxelwodebiT, romelic in vitro

proTrombinaqtivirebuli kompleqsis (proTrombinazas)

16

warmoqmnis dros agrZelebs fosfolipidamokidebuli

koagulaciuri reaqciebis xangrZlivobas proTrombinis Xa da

Va faqtorebTan Ca2+-damokidebul SekavSirebaze zemoqmedebiT.

calke jgufad gamoyofilia antisxeulebi mitoqondriebis

Siga membranaSi asebuli kardiolipinis

(difosfatidiglcerolis) mimarT.

bolo wlebSi dadgenil iqna, rom autoimunuri procsis

realizaciisaTvis organizmSi aucilebelia ara mxolod

antifosfolipiduri antisxeulebis, aramed e.w. kofaqtorebis

arseboba, romlebic xels uwyoben WeSmariti antigen-

antisxeulis kompleqsebis warmoqmnas. kofaqtorebs Soris

kargadaa Seswavlili plazmuri komponenti β2-glikoproteini-

1(apolipoproteini H). kofaqtorebs agreTve miekuTvneba

proTrombini, C da S proteinebi, placenturi

antikoagulanturi proteini (PAP-1).

antisxeulebi fosfolipidebis mimarT warmoiqmneba

sxvadasxva endogenuri da egzogenuri stimulebis

zemoqmedebiT. egzogenuri stimulebiT (infeqciuri agentebiT)

inducirebuli antisxeulebis warmoqmna ar warmoadgens

autoimunur process, atarebs gardamaval xasiaTs da ar

moiTxovs medikamentozur Carevas. Eendogenuri stimulebiT

iducirebuli antisxeulebis warmoqmna dakavSirebulia

endoTeluri homeostazis darRvevasTan. sisxlSi

antisxeulebis maRali koncentraciis SemTxvevaSi vlindeba

protein-kofaqtorebis paTogenuri kavSiri APS-Tan.

dadgenilia APS-is roli iseTi paTologiebis

ganviTarebis procesSi, rogoricaa: paTologiuri orsuloba,

orsulobis dromde miutanlobia, preeklamfsia; agreTve

17

gansakuTrebiT mZime formis placenturi ukmarisobis, nayofis

hipotrfiis, ucnobi etiologiis Trombocitopenis, HELLP-

sindromis (Carp H.J.A., 1994, Ruiz-Irasrorza G., et al., 2002, Lockshin M.D.,

1992). Yyvela SemTxvevaSi garTulebebis ganviTarebas win

uswrebs placenturi ukmarisoba, placentis protein-

masinTezirebeli da hormon-maproducirebeli funqciis

daqveiTeba, hipoqsia da, xSir SemTxvevebSi, nayofis sikvdili

placentis sisxlZarRvebSi sisxlis mimoqcevis mwvave

darRvevis gamo.

orsulobis I trimestris ganmavlobaSi trofoblastis

qsovilze antifosfolipiduri antisxeulebis damazianebeli

zemoqmedeba sisxlZarRovani faqtoebis, Trombomodulinis

warmoqmnis inhibicias da placentis formirebis darRvevas

ganapirobebs. aRsaniSnavia, rom APA-is maRali Semcvelobis

fonze mimdinare orsulobisas orsulobis mTeli periodis

ganmavlobaSi viTardeba darRvevebi homeostazis sistemaSi, rac

vlindeba hiperkoagulaciiT, Trombocitebis hiperaqtivaciiT

da sisxlis Sededebis sistemis gaaqtivebiT (Пономарева И.В., и

др., 1999).

APS-is drouli diagnostika da Terapia, orsulobis

racionaluri momzadeba da marTva, medikamentozuri Terapiis

efeqturi gamoyeneba, amcirebs orsulobis dros garTulebebis

ganviTarebis risks da xels uwyobs mSobiarobis sasikeTo

gamosavals. A

mravali kvleva mowmobs imis Sesaxeb, rom APS-i xSirad

warmoadgens orsulobis Sewyvetis mozezs. janmrTel TagvebSi

antifosfolipiduri antisxeulebis maRali titris mqone

Tagvebis sisxlis Sratis ineqciebi iwvevda recipientebSi

18

orsulobis moSlas (Blank M., et al., 1991); BALB/c Tagvebis

adamianis paTologiuri monoklonaruli antisxeulebiT

aqtiuri imunizacia iwvevda antifosfolipiduri sinromis

manifestacias (Bakimer R., et al., 1992). naCvenebi iqna, rom APA-s

mqone qalebis sisxlis Srati avlens mkveTrad gamoxatul

teratogenul efeqts virTagvas embrionebis kulturaze da

uaryofiTad moqmedebs embrionis zrdaze (Omoy A., et al., 2003).

Aantifosfolipiduri sindromiT daavadebuli qalebis sisxlis

Sratidan gamoyofili IgG-s fraqcia iwvevda embrionis zrdis

SezRudvas (Omoy A., et al. 2003).

cnobilia, rom fosfolipiduri antisxeulebis kofaqtori

(apolipoproteini H an β2GP1 asrulebs antigenis rols.

antigen-antisxeulis divalenturi kompleqsebi (IgG-β2GP1)

xasiaTdebian maRali afinobiT membranuli fosfolipidebis

mimarT (Rand J.H., 2003). aPL-β2GP1-kompleqsebis ujredul

membranebTan, maT Soris trofoblastebis membranebTan

SeerTeba maT dazianebas, an gaaqtivebas iwvevs. Aaqtivacia

SeiZleba mimdinareobdes citokinebis monawileobiT. cnobilia,

rom implantaciis procesSi monawile IL-3-is Semcveloba

mcirdeba antifosfolipiduri sindromis dros (Shoenfeld Y., et

al., 1993), am dros gamovlenilia TNF-α-s mkveTri momateba

(Bertolaccini M.L., et al., 2001).

iTvleba, rom antifosfolipiduri antisxeulebi iwveven

Trombozebis ganviTarebas, zemoqmedebas axdenen

prostaciklin-Tromboqsanul balansze da Trofoblastur

elementebs Soris arsebul adeziur molekulebze (Carp H.J.A.,

1994).

19

antifosfolipiduri sindromis gamomwvevi erT-erTi

meqanizmi - infeqciebia. adamianebSi Cut-yvavila, “A”, “B”, “C”

hepatitebi asocirdeba antifosfolipiduri (β2GP1-

damoukidebeli antikardiolipinis) antisxeulebis

momatebasTan (Guglielmone H., et al., 1989).

antifosdolipiduri antisxeulebi gavrcelebulia

populaciaSi da mcire raodenobiT gvxvdeba qalebSi

orsulobis normaluri mimdinareobiT (mgluras koagulanti

– qalebis 0,2%,-Si, antikardiolipini-2% (Lockshin M.., 1992,

Lockwood C.J., et al., 2001, Harris E.N., Spinnato J.A., 1991).

orsulobis dros antifosfolipiduri sindromi xSirad

warmoadgens orsulobis naadrevi Sewyvetis, placentis

disfunqciis da preeklamfsiis ganviTarebis mizezs (Carp H.J.A.,

1994).

1.2 imunuri sistemis roli orsulobis dros

dedis organizmSi orsulobis SenarCuneba ganpirobebulia

feto-placentaruli barieris arsebobiT, romelic amcirebs

urTierTqmedebas nayofis qsovilsa da dedis limfocitebs

Soris (Chaouat G., et al., 1983) da/an uzrunvelyofs dedis

organizmSi imunuri sistemis pasuxis funqciur cvlilebas

(Sargent I.L., 1993) misi imunokompetentobis SenarCunebiT

infeqciebisa da transplantantebis mimarT (Falkoff R., 1998, Ferst

M.R., et al., 1995). imunotolerantoba nayofis mimarT

ganpirobebulia, ZiriTadad, dedis imunuri sistemis Semdegi

faqtorebiT:

20

1) HLA-G-s eqspresia trofoblastur ujredebze;

2) Th1/Th2 Sefardebis cvlileba;

3) citotoqsiuri T limfocitebis da naturaluri

kilerebis (NK) ujredebis daun-regulacia;

4) “proteqtoruli” antisxeulebis sinTezi (Abbas A.K., et

al, 1994).

BHLA I klasi antigenebi iyofa or ojaxad, romlebic

xasiaTdebian gansxvavebuli homologiurobiT sekvenciis

doneze da gamoxatuli msgavsobiT meorad struqturaSi

(O’Callaghan C.A., Bell J.I., 1998). es ori ojaxi warmodgenilia

“klasikuri,“ farTod eqspresirebadi, maRali polimorfizmis

mqone Ia klasis, HLA-A, -B, -C, da “araklasikuri” seleqtiurad

eqspresirebadi, ZiriTadad monomorfuli Ib klasis, HLA-E, -F

da –G, molekulebiT.

1987 wels klonirebul iqna adamianis leikocitebis

antigenis (HLA) araklasikuri Ib klasis geni (Geraghty et al., 1987),

gamovlenilia HLA-G-s antigenis membranaSekavSirebuli da

xsnadi formebi (Ishitani A., Geraghty D.E., 1992). HLA-G-s

monomorfizmi damtkicebulia sxvadasxva populaciebSi

Catarebuli kvlevebiT (Baibridge D., et al. 2001), Tumca afrikul-

amerikul populaciaSi gamovlenilia HLA-G genis mcire

polimorfizmi (van der Ven K., Ober C., 1994).

HLA-G aregulirebs imunuri ujredebis funqcias.

dadgenilia, rom HLA-G uzrunvelyofs tolerantobas nayofis

mimarT NK ujredebis aqtivobis daqveiTebis meSveobiT (Moreau P.,

1998, Chumbley et al., 1994). citotoqsiuri NK ujredebis blokireba

xorcieldeba maT zedapirze ganlagebul kiler-ujredebis

21

imunoglobulin-msgavsi receptorTan (KIR) SeerTebis (Carosella

E.D., et al., 1999, Rouas Freiss N.I., et al., 1999), an NKAT3

receptorebTan urTierTqmedebis (Munz C., et al., 1997) gziT.

agreTve naCvenebia, rom HLA-G ainhibirebs NK ujredebis trans-

endoTelur migracias (Dorking A., et al., 2000).

bolo wlebSi dadgenilia, rom HLA-G-s molekulebi

urTierTqmedeben CD4 da CD8 molekulebTan da am gziT

monawileoben SeZenili imunitetis regulaciaSi. orsulobis

dros HLA-G akontrolebs citotoqsiuri T limfocitebis (CTL)

alo-CTL pasuxs (Kapasi K., et al., 2000). HLA-G-s molekulebis CD8–s

mimarT maRali afinobis gamo isini uzrunvelyofen

aqtivirebuli CD8+ T limfocitebis apoptozis iniciacias

Fas/Fas-L aqtivaciis gziT (Fournel S.M., et al., 2000, PuppoE.P., et al.,

2000). HLA-G-s molekulebi iwveven CD4+ T limfocitebis

proliferaciis supresias (Bainbridge D.R., et al., 2000), rac

korelirebs monacemebTan HLA-G-s mier T limfocitebis

alogenuri proliferaciuli citotoqsiuri pasuxis inhibiciis

Sesaxeb (Riteau B., et al., 1999). am TvalsazrisiT interess

warmoadgens is garemoeba, rom samizne ujredebis zedapirze

membrana-SekavSirebuli HLA-G proteinis arseboba

periferiuli sisxlis an decidualuri mononuklearuli

ujredebis mier sekretirebul Th1 da Th2-is citokinebis

balansis Th2-saken Secvlas ganapirobebs (Kanai K., et al., 2001).

Tu mxedvelobaSi miviRebT im garemoebas, rom T ujredebi

ar vlindeba, xolo NK ujredebi Warbadaa warmodgenili

orsulebis saSvilosnoSi, SegviZlia vivaraudoT, rom dedis

NK ujredebi miizidebian semiallogenuri nayofis mier,

22

romlis HLA Ia klasis mimarT uaryofiTi da HLA-G-is

maeqspresirebeli qsovili (placenta) ganicdis invazias dedis

organizmSi (Ober C., 1998, Thellin O.B., et al., 2000). HLA-G pasuxs

agebs am lokalurad akumulirebuli ujredebis “funqciur”

inaqtivaciaze da orsulobis warmatebul damTavrebaze.

SesaZloa, rom HLA-G-s xsnadi formebi uzrunvelyofdnen

dedis aloreaqciuli sistemuri pasuxis daun-regulacias

(dedis T ujredebis gandevna placentidan) aqtivirebuli CD8+

ujredebis apoptozis intensifikaciis meSveobiT (Le Bouteiller P.,

Soller C., 2001).

naCvenebia, rom HLA-G-s maeqspresirebeli ujredebi

uzrunvelyofen monoklonur ujredebSi interleikinebis (IL-3,

IL-1β, IL-10) produqciis zrdas da TNF-α-s warmoqmnis

Semcirebas. rogorc cnobilia, IL-3 da IL-1β astimulireben

placentis proliferacias, maSin roca TNF-α xels uwyoben

abortis ganviTarebas. anu HLA-G ainhibirebs CD8+ antigen-

specifiur T ujredebis citotoqsiurobasa da alogenur

proliferaciul pasuxs, ainducirebs Th1/Th2 cvlilebas,

amcirebs IFN-γ da TNF-α-s eqspresias (Bainbridge D., et al., 2001).

maSasadame, rogorc Cans, trofoblastebis mier

eqspresirebul HLA-G-s dedis organizmis limfocit-

makrofagebTan uSualo urTierTqmedebas mniSvnelovani roli

eniWeba orsulobis ganviTarebaSi. Tumca, bolo wlebSi

aRweril janmrTel, homologiur HLA-G-s nuli alelis mqone

individebSi normaluri mSobiarobis SemTxvevebi eWvis qveS

daayenes HLA-G-s feto-placenturi tolerantobis

ganviTarebaSi monawileobis universaloba (Ober C., 1998, Castro

23

M.J., et al., 2000). Zneli warmosadgenia HLA-G-s mcire raodenobiT

arsebul izoformebis (HLA-E) mier HLA-G-s sruli

dublirebis ganxorcielebis SesaZlebloba, Tumca dasaSvebia

maTi warmatebuli monawileoba garemomcveli NK ujredebis

eqspresiis modulaciaSi. HLA-G eqspresia intensiuria

gansakuTrebiT orsulobis pirveli trimestris ganmavlobaSi

da mcirdeba orsulobis vadis matebasTan erTad. aRsaniSnavia,

rom HLA-G-s eqspresia mniSvnelovnad mcirdeba

trofoblastebSi preeklamfsiis (samiano garTuleba,

gamowveuli endoTeluri disfunqciis ganviTarebiT) da

spontanuri abortebis dros (Carosella E.D., et al., 2001, Hara N., et al.,

1996, Goldman-Wohl D.S., et al., 2001 Kapasi K., et al., 2000), rac

metyvelebs placentis ganviTarebis regulaciaSi HLA-G-is

mniSvnelovani rolis Sesaxeb.

aRmoCnda, rom HLA-G-s (mis izoformebs) sxva araimunuri

funqciebic gaaCnia; magaliTad, trofoblastebis invaziis

modulacia da angiogenezis regulacia (Le Bouteiller P., Soller C.,

2001).O orsulobis pirveli trimestris ganmavlobaSi HLA-G

eqspresirdeba fetaluri qorionis sisxlZarRvebis

endoTelur ujredebze (Iaschitz A., et al., 1997), sadac monawileobs

angiogenezis regulaciaSi qorionis bususebSi.

aRsaniSnavia, rom preeklamfsiis dros HLA-G proteinis

eqspresia eqstrabususovan trofoblastebze saerTod ar

vlindeba (Hara N., et al., 1996). rogorc aRvniSneT, orsulobis

dros dedis imunuri sistemis roli fokusirdeba ZiriTadad,

invazirebuli trofoblastebis da, maSasadame, nayofis mimarT

imunuri tolerantobis aspeqtze. orsulobis dros deciduaSi

mravldeba sxvadasxva tipis leikocitebi (Mincheva-Nilsson L., et

24

al., 1994), Tandayolili imunitetis sistemis dominirebiT, maSin

roca limfocitebis done SedarebiT dabalia (1-3%) (Lessin D.L.,

et al., 1988). implantaciis dros leikocitebis simravle

warmodgenilia periferiaze arsebulTan SedarebiT

gansxvavebuli fenotipis NK ujredebiT (Loke Y.W., King A., 2000).

gestaciis ganviTarebis procesSi NK ujredebis ricxvi

mcirdeba, gansakuTrebiT, orsulobis bolo vadebSi (Moffett-

King A., 2002). implantaciis mxares makrofagebi Seadgenen

decidualuri qsovilis 20-30%-s (Kabawar S.E., et al., 1985, Lessin

D.L., et al., 1988, Bulmer J.N., et al., Uckan D., et al., 1997), magram NK

ujredebTan gansxvavebiT maTi raodenoba orsulobis mTeli

periodis ganmavlobaSi rCeba maRal doneze (Lessin D.L., et al.,

1988, Khong T.Y., 1987).

es monacemebi metyveleben imis Sesaxeb, rom Tandayolili

imunuri sistema ar aris indiferentuli nayofis mimarT da,

maspinZeli organizmis infeqciebisagan proteqciis garda

mniSvnelovan rols asrulebs dedis organizmSi nayofis

mimarT imunuri tolerantobis ganviTarebaSi. feto-

placenturi sazRvris zedapirze lokaluri garemocvla

damokidebulia ara marto ujredebis tipze, aramed maT mier

producirebul citokinebze (Piccini M.-P., et al., 2000), romlebsac

didi mniSvneloba eniWeba trofoblastebis zrdis,

diferenciaciis da invaziis procesebis regulaciaSi (Simon C.,

et al., 2000).

Th limfocitebi, maT mier sinTezirebuli citokinebis

mixedviT, iyofa or tipad: Th1 tipis ujredebi aproducireben

IL-2-s IFNγ-s da TNF-γ-s, romlebic Tavis mxriv ainducireben

sxvadasxva citokinebis warmoqmnas, anTebiTi reaqciis

25

ganviTarebas da monawileoben ujred-damokidebuli pasuxis

ganviTarebaSi (Mosmann T.R., CoffmanR.I., 1989, Romagnani S., 1994,

MosmannT.R., Sad S., 1996). Th2 tipis ujredebi axorcieleben IL-4,

IL-5, IL-6, IL-10 da IL-13-s sekrecias da pasuxs ageben humorul

imunur sistemaze. Aamis garda, IFN-γ ainducirebs TNF-α-s da IL-

12-is produqcias makrofagebSi, romlebic SemdgomSi

astimulireben Th1 da ainhibireben Th2 ujredebis

proliferacias. piriqiT, IL-10 pasuxs agebs Th-1-is citokinebis

inhibiciaze. mravali kvlevidan gamomdinareobs, rom

citokinebis balansi mniSvnelovan rols asrulebs asrulebs

orsulobis mimdinareobaSi (Wegmann T.G., et al., 1993).

fiziologiuri orsulobis dros fetoplacentaruli

sazRvris zedapirze dominireben antianTebiTi Th-2 citokinebi

(Wegmann T.G., et al., 1993, Asckenazi S., et al., 2000), xolo

citotoqsiuri T ujredebis raodenoba mcirdeba, maSin roca

periferiuli γδ T ujredebis raodenoba rCeba TiTqmis

ucvleli (Rukavina D., et al., 1997). Ddadginda, romPperiferiuli γδ

T limfocitebi eqspresireben proJesteronis receptorebs,

ainhibireben IL-10-is da PIBF-s maproducirebel NK ujredebis

aqtivobas (Barakonyi A., et al., 1999) da T limfocitebis imunur

pasuxs TGF-β-s sekreciis meSveobiT (Mincheva-Nilsson L., et al., 1992).

spontanuri abortebis da garTulebuli orsulobis

(preeklamfsia) dros izrdeba Th-1 da mcirdeba Th2 tipis

citokinebis Semcveloba (Marzi et al ., 1996, Hill et al., 1995, Makhseed

M., et al., 2001, Saito S., et al., 1999, Darmochwal-Kolarz D., et al., 1999,

Zenclussen A.C., et al., 2004). adgili aqvs NK ujredebis aqtivacias

periferiaze da saSvilosnoSi (Coulam C.B. et al., 1995).

26

iTvleba, rom trofoblastebis dazianeba NK ujredebis da

T limfocitebis mier xorcieldeba citokinebis meSveobiT

(Baines M.G., et al., 1997). proanTebiTi citokinebis zemoqmedebiT

NK ujredebi gardaiqmnebian LAK (limfokin-aqtivirebuli

kilerebi) ujredebad, romlebic iwveven trofoblastebis

liziss. gamovlenilia korelacia mocirkulire LAK-msgavsi

ujredebis raodenobasa da abortebis sixSires Soris.

trofoblastebis dazianeba SeuZlia agreTve decidualur

makrofagebs. decidualuri NK ujredebi aproducireben

citokinebs, romlebic SemdgomSi iwveven decidualur

makrofagebSi azotis Jangis da proanTebiTi citokinebis

hipersekrecias (Baines M.G., et al., 1997). makrofagebis mier

warmoqmnili NO-sa da TNF-α-s toqsiuri raodenobebi (Haddad

E.K., et al., 1997) iwveven ganayofierebuli kvercxujredis

dazianebas. Baines da Tanaavtorebma aCvenes, rom decidualuri

makrofagebis mier citokinebis produqciis mateba win uswrebs

adreuli abortebis ganviTarebas.

zemoT Tqmulidan gamomdinareobs, rom Th-1 tipis

citokinebis mier aqtivirebul NK ujredebs da makrofagebs

mniSvnelovani roli eniWeba naadrevi abortebis ganviTarebaSi.

am TvalTaxedviT Th-1 citokinebi uzrunvelyofen placentis

damazianebeli efeqtoruli ujredebis aqtivacias, maSin, roca

Th-2 citokinebis roli mdgomareobs Th1 - NK- makrofagebis

sistemis supresiaSi (Wegmann T.G., et al., 1993, Arck P., Dietl J., Clark

D., 1999). orsulobaze Th-1 tipis citokinebis mavne zemoqmedebis

gaTvaliswinebiT da orsulobis dros ujreduli imunitetis

daunr-egulaciis damadasturebel dakvirvebebze (rac

vlindeba Senelebuli tipis hipermgrZnobelobis daqveiTebiT

27

(Holland et al., 1984), NK aqtivobis (Luft B.J., Remigngton, J.S., 1984) da

Sidaujredovani infeqciebis mimarT rezistentobis SesustebiT

(Wehmann T.G., et al., 1993)) dayrdnobiT gakeTebul iqna daskvna

gestaciis procesSi Th-1 da Th-2–is citokinebis aqtivobis

cvlilebebis Sesaxeb, Th-2-is mier inducirebuli humoruli

imunuri pasuxis sasargeblod (Wegmann T.G., et al., 1993, Kishan L., et

al., 1996, Hill J.A., et al., 1995, Guilbert L.J., 1996, Krishan L., et al., 1996, Marzi

M., et al., 1996, Vince G.S., 1996, Ekerfelt C., et al., 1997, Haynes M.K., et al.,

1996, Piccinni M.P., et al., 1995, Raghupathy R., 1997). sxvaoba Th-1 da Th-

2-is citokinebis Semcvelobebs Soris gansakuTrebiT

mkveTradaa gamoxatuli feto-placenturi sazRvris zedapirze;

agreTve vlindeba dedis organizmSi mocirkulire sisxlSic.

fetoplacentaruli kompleqsis warmoqmna iwyeba

trofoblastebis invaziiT dedis deciduas qsovilSi. Aam

processD xels uwyobs dedis organizmis imunuri sistema.

sawyis fazaSi yviTeli sxeulis mier producirebuli

progesteroni ainducirebs Th-0 limfocitebis Th-2-ad

diferenciacias. Th-2 ujredebi IL-4, IL-10 IL-13-is produqciis da

antigenprezentirebuli ujredebis (APC) aqtivaciis meSveobiT

(romlebic Tavis mxriv gamoyofen IL-4, IL-6 da IL-10-s)

ainhibireben Th-1-s. fetoplacentaruli urTierTqmedebis dros

APC TiTqmis mTlianad warmodgenilia dendriduli ujredebiT.

IL-4, IL-6, IL-10 maproducirebeli Th-2 limfocitebi

astimulireben, agreTve B ujredebis diferenciacias da,

nawilobrivad, zogierTi trofoblastebis mier proteqtoruli

antisxeulebis sinTezs (IgG da R80K antisxeulebi). Th-2

limfocitebis mier producirebuli IL-4 Trgunavs NK

ujredebis mier eqspresirebuli kilerebis aqtivatoris

28

receptoris (KAR) inhibitors. es receptori (KAR)

trofoblastebze eqspresirebul HLA-G molekulebTan

kompleqsis warmoqmnis meSveobiT uzrunvelyofs NK

limfocitebis trofoblasturi ujredebis mimarT kileruli

aqtivobis blokirebas. NK ujredebis inhibireba SesaZlebelia,

agreTve anti-R80K antisxeulebis mier. amave dros, IL-4

astimulirebs KAR-is maeqspresirebel NK ujredebs. NK

ujredebi iwyeben LIF-is da MCSF-is (monocitebis zrdis

mastimulirebeli faqtori) warmoqmnas, romlebic

aregulireben trofoblasturi qsovilis invazias.

preeklamfsiis dros placentis trofoblastebis zedapirze

mkveTrad mcirdeba IL-10-is da IL-4-is eqspresia (Hennessy A., et al.,

2003).

Th-2-is citokinebi producirdeba ara mxolod imunuri

ujredebis, aramed placentis mier. nawilobriv, placentaSi

producirebul IL-4, IL-6 da IL-10 SeuZlia Th-0-is limfocitebis

Th-2-ad diferenciaciis pirdapiri stimulacia.

orsulobis dros Horganizmis hormonuli statusi

regulirdeba fetoplacentaruli kompleqsis mier da

damokidebulia urTierTqmedebaze dedasa da nayofs Soris

(Marzi M., et al.., 1996). trofoblastebSi da sxva imunur

ujredebSi sinTezirebuli Th-1 da Th-2 citokinebi

monawileoben dedis organizmis da TviT trofoblastebis

endokrinuli funqciis regulaciaSi (Nishino E., et al., 1990, De

Moraes Pinto M.L., et al., 1996, Roth I., et al., 1996, Saito S., et al., 1997). Th-2-

is citokinebi, IL-4, IL-6, IL-10 da LIF (leikimia mainhibirebeli

faqtori) xels uwyoben trofoblastebidan hCG-is (adamianis

qorionuli gonadotropini) gamoyofas (Nishino E., et al., 1990, Saito

29

S., et al., 1997, Sawai K., et al., 1995). orsulobis adreul etapze

trofoblastebSi sekretirebuli hCG uzrunvelyofs

folikulebis apoptozis prevencias d xels uwyobs

orsulobis ganviTarebas. hCG-is gamoyofa zrdis

folikulebSi progesteronis produqcias.

progesteroni orsulobis SenarCunebisaTvis aucilebeli

hormonia. ovulaciis Semdeg folikulis ganTavisuflebis

dros progesteroni amzadebs saSvilosnos ganayofierebuli

kvercxujredis miRebis da ganviTarebisaTvis, ainducirebs

miometriumis diferenciacias proliferaciul da sekretorul

fazamde (Saito S., et al., 1999).Hgestaciis pirveli 6-8 kviris

ganmavlobaSi progesteroni sekretirdeba yviTeli sxeulis

mier, xolo Semdeg warmoiqmneba placentaSi. Ffiziologiuri

orsulobis dros sisxlSi progesteronis done 4-6 jer

maRalia, vidre araorsuli qalebis sisxlSi. Pprogesteroni

orsulobis sawyisi periodis ZiriTadi hormoni da sxva

fetaluri hormonebis winamorbedia, mas gaaCnia mravali

funqcia, romelTa nawili dRemde ucnobia. progesteronis erT-

erTi metabolitis, dezoqsikortikosteronis Semcveloba 100

jer izrdeba orsulobis dros magram am hormonis

fiziologiuri roli dadgenili ar aris (Marzi M., et al.., 1996).

Oprogesteroni astimulirebs TH-0-ad Th-2 ujredebis

diferenciacias. igi ainducirebs, agreTve “progesteron-

inducirebuli mablokirebeli faqtoris” (PIBF) produqcias

(Szekeres-Bartho J., Wegmann T.G., 1996), romelic astimulirebs IL-4-

is da IL-10-is sekrecias aqtivirebuli T ujredebis mier, iwvevs

Th1 limfocitebis ganviTarebis supresias da ainhibirebs IFN-γ-

s produqcias (Piccini M.P., et al., 1995). iTvleba, rom orsulobis

30

dros progesteroni aregulirebs T limfocitebis

diferenciacias nawilobrivad maT zedapirze ganlagebuli

progesteronis receptorebis meSveobiT, Tumca ar aris

gamoricxuli arapirdapiri regulaciis meqanizmi sxva tipis

ujredebze arsebuli receptorebis meSveobiT. Aarapirdapiri

meqanizmi monawileobs saSvilosnos mukozaSi NK ujredebis

akumulaciis da gadarCenis regulaciaSi, vinaidan am

ujredebis zedapirze ar gamovlinda arc progesteronis da

arc estrogenebis receptorebis arseboba. progesteronis

receptorebi nanaxia Timusis retikuloepiTelur ujredebze.

isini aucilebelia normaluri ganayofierebisaTvis da

parakrinuli meqanizmis saSualebiT orsulobis dros

ablokireben T ujredebis limfopoezs (Miyaura H., Iwata M., 2002).

progesterons, agreTve mniSvnelovani roli eniWeba LIF

(leukaemia inhibitory factor) induqciaSi, romelic aucilebelia

nayofis normaluri implantaciisaTvis (Miyaura H., Iwata M., 2002).

Ffiziologiuri orsulobis dros interleikinebis

produqcia periferiuli limfocitebis mier progresiulad

izrdeba (Kupfermine M.J., et al., 1995). naCvenebi iqna, rom

orsulobis da, gansakuTrebiT, mSobiarobis dros sisxlis

SratSi IL-6-is done TandaTan izrdeba (Branch D.W., 1992). TNF-α-s

done ar icvleba, xolo TNF-α-s xsnadi receptorebis

raodenoba matulobs, rac warmoadgens nayofis dacvas TNF-α-s

damazianebeli moqmedebisagan (Lin H., et al., 1993, Greig P.C., et al.,

1995).

Oorsulobis dros afreTve mniSvnelovnad (3-8 jer)

izrdeba estrogenebis koncentracia (Marzi M., et al.., 1996). es

zrda ganpirobebulia unikaluri urTierTqmedebiT dedasa da

31

nayofs Soris. nayofi iyenebs placentaSi producirebul

progesterons adrenaluri dehidroepiandrosteronis da

dehidroepiandrosteron sulfatis warmoqmnisaTvis. Ees

hormonebi Tavis mxriv gardaiqmnebian placentaSi

androstenedionad da testosteronad. Semdeg xdeba maTi

swrafi konvercia estronad da estradiolad, romlebic

gamoiyofa da dedis sisxlis mimoqcevaSi (Marzi M., et al.., 1996).

Ddehidroepiandrosteronis metabolitis, 16 hidroqsilatis,

estriolad gardaqmna mimdinareobs nayofis RviZlSi.

progesteroni monawileobs orsulobis pirvel fazaSi,

xolo orsulobis meore periodSi gacilebiT didi

mniSvneloba eniWeba estrogenebs, romlebic didi raodenobiT

warmoiqnebian placentis mier. meore da mesame trimestris

ganmavlobaSi placentaSi producirebuli estrogenebis

maRali koncentraciebi astimulireben IL-6-is, IL-10-is da IFN-γ-

s warmoqmnas, monawileoben Th-1/Th-2 balansis regulaciaSi

(Matalka K.Z., 2003);Eestrogenebi xels uwyoben B ujredebis

momwifebas da antisxeulebis sinTezs (Cutolo M., et al., 1995).

Ffiziologiur koncentraciebSi progesteroni

astimulirebs IL-4-is (Th-2-is citokini) sinTezs, maSin roca

esteradioli astimulirebs TNF-α-s (Th-1-is citokini)

produqcias. orsulobis meore naxevarSi progesteroni

farmakologiur dozebSi ainhibirebs TNF-α-s sekrecias da

astimulirebs IL-10-is produqcias T limfocitebis klonis

mier, rac ganapirobebs humoruli imunuri pasuxis gaZlierebas

(Piccini M.P., et al., 1995, Cutolo M., et al., 1995).

Oorsulobis dros estradiolis donis momatebis erT-

erTi mniSvnelovani gverdiTi efeqti mdgomareobs dedis

32

organizmSi (RviZlSi) proteinebis sinTezis intensifikaciaSi,

rac ganapirobebs sisxlSi zogierTi proteinebis

koncentraciis momatebas (Marzi M., et al.., 1996).

gamovlenilia koagulaciis procesSi monawile zogierTi

proteinebis Semcvelobis zrda, rac SesaZloa pasuxs agebs

orsulobisaTvis damaxasiaTebel hiperkoagulaciur

mdgomareobaze.

Ffeto-placenturi hormonebi, kerZod, progesteroni,

estrogenebi da placentaruli laqtogeni, pasuxs ageben

karbohidratebis metabolizmis cvlilebebze gestaciis dros.

orsulobis meore naxevarSi dedis organizmSi viTardeba

susti periferiuli rezistentoba insulinis mimarT, rac

pankreasSi insulinis warmoqmnis da sekreciis gaZlierebas

ganapirobebs (Marzi M., et al.., 1996). Gglukozis mimarT

tolerantobiT ganviTarebuli fiziologiuri stresis gamo,

orsulobis meore naxevarSi orsulebis 5%-Si viTardeba

gestaciuri diabeti (Marzi M., et al.., 1996), rac ganpirobebulia

hormonuli regulaciis ukmarisobiT.

cnobilia, romKkortizoli ainhibirebs NK ujredebis

aqtivobas (Allen L.H., 2001); glukokortikoidebi ainhibireben IL-1-

is, TNF-α-s, IFN–γ-s da IL-2-is produqcias da astimulireben IL-

10, IL-4 da IL-13-is sinTezs, ris saSualebiTac uzrunvelyofen

orsulobis dros antianTebiTi da imunosupresorul pasuxebs

Soris balansis modulacias (Ramirez F., et al., 1996).

maSasadame, SegviZlia davaskvnaT, rom orsulobis dros

sisxlSi kortizolis da saseqo hormonebis (estrogenebis da

progesteronis), donis progresuli zrda, zemoqmedebas axdens

dedis organizmSi imunuri pasuxis ganviTarebaze, xels uwyobs

33

Th-2-is pasuxis stimulacias da proanTebiTi citokinebis (IL-1β,

IL-6, IL-8, IL-12, TNF-α, IFN-γ) eqspresiis inhibicias (Elenkov I.J., et al.,

1997, Piccini M.P., et al., 2000). O

orsulobis pirveli trimestris ganmavlobaSi

kortizolis, progesteronis da estradiolis gamoyofis

fiziologiuri gaZliereba iwvevs Th-2 citokinebis

polarizacias, rogorc sistemur, aseve feto-placenturi

urTierTqmedebis doneze (Munoz-Valle J.F., et al., 2003, Opsjon S.L., et

al., 1993). maSasadame, Th-2-inducirebuli Th-1-ze damokidebuli

imunuri pasuxis supresia rogorc Cans mniSvnelovania nayofis

gadarCenisaTvis.

Oorsulobis da mSobiarobis magaliTze naTlad Cans, rom

steroiduli hormonebis Semcvelobis cvlilebebi

uzrunvelyofen qalSi imunur da anTebiT pasuxis,

imunoregulatoruli molekulebis (citokinebis)

koncentraciis modifikacias.

saSvilosnoSi nayofis ganviTarebis da gadarCenis

procesSi didi mniSvneloba eniWeba proteqtorul asimetriul

antisxeulebs (AAb), (magaliTad, IgG-s (Malan Borel I., et al., 1991,

Marfni R.A., Malan Borel I., 1999)), romlebic uzrunvelyofen

imunuri pasuxis dros fetoplacentaruli kompleqsSi mamis

antigenebis proteqcias. Tavisi molekuluri asimetriulobis

gamo AAb-s ar gaaCnia antigenebis sawinaamRdegod mimarTuli

imunuri reaqciis gamowvevis unari (Cgaoauat G., et al., 1990).

Oorsulobis dros gamovlenilia maTi momateba rogorc

sisxlis SratSi, aseve placentaSi, sadac isini uzrunvelyofen

mamis antigenebis blokirebas (Margni R.A., Malan Borel I.., 1998).

34

cnobilia, rom AAb-is sinTezis regulacia mimdinareobs

IL-6-s monawileobiT. amasTan, IL-6-is dabali Semcveloba

asocirdeba AAb-is maRal donesTan da orsulobis normalur

mimdinareobasTan, maSin roca IL-6-is momatebas Tan sdevs AAb-

is Semcvelobis daqveiTTeba da orsulobis moSla (Zenclussen

A.C., 2003).

1.3 Tavisufalradikaluri Jangva da misi roli

orsulobis paTogenezSi

dResdReobiT kargadaa cnobili, rom fiziologiuri

procesebisa da mravali daavadebis paTogenezSi

Tavisufalradikaluri Jangvis procesebi umniSvnelovanes

rols asruleben. (Haddan J.I., 2002; Allen R.G., Tresini I., 2000).

Tavisufalradikaluri Jangvis intensivobazea

damokidebuli organizmze misi pozitiuri da negatiuri

gavlena. ZuZumwovrebSi Jangbadis reaqciuli naerTebis dabali

koncentraciebis dadebiTi moqmedeba dRes-dReobiT aRar aris

paradoqsuli. cnobilia, rom wyalbadis zeJangis

minimolaruli koncentraciebi ar azianeben genoms. piriqiT,

aaqtiveben antioqsidanturi fermentebis genebis eqspresias

(Dempe D. et al., 1982). Bcl-2-is antioqsidantur moqmedebas

safuZvlad udevs misi prooqsidanturi aqtivoba, romelic

xels uwyobs 13-jer metad aqtiuri katalazas genis eqspresias

(Steiman H.M., 1995). wyalbadis zeJangi mitoqondriebSi atf-is

sinTezis aucilebeli komponenti (Кондрашова М.Н., Миронова Г.Д.,

1971) da neitrofilebis fagocitaluri aqtivobis

35

stimulatoria (Gamaly L.A. et al., 1994; Klyubin J. et al., 1996).

wyalbadis zeJangi mikromolarul koncentraciebSi

astimulirebs superoqsiddismutazas aqtivobas (Kosenko E.A. et

al., 1997). reaqciuli Jangbadis zemoqmedebiT aqtiurdeba agreTve

iseTi antioqsidanturi fermentebis redoqs-mgrZnobiare genebis

eqspresia, rogoricaa glutaTionperoqsidaza, qinonreduqtaza,

Tioredoqsini, Tioredoqsinreduqtaza, metaloTionini, ciklo-

oqsigeneza-2 da glutamilcisteinsinTaza (Thannickal V.J. et al.,

2000; Reiter J., 1995).

lipidebis zeJanguri Jangvis produqtebi dabali

koncentraciisas xels uwyoben mitoqondriuli sunTqviTi

jaWvis funqcionirebas, steroiduli da Tiroiduli

hormonebis, prostaglandinebis, progesteronis, proTrombinis,

kolagenis biosinTezs (Лузиков В.М., 1980). wyalbadis zeJangi

monawileobs insulin-inducirebuli dnm-is sinTezis

stimulaciaSi, ribosomebSi cilis fosforilirebaSi (Larsson R.

et al., 1988). Jangbadis aqtiuri formebi uzrunvelyofen agreTve

mikroorganizmebis detoqsikacias, destruqcias (Кондрашова

М.Н., 1999), anu dabali intensivobisas Tavisufalradikaluri

Jangva ujredebSi mimdinare procesebisa da maTi normaluri

funqcionirebis aucilebeli etapia (Герасимов А.М., 1981).

fiziologiur pirobebSi Tavisufalradialuri Jangva

uwyvetad, dabali intensivobiT mimdinareobs organizmSi.

Jangbadi monawileobs mitoqondriebis sunTqviTi jaWvis

funqcionirebaSi, sadac asrulebs eleqtronebis saboloo

aqceptoris rols. oqsigenazebisa da oqsidazebisaTvis ki igi

substratis rols asrulebs.

cnobilia, rom aerobuli organizmebis ujredebSi

36

Jangbadis TiTqmis 95% aRdgeba mitoqondriuli

citoqromoqsidazebis mier, xolo danarCeni - gadamuSavdeba

mravalricxovani oqsidazebis da dehirogenazebis

monawileobiT.

ujredSi arsebobs Jangbadis gamoyenebis ori gza:

oqsidazuri da oqsigenazuri. oqsidazur reaqciebSi adgili

aqvs organuli naerTebis (naxSiwylebis, cximebis)

Tanmimdevrul dehidrirebas, SemdgomSi mitoqondriebSi wyal-

badis atomis transportis saboloo etapze, ferment citoqrom

C oqsidazaze gadataniT da Jangbadis molekulis

oTxeleqtroniani aRdgeniT da wylis molekulis warmoqniT.

Jangbadis oqsidazuri daJangvis Sedegad miiReba universaluri

biologiuri naerTi atf da wyali. am procesis dros, romelic

mudmivad mimdinareobs ujredebSi SesaZlebelia reaqciuli

Jangbadis intermediantebis (Zalian mcire koncentraciiT - 1%)

warmoqmna (Hakin J., Torres H., 1981). reaqciuli Jangbadis naerTebi

(superoqsidradikalebi) warmoiqmnebian mitoqondriebSi

naxevrad aRdgenili ubiqinonis arafermentuli daJangvis dros

(Raha S. et al., 2000) (suraTi 1). mitoqondriebis garda reaqciuli

Jangbadis wyaros warmoadgens plazmur membranaze ganla-

gebuli NAD(P)H-oqsidaza da 5-lipooqsigenaza. NAD(P)H-oq-

sidazas eqspresia damaxasiaTebelia sisxlis fagocituri

rigis (neitrofilebi, eozinofilebi, makrofagebis) da endoTe-

luri ujredebisaTvis (Клюбин И.В. и др., 1997). 5-lipooqsigenazas

eqspresia damaxasiaTebelia limfocitebisa da

astrocitebisaTvis (Bonizzi G. et al., 2000).

oqsigenazuri reaqciebi ZiriTadad mimdinareoben mikro-

somalur sistemaSi citoqrom P-450-is monawileobiT.

37

oqsigenazur reaqciebSi endogenuri substratis molekulis

daJangvisas molekuluri Jangbadi pirdapir uerTdeba organul

naerTebs, rac Jangbadis erTeleqtronian, arasrul aRdenas da

superoqsidradikalis warmoqmis SesaZleblobas qmnis (sur. 1).

citoplazma mitoqondria

citoqrom P-450

O2+e- NO

peroqsi-nitriti

hidroqsil-radikali

superoqsidi

wyalbadis zeJangi

H2O+O2

glutaTion-peroqsidaza katalaza

Cu/Zn sod

NO

superoqsidi

wyalbadis zeJangi

H2O+O2

O2+e- eleqtronebis satransporto

jaWvi

Mn sod

glutaTion-peroqsidaza katalaza

sqema4

ujredSi Jangbadis reaqciuli naerTebis warmoqmnis sqema

superoqsidradikalebis (O2-) udidesi nawili warmoiqmneba

oqsidaciur reaqciebSi.

O2--is warmoqmna SeaZlebelia agreTve sxvadasxva

arafermentul reaqciebSi kateqolaminebis, hidroqinonebis,

leikoflavinebis, Tiolebis, tetrahidropterinebis da

hemoglobinis daJangvis dros.

molekuluri Jangbadis or eleqtroniani daJangvis

Sedegad warmoiqmneba wyalbadis zeJangi (H2O2). es procesi

aqtiurad mimdinareobs L-aminomJavebis oqsidazebis, aldehid-

dehidrogenazebis, NO-sinTazebis, monoaminooqsidazebis, 5-

38

lipooqsigenazas, superoqsiddismutazas da mTeli rigi sxva

fermentebis monawileobiT (Thannickal V.J. et al., 1998; Reiter R.J., 1995;

Турпаев К.Т., 2002).

peroqsidradikalisagan gansxvavebiT wyalbadis zeJangs

ujredul membranebSi SeRwevisa da misi sinTezis adgilidan

sakmaod did manZilze gadaadgilebas da ujredul

komponentebTan urTierTqmedebis unari gaaCnia. rac am

naerTis SedarebiT maRali stabilobiT da maRali

reaqtiulobis unariTa aris ganpirobebuli. cvalebadi valen-

tobis mqone metalTa ionebTan (Fe2+, Cu+, Mn2+) H2O2-is

urTierTqmedebisas (fentonis reaqcia) warmoiqmneba

maRalreaqciuli hidroqsilradikali HO•:

H2O2+Fe2+→-OH+•OH+Fe3+

hidroqsilradikalebis warmoqmna SesaZlebelia agreTve

haber-vaisis reaqciaSic wyalbadis zeJangis da superoqsid-

radikalis urTierTqmedebis Sedegad, romelic katalizdeba

gardamavali jgufis metalTa ionebis mier:

O2-+H2O2→HO•+HO- +O2

hidroqsilradikali (HO•) - xanmokle sicocxlis mqone (r

≈10-9 wm) radikalia, romelic Jangavs sxvadasxva bunebis

organul naerTebs. igi iwvevs nukleinuri mJavebis da cilebis

Seuqcevad modifikacias, ujeri cximovani mJavebis zeJanguri

Jangvis jaWvuri reaqciebis iniciacias, DNA-is dazianebas.

maSasadame, Jangbadis reqaciuli naerTebi ujredebis

cxovelqmedebis (mitoqondriuli sunTqvis, mikrosomuli

Jangvis, leikoflavinebis, kateqolaminebis, Tiolebis da sxv.)

autodaJangvis Cveulebriv metabolitebs warmoadgenen, xolo

Tavisufalradikaluri Jangva - ujredis cxovelqmedebis

39

aucilebeli komponentia. misi done organizmSi Cveulebrivad

regulirdeba antioqsidanturi sistemis mier (Журавлев А.И.,

1982; Кричевская А.А. и др., 1985; Ермак И.С., 1990; Kozlov A.V. et al., 1993;

Журавлев Ю.И. и др., 1996), romelic warmodgenilia fermentuli

da arafermentuli naerTebis didi jgufiT, lokalizebuli

sxvadasxva subujredul organelebSi da ujredTaSoriso

siTxeSi.

antioqsidantur fermentul sistemas miekuTvneba:

katalaza, superoqsiddismutaza, glutaTionperoqsidaza,

ceruloplazmini (suraTi 1) (Косовер Н., Косовер Э., 1979; Шайдиев

Д.Д., 1985; Ласкаржевская И.А. и соавт., 1990; Лебедева Е.С. и соавт., 1992;

Иванов И.И., 1975; Маринов Б.С. и соавт., 1987; Журавлев А.И., 1982;

Политова Л.Н. и соавт., 1992; Дурнев А.Ж. и соавт., 1996); xolo

arafermentuls: tokoferoli, serotonini, Tiroqsini,

steroiduli hormonebi, askorbinis mJava, karotinoidebi,

haptoglobini, ubiqinoni (Владимирова Ю.А. и соавт., 1986; Иванов

И.И., 1975; Ломоносов Е.Е. и соавт., 1994; Храпович Н.Г., 1982; Горбань

Е.Н., 1989).

superoqsiddismutazebi (sod) arsebobs sami tipis: Cu, Zn,

sod lokalizebuli citozolSi; eqstraceluluri sod,

lokalizebuli sisxlis plazmaSi da Mn-sod, lokalizebuli

mitoqondriul matriqsSi. sod akatalizebs

superoqsidradikalebis (O2-) aRdgenis reaqcias wyalbadis

zeJangis warmoqmniT. sod

O2-+O2

-+2H → H2O2+O2

sod ganixileba, rogorc integraluri antioqsidanturi

fermenti, vinaidan misi substrati, superoqsidradikali,

warmoiqmneba ara marto mitoqondriuli da mikrosomuli

40

eleqtronebis gadamtan jaWvebSi, aramed birTvebSi,

mikrosomebSi; agreTve endoTelur ujredebSi fagocitozis

dros, sxvadasxva warmoSobis JangviTi stresis dros, dabal-

molekuluri metabolitebis (glutaTionis) autodaJangvis

dros (Winterbourn C.C., 1995; Вартанян П.С. и соавт., 2001).

dacviTi fermentebis meore jgufs miekuTvneba gluta-

Tiondamokidebuli fermentebi, romlebic monawileoben

wyalbadis zeJangis da organuli hidroperoqsidebis

detoqsikaciaSi. glutaTionperoqsidazebi arseboben cito-

zolSi da mitoqondriebSi. glutaTionperoqsidaza wyalbadis

donoris saxiT iyenebs glutaTions, romelic TviT endogenur

antioqsidants warmoadgens (Chance B., Sies H., Bovers A., 1979; Ursini

F., Bindoli A., 1987).

glutaTionperoqsidaza akatalizebs reaqcias hidrogen-

peroqsidsa da organul peroqsidebs da glutaTions Soris da

am gziT aqveiTebs lipidebis peroqsidaciis intensivobas

(Madiipati K.B., Mernett L.J., 1987).

antioqsidantur fermentul sistemas miekuTvneba agreTve

katalaza, romelic urTierTqmedebs wyalbadis zeJangTan

wylis da molekuluri Jangbadis warmoqmniT. glutaTion

peroqsidazas da katalazas garda wyalbadis zeJangis

detoqsikaciaSi monawileobs Tioredoqsinperoqsidazac.

glutaTionisa da Tioredoqsinis Tioluri jgufebis Semdgomi

aRdgena NADPH-is monawileobiT xorcieldeba.

sisxlis Sratis ZiriTadi antioqsidaturi fermenti -

ceruloplazminia. igi superoqsidradikaluri peroqsidazuli

da feroqsidazuli aqtivobiT xasiaTdeba. feroqsidazuri

41

aqtivobis gamo ceruloplazmini Jangavs Fe2+ ionebs Fe3+-mde

da xels uwyobs maT CarTvas apotransferinSi da am gziT

sisxlis SratSi Tavisufldeba rkinis ionebisagan (Fe2+),

romlebic •OH radikalebis warmoqmnis da lipidebis zeJanguri

Jangvis uSualo promotorebi arian. ujredSi HO•-radikalebis

warmoqmnisagan dacvaSi monawileoben agreTve rkinis ionebis

xelatorebi - ferodoqsini, metaloTionini, pikolinis mJava,

hemoqsigenaza, romlebic rkinis ionebis imobilizacias da

labiluri hemuri jgufebis mocilebas uzrunvelyofen (Reiter

R.J., 1995; Platt J.L., Nath K.A., 1998).

Tavisufali radikalebis generacias xels uSlis qinonre-

duqtaza. ujredis membranul komponentebSi lipidebis

peroqsidaciis iniciaciisagan dacvaSi monawileoben askorbinis

mJava, lipofiluri antioqsidanti - tokoferoli (E vitamini),

melaTionini da bilirubini. es dabalmolekuluri naerTebi

asruleben eleqtronebis donorebis rols da maRalaqtiuri

Tionilur, alkoksilur da peroqsidul radikalTa

dauwyvilebeli eleqtronebis neitralizacias uzrunvelyofen

da qimiurad inertul Tavisufalradikalur naerTebad

gardaqmnebian (Reiter R.J., 1995).

antioqsidanturi fermentebi warmoqmnian metabolur

jaWvs, romelSic wina rgolis produqti momdevno rgolis

substrats warmoadgens da fiziologiur pirobebSi mkacr

kontrols awarmoeben Jangbadis reaqciuli naerTebis

produqciis intensivobaze.

JangviTi metabolizmi warmoadgens umniSvnelovanes

fiziologiur faqtors, romelic zegavlenas axdens

placentaSi proliferaciis, decidualuri invaziis,

42

diferenciaciisa da spiraluri arteriebis remodelirebis

procesebis intensivobaze. hestaciis me-10-12 kviras, placenturi

cirkulaciis Camoyalibebis Semdeg, adamianis placentaSi

swrafad izrdeba Jangbadis parcialuri wneva (Jauniaux E., et al.,

2000), adgili aqvs antioqsidanturi fermentebis aqtivobas da

mRNA-is momatebas (Michiels C., 1994, Huang W.M., 2001). anu,

antioqsidantebi akontroleben Jangbadis Tavisufali

radikalebis Semcvelobas. Mme-10 kviris Semdeg dediseuli

sisxli ufro Tavisuflad Sedis intrabususovan areSi, rac

vlindeba ultrabgeriTi doplerografiis monacemebiT (Jaffe R.,

1997) da ganapirobebs intrabususovan areSi ganTavisuflebuli

Jangbadis totalur momatebas. ukanaskneli xels uwyobs

placentis Aaerobuli metabolizmis gaaqtivebas, Jangbadis

reaqciuli naerTebis gaZlierebul warmoqmnas da oqsidaciuri

stresis ganviTarebas.

Jangbadis Semcvelobis cvlilebebi uzrunvelyofs

sxvadasxva transkripciuli faqtorebisa da biologiurad

aqtiuri naerTebis (VEGF (vascular endothelial growth factor), leptinis,

HIF-1α (hypoxia inducible factor-1α) da sxv. JangviTi metabolizmis

regulacias; agreTve glikolizis, glukozis transportis,

eriTropoezisa da angiogenezis regulacias (Challier JC, Uzan S.,

2003, Genbacev O, et al., .1997, Bunn H.F., Poyton R.O., 1996, Wegner R.H.,

Gassmann M., 1997). placentaSi Jangbadis sensoris rols

mitoqondriebi da/an hemoproteidebi asruleben (Huppertz B,. 2003).

rogorc zemoT ukve aRvniSneT, Tavisufalradikaluri

naerTebis generaciis intensifikacia ganpirobebulia

ZiriTadad, mitoqondriuli eleqtronebis satransporto

jaWvis NADH-ubiqinon-oqsidoreduqtazul ubansa da

43

endoplazmur retikulumze eleqtronebis transportis

darRveviT (Freeman B.A., Crapo J.D., 1981).

superoqsidradikalebi generirdeba agreTve fermentuli

gziT NO-sinTzis, qsantinoqidazis da NADPH-oqsidazis mier

(Myatt L., Cui X., 2004). dadgenilia, rom gestaciuri asakis

momatebasTan erTad izrdeba antioqsidanturi fermentebis

aqtivoba da eqspresiis intensivoba, es SesaZloa, warmoadgens

sapasuxo reaqcias placenturi sisxlis mimoqcevis

cvlilebebiT ganpirobebuli JangviTi metabolizmis

aqtivaciaze (Jauniaux E., 2000). Tu Jangbadis Tavisufali

radikalebis generaciis intensivoba aWarbebs antioqsidanturi

dacvis sistemis SesaZleblobas, viTardeba oqsidaciuri

stresi. am SemTxvevaSi adgili aqvs proteinebis, lipidebis da

DNA molekulebis ganurCevel dazianebas da ujredis funqciis

dakargvas.Bbolo wlebis SromebSi naCveneb iqna, rom

proteinebis oqsidaciuri dazianeba ainducirebs Hsps 70 (heat

shock protein 70) eqspresias (Freeman M.I., et al., 1999). Hsps cila

moqmedebs rogorc molekuluri regulatori, romelic

uzrunvelyofs proteinebis proteolizisisagan prevencias da

warmoadgens adaptaciur reaqcias mimarTuls ujredis

oqsidaciuri stresis sawinaaRmdegod (Su C.-Y., 1998).

fiziologiuri orsulobis dros placentaSi dediseuli

arteriuli cirkulirebis aqtivacia asocirdeba JangviTi

stresis xanmokle ganviTarebasTan, romelic ganpirobebulia

disbalansiT swrafad momatebul Jangbadis daZabulobasa da

antioqsidanturi sistemis aqtivobas Soris. JangviTi

metabolizmis afeTqeba placentis nirmaluri ganviTarebis

dros atarebs mniSvnelovan fiziologiur daniSnulebas,

44

romelic gamoixateba diferenciaciis induqciiT (Sun Y., Oberley

L.W., 1996, Arrigo A.-P., 1999). magaliTad, mas SeuZlia

citotrofoblastebis gadarTva proliferaciulidan invaziur

fenotipze da am gziT uzrunvelyofs eqstrabususovani

trofoblastebis endometriumSi migraciis stimulacias, sadac

isini mniSvnelovan rols asruleben spiraluri arteriebis

gardaqmnis procesSi (Genbacev O, et al., 1997, Canigga I., et al., 1996,

Kam E.P., et al., 1999).

JangviTi stresis pirobebSi SesaZlebelia

fosfotidilinozitol-3-isa da mitogenaqtivirebul protein-

kinazebis (PI-3-K, MAPK) spontanuri aqtivacia. fiziologiuri

orsulobis mesame trimestris dros, trofoblastebis kvdomis

intensifikaciaSi, swored am kinazebis aqtivacias eniWeba

mniSvnelovani roli (Mackova M., 2003). JangviTi stresi

kolagenazebis ММР-2-is da ММР-99-is aqtivobaze zemoqmedebis

meSveobiT aregulirebs trofoblastebis invazias.

oqsidaciuri stresi orsulobis garTulebebis potenciur

mizezs warmoadgens.

eqstrabususovan citotrofoblastebis miometriumSi

invaziis darRveva pirveli trimestris ganmavlobaSi

orsulobis garTulebebis ganviTarebis erT-erT winapirobas

warmoadgens (Drosens I., 1972). orsulobis garTulebis albaToba

da gamosavali mniSvnelovnad damokidebulia spiraluri

arteriebis epiTeliumSi eqstrabususovani citotrofo-

blastebis invaziis xarisxze (Drosans I., et al., 1972, Takehara Y.,

et al., 1990). saSvilosnos spiralur arteriebSi scinciti-

otrofoblastebis invaziis SezRudva cititrofoblastebSi

adeziuri molekulebis, integrinebis, eqspresiis darRvevasa da

45

invazirebuli citotrofoblastebis apoptozis intensi-

fikacias ganapirobebs (DiFderico E., et al., 1999, Genbasev O., et al.,

1999). spiraluri arteriebis arasruli gardaqmnis Sedegad

adgili aqvs utero-placenturi perfuziis daqveiTebas

(KhongT.Yet al., .1986) da iSemiis ganviTarebas. Pplacentis iSemia

iwvevs mTeli rigi metaboluri procesebis cvlilebebisa da

oqsidaciuri stresis ganviTarebas.

arsebobs mosazreba, rom arasrulad remodelirebuli ar-

teriebi cvalebadi reaqtiulobiT xasiaTdebian, rac

intrabususovan areSi sisxlis mimoqcevisa da placentis

perfuziis cvalebadobas ganapirobebs. placentis

fluqtuaciuri perfuziiT gamowveuli misi qsovilis

reperfuzia-oqsigenacia xels uwyobs qronikuli oqsidaciuri

stresis ganviTarebas (Roberts J.M., Hubel C.A., 1999, Wang Y., Walsh

S.W., 1998 Allaire A.D., 2000).

placentaSi oqsidaciuri stresis intensifikacia

SeiZleba, agreTve ganpirobebuli iyos dedis organizmSi

sistemuri anTebis ganviTarebiT. garTulebuli orsulobis

dros pacientebis sisxlis leikocitebSi (Gervasi M.T., et al., 2001,

Lee V.M., et al., 2003), neitrofilebsa (Aly A.S., et al., 2004) da

makrofagebSi (Conrad K.P., et al., 1998) gamovlenilia reaqciuli

Jangbadis konstituciuri da citokin-inducirebuli

hipergeneracia.

angiotenzin II tipi I-is mimarT agonisturi autoimunuri

antisxeulebi, Warbad eqspresirebuli garTulebuli

orsulobis dros, iwveven placentaSi NADPH-is receptor-

damokidebul aqtivacias (Dechend R., et al., 2003).

46

maSasadame, garTulebuli orsulobis dros

matulobs placentis oqsidaciuri potenciali, izrdeba

lipidebis zeJanguri Jangvis procesebis aqtivoba. ukanaskneli

vlindeba araqidonis mJavisa da malonis dialdehidis

koncentraciis momatebiT (Cester N., et al., 1994). oqsidaciuri

stresis potenciurad damazianebeli efeqti placentaSi

vlindeba qsovilis mwvave dazianebiTa da infarqtebis

ganviTarebiT. Siga mitoqondriul membranaze Tioluri

jgufebis daJangva xels uwyobs mitoqondriuli membranebis

ganvladobis cvlilebas BCL-2-is mier regulirebadi mega-

forebis gaxsniT. ionuri gradientebis dakargva da

citoplazmaSi mcire proteinebis, magaliTad, citoqromi c-s,

ganTavisufleba iwvevs kaspazebis kaskadis aqtivacias da

apoptozis ganviTarebas (Kowaltowski A.J., Vercesi A.E., 1999).

Ooqsidaciuri stresis dros mitoqondriuli membranebis

peroqsidaciuli gardaqmnis fonze adgili aqvs mitoqondriul

matriqsSi da Siga membranaze ganlagebuli fermentebis

dazianebas (Yamakura F., et al., 1998, Du G., et al., 1998, Cardoso S.M., et al.,

1999). Tu es cvlilebebi sakmaod Zlieria, isini iwveven

sincitiotrofoblastebSi energetukuli maragis gamolevas,

nekrozis, an apoptozis ganviTarebas. (Huppertz B, et al., 2003).

Ooqsidaciuri stresis intensivoba damokidebulia

intrabususovan areSi Jangbadis daZabulobis doneze da

antioqsidanturi dacvis sistemis aqtivobaze.

sincitiotrofoblastebi friad mgrZnobiarea oqsidaciuri

stresis mimarT, vinaidan isini ganlagebuli arian bususebis

zedapirze da sxva ujredebze adre ganicdian intrabususovani

pO2–is mavne zemoqmedebas. Aamis garda,

47

sincitiotrofoblastebi sxva bususovan qsovilebTan

SedarebiT xasiaTdebian antioqsidanturi fermentebis dabali

SemcvelobiT (Watson A.L., et al., 1997). intrabususovan areSi

dediseuli sisxlis naadrevad, didi raodenobiT SeRweva,

xSirad naadrevi mSobiarobis da spontanuri abortebis erT-

erT mizezs warmoadgens (Jauniaux E., et al., 1994).

imunohistoqimiuri kvlevebis Sedegebis Tanaxmad,

preeklampsiis dros spiraluri arteriebis endoTeliumi

gluvi muskulaturis ujredebTan da

sincitiotrofoblastebTan erTad eqvemdebarebian

oqsidaciuri stresis zemoqmedebas. Jangbadis reaqciuli

naerTebi moqmedeben, rogorc Sigaujredovani sasignalo

molekulebi, romlebic inicireben endoTeluri ujredebis

proliferaciasa da sisxlZarRvebis gluvi muskulaturis

ujredebis hipertrofias (Irani K., 2000). Ees yvelaferi ki

ganapirobebs placentis cirkulaciis darRvevebis gaRrmavebas

(Khalil R.A., Granger J.P., 2002). placentaSi ganviTarebuli hipoqsia

xels uwyobs trofoblastebis invaziis Semdgom daqveiTebas,

bususovani angiogenezis darRvevas, placentis qsovilSi

metabolizmis Secvlas, sisxlZarRvebis reaqciulobis

cvlilebas, sisxlis mimoqcevis sistemaSi darRvevebis

ganviTarebas, organizmis humaruli homeostazis Secvlas,

dedis organizmSi preeklampsiis sindromis ganviTarebas. A

maSasadame, SeiZleba iTqvas, rom preeklampsia warmoadgens

kompleqsuri darRvevebiT inducirebul multisistemur

sindroms.

48

Tavi 2. kvlevis masala da meTodebiK

2.1. klinikuri masalis mimoxilva

(pacientebis SerCeva)

klinikuri dakvirvebebi da laboratoriuli kvlevebi

CautardaT 100 qals. aqedan 15 pacienti reproduqciuli asakis

janmrTeli, araorsuli qalia, 25 - orsuli qali orsulobis

fiziologiuri mimdinareobiT, gestaciis vadiT 21-36 kvira (10

orsuli – gestaciis vada 21-27 kvira, 15 orsuli – gestaciis

vada 27-36 kvira); 60 orsuli qali –preeklamfsiiT

garTulebuli orsulobiT, romelTa sisxlSi gamovlinda

antifosfolipiduri antisxeulebi (28 orsuli - gestaciis

vada 21-27 kvira, 32 orsuli - gestaciis vada 27-36 kvira). preek-

lamfsiis diagnozi ismeboda Tanamedrove klasifikaciis

kriteriumebis (Gifford J.M., et al., 2000)… safuZvelze. kerZod,

sistoluri arteriuli wneva gestaciis me-20 kviris Semdeg iyo

> 140 Hg mm, diastoluri - > 90 Hg mm. adgili hqonda

proteinurias, SeSupebas.

gamosakvlevi pacientebi SerCeul iqnen q. Tbilisis …# 2

samSobiaro saxlsa da qalaqis sxva samSobiaro saxlebSi.

Seswavlil iqna orsulTa anamnezuri monacemebi.

orsulTa gamokvlevebis dros yuradReba eqceoda

memkvidreobiT faqtorebs, bavSvobaSi gadatanil

daavadebebs, sqesobrivi momwifebisa da reproduqciuli

sistemis Camoyalibebas. eqstragenitalur daavadebebs,

romlebsac SeeZlo gamokvlevis Sedegebze moexdina

gavlena. menstrualuri funqciis gamokvlevisas yuradReba

gamaxvilda menarxes periodze, menstruaciis

49

xangrZlivobaze, mtkivneulobaze, dakarguli sisxlis

raodenobaze.

socialuri statusis Seswavlisas mxedvelobaSi

viRebdiT sacxovrebel pirobebs, stresuli faqtorebis

arsebobas.

yvela orsuls utardeboda rutinuli gamokvlevebi:

sisxlis saerTo analizi, Sardis analizi, koagulograma,

saSos floris baqteriologiuri Seswavla, sasqeso

sistemis ultrabgeriTi gamokvleva, sisxlis jgufis da

rezus-faqtoris gansazRvra.

Catarebuli gamokvlevebis Taviseburebebis

gaTvaliswinebiT, orsulebi, romlebsac aReniSnebodaT

infeqciuri an eqstragenitaluri daavadebebi, ganviTarebis

sxvadasxva mankebi, gamosakvlev jgufSi CarTulni ar

yofilan.

preeklamfsiis diagnostikisaTvis yuradReba eqceoda

anamnezs, obieqtur Civilebsa da klinikur simptomebs.

kvlevis masalad SerCeuli iyo orsulebis venuri

sisxli da placenta. kvlevebi Catarda Tbilisis

saxelmwifo samedicino uneversitetis bazaze.

2.2 laboratoruli kvlevebi

2.2.1 sisxlis imunologiuri maCveneblebis gansazRvra

2.2.1.1 periferiul sisxlSi antifosfolipiduri

antisxeulebis Semcvelobis gansazRvra

periferiuli sisxlis SratSi antifosfolipidur

antisxeulebs kardiolipinis (ACA), fosfatidilserinis (APS)

50

da mgluras antikoagulantis (Lupus index) mimarT vsazRvravdiT

ELISA-s meTodiT, imunofermentul riderze (reaqtivi –

M.B.S. - Medical Biologikal Servise scl. – milani – italia).

2.2.1.2 periferiul sisxlSi СMV da HSV mimarT antisxeulebis

Semcvelobis gansazRvra

sisxlSi СMV da HSV mimarT antisxeulebis Semcvelobas

vsazRvravdiT ELISA-s meTodiT, imunofermentul riderze.

sinjebi da kontrolebi gaizoma 450 nm filtrze,

sakontrolo fosos 620-630 nm filtris mniSvnelobis

mimarT (reaqtivi – M.B.S. - Medical Biologikal Servise scl. – milani

– italia).

2.2.1.3 periferiul sisxlSi steroiduli hormonebis

Semcvelobis gansazRvra

sisxlSi steroiduli hormonebis, progesteronis,

estradiolis da testosteronis Semcvelobas

vsazRvravdiT ELISA-s meTodiT (reaqtivi – M.B.S. - Medical

Biologikal Servise scl. – milani – italia).

2.2.1.4 T – da B- limfocitebis raodenobrivi gansazRvra

gamosakvlevi qalebis periferiul sisxlSi T- limfocitebis

raodenobrivi gansazRvra xorcieldeboda cxvris

eriTrocitebTan spontanuri E-rozetowarmoqmnis meTodiT,

xolo B- limfocitebis procentuli Semcveloba _

isazRvreboda komplementuri rozetowarmoqmnis meTodiT

(Jondal M., et al., 1965, Новиков Д.К., 1987).

2.2.1.5 leikocitebis interferonuli reaqcia

sisxlis leikocitebis mier interferonis in vitro

producirebis unari fasdeboda v. d. soloviovisa da t. a.

bektemirovis meTodiT (1991).

51

2.2.1.6 periferiuli sisxlis limfoiduri ujredebis

maCveneblebis gansazRvra

gamosakvlevi qalebis imunuri statusis Sefasebis mizniT

vsazRvravdiT Semdeg parametrebs: perifriul sisxlSi T- da B-

limfocitebsa da maT subpopulaciebs (T-aqtiuri, T-helperebi,

T-supresorebi).

sisxlis neitrofilebis fagocituri aqtivoba fasdeboda

sami maCvenebliT: fagocituri ricxvi, indeqsi, monelebis

procenti.

A α da γ interferonebis aqtiuroba fasdeboda sisxlis

leikocitebis mier maTi produqciis unaris SefasebiT in vitro.

2.2.1.7 sisxlis neitrofilebis fagocituri aqtivobis

maCveneblebis gansazRvra

fagocitozis SefasebisaTvis isazRvreboda sami

maCvenebeli: fagocituri ricxvi (fr) – STanTqmis unaris mqone

neitrofilebis raodenoba ujredebis 100 ujredze);

fagocituri indeqsi (fi) – mikrobebis saSualo ricxvi 1

neitrofilze; fagocitozis dasruleba (fd) - monelebuli

mikrobebis procenti mikrobebis saerTo raodenobidan (Кост

Е.А., Степко М.Н., 1975, Мотавкина Н.С. и др., 1987).

2.2.2 sisxlis bioqimiuri maCveneblebis gansazRvra rezonansis

(epr) speqtroskopuli meTodiT

placentaSi da sisxlSi JangviTi homeostazis

gansazRvris mizniT viyenebdiT eleqtronuli

paramagnituri rezonansis (epr) meTods) (Пулатова М.К., и

52

др., 1989). epr speqtroskopuli kvlevebi tardeboda

radiospeqtrometrze РЭ1307 (ruseTi), romelic operirebs

zemaRal sixSireze 9.77 GHz modulaciis sixSiriT 50 kHz

Txevadi azotis temperaturaze (-1960C).

sisxlSi vsazRravdiT Jangbadis (О2-), lipidebis (LOO.)

da azotis Jangis (NO) Tavisufalradikalur formebs epr

speqtroskopiis meTodis da Sesabamisi spin-xafangebis

gamoyenebiT. Tavisufali azotis Jangis gansazRvris mizniT

viyenebdiT spin-xafangs natriumis dieTildiTiokarbomats

(DETC) (Sigma). vawarmoebdiT sisxlis inkubacias DETC-Tan

(0,34mg/ml) da Fe2+ -citratTan (0,03 mg FeSO4. 7H2O+ 3,7 mg natriumis

citrati oTaxis temperaturaze 10 wuTis ganmavlobaSi, ris

Semdegac vyinavdiT Txevadi azotis temperaturaze. NO-Fe2+-

(DETC)2 – kompleqsebis epr speqtrebis registracias vaxdendiT

Txevadi azotis temperaturaze da mikrotalRovani simZlavris

mniSvnelobaze 20 mVt (Галаган М.Е., и др., 1997).

sisxlSi Jangbadis Tavisufali radikalebis

(superoqsidradikalebis) gansazRvris mizniT viyenebdiT

spin-xafangs 5,5 dimeTil-I-pirolin-IV-oqsids (DMPO)

(SIGMA). vawarmoebdiT sisxlis inkubacias DMPO-Tan

(doziT 50 mM 1 ml sisxlze) 3 wuTis ganmavlobaSi oTaxis

temperaturaze (Xia Y., Zweer J.L., 1997).

sisxlSi lipidebis Tavisufali radikalebis (LOO.)

gansazRvris mizniT viyenebdiT spin-xafangs α-fenil-tert-

buTilnitron (PBN) (SIGMA) (SIGMA). vawarmoebdiT sisxlis

inkubacias PBN -Tan (doziT150 mM/ml PBN tris-HCl buferis 2,5

53

mM/ml-Si (pH 7.4) (Stoker R., et al., 1987) 3 wuTis ganmavlobaSi

oTaxis temperaturaze (Xia Y., Zweer J.L., 1997).

superoqsidradikalebis (O2-) da lipoperoqsidebis LOO.-

s epr speqtrebs vsazRravdiT oTaxis temperaturaze

mikrotalRovan simZlavreze 20 mVt. (Kramer H.J., et al., 1994).

2.3. Mmasalis statistikuri damuSaveba. Eepr speqtroskopuli maCveneblebis statistikur

analizs vawarmoebdiT standartuli meTodis gamoyenebiT,

xolo sxvaobis sarwmuno Sefasebas _ vawarmoebdiT

stiudentis t kriteriumis gamoyenebiT.

imunologiuri maCveneblebis statistikur damuSavebas

vaxorcielebdiT fiSeris formulisa d kompiuteruli

programebis (versiebi Excel da SPSS) gamoyenebiT.

54

Tavi 3. gamokvlevis Sedegebi

3.1 PorsulTa pereferiul sisxlSi antifosfolipiduri

antisxeulebis Semcveloba

cxrilSi N 1 moyvanilia preeklamfsiiT garTulebuli

orsulobis dros gestaciis mesame trimestrSi pacientebis

sisxlSi antifosfolipiduri sxeulebis Semcvelobis

maCveneblebi.

Cveni kvlevebis SedegebiT dadginda, rom preeklamfsiiT

garTulebuli orsulobis mimdinareobiT gamokvleuli 60

orsuli qalidan, 42 qals aRmoaCnda kardiolipinis mimarT

antisxeulebis maRali Semcveloba, (antikardiolipinuri

antisxeulebi (ACA)), aqedan, 5 qalSi paralelurad gamovlinda

mgluras antikoagulanti (Lupus index), 10 orsul qals aRmoaCnda

antifosfatidilserinis antisxeulebi (APA), xolo 6 qals -

mxolod mgluras antikoagulanti (Lupus index) (cxrili 1,

diagrama 1).

0

1

2

3

4

5

6

7 diagrama 1

55

cxrili 1 orsuli qalebis periferiul sisxlSi

antifosfolipiduri antisxeulebis Semcveloba

ACA

(U/ml)

APS

(U/ml) Lupus index

fiziologiuri orsuloba < 0,030

Opt<0,150 <1,0 <1,2

antifosfolipiduri

sindromiT garTulebuli

Oorsuloba (21-27 kvira)

0,598±0,109

p<0,001

6,23±1,0

p<0,001

1,3±0,1

p>0,1

N 22 4 4

Oantifosfolipiduri

sindromiT garTulebuli

Oorsuloba (27-36 kvira)

0,617±0,118

p<0,001

5,08±1,1

p<0,001

1,43±0,1

p>0,1

N 20 6 7

3.2 PorsulTa pereferiul sisxlSi anti-CMV IgG da

anti-HSV IgG Semcveloba

cxrilSi N 2 moyvanilia preeklamfsiiT garTulebuli

orsulobis dros gestaciis mesame trimestrSi pacientebis

sisxlSi anti-CMV IgG da anti-HSV IgG Semcvelobis maCveneblebi.

rogorc cxrilSi moyvanili monacemebidan gamomdinareobs,

kvlevis Sedegad gamovlinda, rom gamokvleuli 60 orsulidan

umetesobas aRmoaCnda СMV da HSV mimarT antisxeulebis

Semcveloba (gestaciis 21-27 kvira: anti-СMV IgG _ 20 orsuls, anti-

HSV IgG _ 8 orsuls; gestaciis 27-36 kvira anti-СMV IgG _ 25

orsuls, anti-HSV IgG _ 14 orsuls), rac gestaciis am vadaze

imunodepresiis gaRrmavebaze miuTiTebs.

56

cxrili 2 orsuli qalebis periferiul sisxlSi anti-CMV

IgG da anti-HSV IgG Semcveloba

anti-CMV IgG anti-HSV IgG

anti-CMV IgG

anti-HSV IgG

fiziologiuriOorsuloba

(gestaciis 21-27 kvira) 1

4

1

-

Ffiziologiuri orsuloba


7

2 -

antifosfolipiduri sindromiT

garTulebuli Oorsuloba


20 8 2


garTulebuliOorsuloba


25 14 7

3.3 orsulTa placentis paramagnituri centrebis cvlilebebi

antifosfolipiduri sxeulebis Tanaobisas

cxrilSi N3 da diagrama 2 moyvanilia placentis paramagni-

turi centrebis maCveneblebi: orsulobis fiziologiuri

mimdinareobisa da antifosfolipiduri sxeulebis gamoCenis

pirobebSi.

rogorc cxrilSi moyvanili monacemebidan

gamomdinareobs, fiziologiuri orsulobis dros placentis

epr speqtrSi vlindeba FeS –centrebis, citoqrom P-450-is, Mn2+

da Fe2+ ionebis da Tavisufali azotis Jangis (NO).

cnobilia, rom adamianis drouli placentis mitoqon-

driebSi arsebobs eleqtronebis satransporto jaWvis ori

57

tipi – pirveli pasuxisgebelia atf-is sinTezze, xolo meore

monawileobs steroidogenezis procesebSi (Klimek J., et al., 1998).

Tavisi daniSnulebis mixedviT placentis mitoqondriebis

eleqtronebis satranporto jaWvebi Seicaven citoqromebs

sxvadasxva tipebs (citoqrom c-s da citoqrom P-450-s), xolo am

jaWvebSi monawile FeS-Semcveli centrebi miekuTvnebian

sxvadasxva fermentebs (NADH-dehidrogenazas da

adrenodoqsins). mitoqondriebis satransporto jaWvis NADH-

dehidrogenaza monawileobs eleqtronebis

flavoproteidebidan qinonebze gadatanaSi.

cxrili 3 placentis paramagnituri centrebi mSobiarobis Semdgom

placentaSi

T.r. cit.

Р-450 NO

g┴=,01 LOO. Mn2+

HbNO

gc=2,01

FeS

g║=1,94 I ΔH g┴=2,25

fiziologiuri

orsuloba 1

24,0±0,9 2,0±0,8 0,9±1,5 - 22,0±1,9 4,5±0,9 12,0±0,5 8,7±0,9

antifosfo-

lipiduri

sindromiT

garTulebuli

orsuloba 2

8,0±1,1

P12<0,001

15.0±1,5

P12<0,001

3,5±1,5

P12<0,001

11,0±1,5

P12<0,001

6,0±1,2

P12<0,01

9,0±0,6

P12<0,01

20,8±1,7

P12< 24,0±2,3

0,001

58

0

5

10

15

20

25

diagrama 2

adrenodoqsini asrulebs eleqtronebis donoris rols

steroidebis 11β mdgomareobaSi hidroqsilirebis reaqciaSi.

adrenodoqsini aRdgeba NADFH-damokidebuli adrenodoq-

sinreduqtazas mier da, Tavis, mxriv aZlevs eleqtronebs or

citoqrom P-450-s, romlebic 11β mdgomareobaSi steroidebis

hidroqsilirebis da qolesterinis pregnenalonamde daSlis

reaqciebs akatalizeben. rogorc cnobilia, (Strauss I.H., et al.,

1995), citoqrom Р-450 paramagnituria daJangul dabalspinur

mdgomareobaSi.

steroidogenezis intensifikaciis dros fericitoqrom Р-

450-is epr signalis intensivoba (g1=2,42; g2=2,25; g3=1,92) mcirdeba,

rac ganpirobebulia an substratis mierTebiT, da fermentis

maRalspinur mdgomareobaSi gadasvliT (g=8,0), an, substratis

Tanaobisas, erTeleqtroniani aRdgenis Sedegad

araparamagnituri kompleqsebis warmoqmniT (Пулатова М.К., и др.,

1989). A am dros aRdgenili adrenodoqsinis FeS-centrebis

epr signalis intensivoba mcirdeba.

59

cxrilSi moyvanili monacemebidan gamomdinareobs, rom

antifosfolipiduri sindromis dros adrenodoqsinis FeS –

Semcveli centrebis epr signalis intensivoba 50%-iT mcirdeba,

xolo citoqrom Р-450-is epr signali 139%-iT izrdeba

fiziologiurad mimdinare orsulobisaTvis damaxasiaTebel

maCveneblebTan SedarebiT.


orsulobis dros placentis epr speqtrSi vlindeba Mn2+–

Semcveli kompleqsebis signalis intensivobis mkveTri

momateba, rac membranuli struqturebis dazianebiTda

mitoqondriuli superoqsiddismutazas inaqtivaciiT SeiZleba

iyos ganpirobebuli (Пулатова М.К., и др., 1989). Mn2+ ionebis

dagroveba xels uwyobs Jangbadis reaqciuli naerTebis

(superoqsidradikalebis) gaZlierebul warmoqmnas,

Tavisufalradikaluri Jangvis procesebis da membranuli

lipidebis peroqsidaciis intensifikacias, rac placentis epr

speqtrSi lipoperoqsidebis (LOO.) epr signalebis gamoCeniT

vlindeba.

membranuli lipidebis peroqsidaciis procesebis

intensifikacia membranebis funqciis darRvevas, membranuli

fermentuli da receptoruli cilovani kompleqsebis kerZod,

transferinis receptoris Fe3+–transferinis mimarT

mgrZnobelobas daqveiTebas ganapirobebs. ukanaskneli ki

placentaSi nayofis ganviTarebisaTvis aucilebel rkinis

Semcvelobis daqveiTebas iwvevs, rac Tavisufali rkinis epr

signalis intensivobis daqveiTebiT vlindeba (cxrili 3).

interess warmoadgens placentaSi Tavisufali azotis

Jangis Semcvelobis Semcireba Uantifosfolipiduri sindromiT

60

garTulebuli orsulobis dros (ix. cxrili №6). Tavisufali

azotis Jangis Semcvelobis Semcirebas Tan axlavs

hemSemcveli cilebis (citoqrom с oqsidazas, GMP-ciklaza,

citoqrom P-450 da a.S.) nitrozilireba, rac HbNO-s

kompleqsebis gamoCeniT vlindeba).

placentasMmitoqondriuli cilebis nitrozilireba

eleqtronuli transportis Seferxebas, energogenezis da

steroidogenezis darRvevas ganapirobebs.

vvaraudobT, rom azotis Jangis mitoqondriul cilebTan

urierTqmedeba da hemur rkinasTan kompleqsebis warmoqmna

placentaSi azotis Jangis Semcvelobis Semcirebis erT-erT

mizezs warmoadgens. Aar aris gamoricxuli agreTve arsebuli

oqsidaciuri stresis pirobebSi NO-s peroqsinitritad

transformacia.

suraTi 1

HbNO kompleqsebis epr signali placentaSi

antifosfolipiduri sindromiT garTulebuli orsulobis

dros.

61

3. 4 orsulTa pereferiul sisxlSi steroiduli hormonebis

Semcvelobis cvlilebebi

cxrilSi #4 da diagrama #3 moyvanilia gestaciis mesame

trimestrSi orsuli qalebis sisxlSi steroiduli hormonebis,

progesteronis, estradiolis da testosteronis Semcvelobis

cvlilebebi fiziologiuri orsulobis da preeklamfsiiT

garTulebuli orsulobis dros.

cxrilSi moyvanili monacemebidan gamomdinareobs,

preeklamfsiiT garTulebuli orsulobis dros

progesteronis Semcveloba 32%-iT, estradiolis - 37%-iT

mcirdeba, xolo testosteronis 51%-iT izrdeba

fiziologiuri orsulobisaTvis damaxasiaTebel

maCveneblebTan SedarebiT.

cxrili №4 orsuli qalebis periferiul sisxlSi steroiduli

hormonebis Semcveloba

Pprogeste-

roni

(ng/ml)

Eestradi-

oli

(pg/ml)

testosteroni

(ng/ml)

fiziologiuri orsuloba

(gestaciis 21-27 kvira) 11550±78 319±65 142±36



1610±77

P12>0,1

410±48

P12>0,1

130±36

P12>0,1


garTulebuli orsuloba

(gestaciis 21-27 kvira) P 3

1100±85

P13<0,01

239±59

P13>0,1

224±42

P13>0,1




1250±83

P24<0,01

P34>0,1

290±77

P23>0,1

P34>0,1

180±40

P23>0,1

P34>0,1

62

0

100

200

300

400

500

diagrama 3

rogorc cnobilia, fiziologiuri orsulobis dros sisxlis

plazmaSi progesteronis maRali Semcveloba K+ ionebis

Semcvelobis SenarCunebas da am gziT sisxlZarRvebis

membranuli potencialis da reaqciulobis regulacias

uzrunvelyofs. preeklamfsiis dros sisxlis plazmaSi

progesteronis donis Semcireba, SesaZloa, K+-is homeostazis

darRvevis, sisxlZarRvebis gluvi muskulaturis ujredebSi

membranuli potencialis cvlilebebis, Са2+ neli arxebis

gaxsnis da arteriuli wnevis momatebis erT-erT mizezs

warmoadgens (Losel R.M., et al., 2003).

63

I. Buhimschi (1995) TanaavtorebTan erTad aCvenes, rom

progesteronis ineqciebi xels uwyobdnen LNAME-inducirebuli

hupertenziis daqveiTebas eqsperimentul make virTagvebSi.

preeklamfsiiT garTulebuli orsulobis dros Cvens mier

gamovlenili testosteronis Semcvelobis momateba Seesabameba

literaturul monacemebs (Jirecek S., et al., 2003, Steier J.A., et al., 2002).

am hormonis Semcvelobis momateba preeklamfsiis dros

ganpirobebuli SeiZleba iyos placentaSi citoqrom-Р-450-

aromatazas inhibiciiT Warbad sinTezirebuli NO-s mier.

aRniSnulis gamo mcirdeba estrogenebis Semcveloba

pacientebis sisxlSi. mravalricxovani kvlevebi mowmoben

estradiolis mniSvnelovani rolis Sesaxeb arteriuli wnevis

regulaciaSi (Svedas E., et al., 2002). iTvleba, rom es procesi

xorcieldeba NO-damokidebuli meqanizmiT estradiolis

receptorebis monawilebiT, romlebic zegavlenas axdenen

endoTeluri NO-sinTazas aqtivobaze (eNOS) kompleqsis PI3-

kinaza-serin-trionin Akt-kinaza aqtivaciis gziT (Losel R.M., et al.,

2003).

maSasadame, miRebuli Sedegebisa da sakuTari monacemebis

analizis safuZvelze SegviZlia davaskvnaT, rom Cvens mier

gamovlenili hormonyli homeostazis darRveva preeklamfsiis

dros mniSvnelovan rols asrulebs preeklamfsiisaTvis

damaxasiaTebeli endoTeluri difunqciis paTogenezSi.

vazodilataciuri hormonebis (progesteronis da estradiolis)

Semcvelobis Semcireba sisxlZarRvebis reaqciulobis momatebis

da hipertenziis ganviTarebis erT-erT mizezs warmoadgens.

64

3.5 orsulTa pereferiul sisxlSi Jangbadis parcialuri

wnevis (pO2) cvlilebebi

cxrilSi N5 da diagrama #4 moyvanilia monacemebi

orsuli qalebis sisxlSi Jangbadis parcialuri wnevis (pO2)

cvlilebebi Taobaze.

Cveni kvlevebis Sedegad dadginda, rom orsuli qalebis

sisxlSi preeklamfsiiT garTulebuli oesulobis dros

statistikurad sarwmunod mcirdeba Jangbadis parcialuri wnev

(fiziologiuri рО2= 34,0±2,8; preeklamfsia - рО2=25,6±3,0), rac

hipoqsiis ganviTarebaze miuTiTebs.

cxrili N 5 orsuli qalebis sisxlSi Jangbadis parcialuri wneva (pO2)

pO2

fiziologiuriOorsuloba

(gestaciis 21-27 kvira) 1 34,0±2,8

FfiziologiuriOorsuloba


32,0±2,5

P12>0,1

Oantifosfolipiduri sindromiT



25,6±2,0

P13<0,01

Oantifosfolipiduri sindromiT



20,9±2,8

P24<0,01

P34<0,01

65

0

510

15

20

25

3035

1 2 3 4

1 – fiziologiuriOorsuloba (gestaciis 21-27 kvira) 2 - fiziologiuriOorsuloba (gestaciis 27-36 kvira) 3 - antifosfolipiduri sindromi (gestaciis 21-27 kvira) 4 - antifosfolipiduri sindromi (gestaciis 27-36 kvira)

diagrama 4

3.6 orsulTa pereferiul sisxlSi Tavisufali azotis

Jangis Semcvelobis cvlilebebi

cxrilSi N6 da diagrama #5 moyvanilia monacemebi orsuli

qalebis sisxlSi Tavisufali azotis Jangis Semcvelobis

cvlilebebis Sesaxeb fiziologiuri da preeklamfsiiT

garTulebuli orsulobis dros.

rogorc qvemoT moyvanili monacemebidan gamomdinareobs,

preeklamfsiis dros Tavisufali Jangis Semcveloba 32%-iT

mcirdeba sakontrolo maCveneblebTan SedarebiT.

preeklamfsiiT garTulebuli orsulobis dros qalebis

sisxlSi vlindeba azotis Jangis hemur rkinasTan kompleqsebis

(HbNO) intensiuri epr signali.

rogorc cnobilia, eriTrocitebis hemoglobini xasiaTdeba

azotis Jangis mimarT gacilebiT maRali afinobiT, vidre

Jangbadis mimarT (Jia L., et al., 1996). Ffiziologiur pirobebSi

sisxlSi HbNO-kompleqsebis dabali koncentraciebi (azotis

66

Jangis JangbadTan SedarebiT dabali Semcvelobis gamo)

praqtikulad ar deteqtirdeba epr meTodiT (Perutz M.F. 1996).

magram, sxvadasxva paTologiuri mdgomareobebis dros

hipoqsiis pirobebSi, NO-s gaZlierebuli warmoqmnisas

SesaZlebeli xdeba HbNO-kompleqsebis warmoqmna. Ees

kompleqsebi gamovlenil iqna jer kidev adrindel naSromebSi

orsuli qalebis sisxlSi Zlieri toqsikozis (Чхаидзе Т., и др.,

2000?), orsulobis naadrevi Sewyvetis saSiSroebisa (Khugashvili R.

et al.,2000) (Khugashvili N., et al., 2000) da sxvadasxva genezis

infeqciuri daavadebebis dros (Хочава М., и др., 2002).

NO-s hemoglobinTan SekavSireba mocirkulire sisxlSi

Tavisufal NO-s Semcvelobis mkveTr Semcirebas ganapirobebs

da agreTve xels uwyobs hemoglobinis Jangbadis satransporto

funqciis SezRudvas, rac hipoqsiis xarisxis zrdasa da

oqsidaciuri stresis gaRrmavebas uwyobs xels.

cxrili N 6 orsuli qalebis periferiul sisxlSi Tavisufali azotis

Jangis Semcveloba

NO HbNO

FfiziologiuriOorsuloba

(gestaciis 21-27 kvira) 1 14,5±0,7 -

Ffiziologiuri orsuloba


14,0±0,8

P12>0,1 2,5±0,9


garTulebuli Oorsuloba


10,0±0,8

P13<0,01

15,0±1,6

P23<0,01




10,8±0,7

P14<0,01

P34>0,1

15,0±1,6

P24<0,01

P34>0,1

67

0

5

10

15

diagrama 5

3.7 orsulTa pereferiul sisxlSi superoqsid- da

lipoperoqsid radikalebis Semcveloba

cxrilSi N7 da diagrama #6 mocemulia Jangngbadis da

lipidebis Tavisufalradikaluri naerTebis Semcvelobis

cvlilebebi orsuli qalebis sisxlSi gestaciis vadiT 21-36

kvira preeklamfsiiT garTulebuli orsulobis dros da

sisxlSi antifosfolipiduri antisxeulebis Tanaobisas.

cxrilSi mocemuli monacemebodan gamomdinareobs, rom

preeklamfsiis dros orsulTa sisxlSi mkveTrad izrdeba

Jangbadis da lipidebis Tavisufalradikalururi naerTebis

68

Semcveloba, rac oqsidaciuri stresis ganviTarebis Sesaxeb

metyvelebs.

cxrili 7 orsuli qalebis periferiul sisxlSi superoqsid-

da lipoperoqsid- radikalebis Semcveloba

NO

g=2,03 O2

- LOO.


(gestaciis 21-27 kvira) 125,9±0,1 - 0,8±0,1


(gestaciis 27-36 kvira) 224,9±0,1 - 1,0±0,1


garTulebuli orsuloba 20,8±1,0

P13<0,001 6,1±0,7

4,2±0,7

P13<0,001 (gestaciis 21-27 kvira) P 3



(gestaciis 27-36 kvira) 4 P

18,8±1,2

P13<0,001

P43>0,1

6,1±0,7

P43>0,1

4,2±0,7

P24<0,001

P43>0,1

0

2

4

6

8

10

12

14

diagrama 6

69

3.8 sisxlis imunologiuri maCveneblebis cvlilebebi


preeklamfsiis dros, organizmis imunologiuri rezistentobis

donis Sefasebis mizniT, Cven SeviswavleT periferiuli

sisxlis limfoiduri ujredebis funqciuri da raodenobrivi

cvlilebebi.


preeklamfsiis dros, limfoiduri ujredebis subpopulaciis

Seswavlisas, dafiqsirda am ujredebis funqciuri aqtivobisa

da fenotipis gadanawilebis Taviseburi cvlilebebi.

dadgenda: T- limfocitebis saerTo raodenobisa (50,4%-mde)

da misi aqtiuri fraqciis (26,5%-mde) Semcirebis faqti.

Semcirda T- limfocitebis helperebis raodenoba (26%-mde) da

imunoregulaciis indeqsi (1,93-mde) (cxrili 8).

Tu fiziologiuri orsulobis III trimestris bolos B

limfocitebis Semcveloba praqtikulad ar gansxvavdeba

araorsuli qalebisaTvis damaxasiaTebeli analogiuri

maCveneblebisagan (24,1% da 24,5%), antifosfolipiduri

sindromiT garTulebuli preeklamfsiis dros es maCvenebeli

statistikurad sarwmunod mcirdeba 20,7%-mde (p<0,005).


preeklamfsiis dros neitrofilebis fagocituri aqtivobis

maCvenebeli (φh=67,3%, φb=3,8% φ1 =58,1%) mcirdeboda

fiziologiuri orsulobisaTvis damaxasiaTebel analogiur

maCveneblebTan SedarebiT (φh=72,1%, φb=5,5%, φ1=66,3%).

70

kvlevis Sedegad miRebuli monacemebis analizis

safuZvelze SegviZlia davaskvnaT, rom fiziologiuri

orsulobis III trimestris bolos garkveuli xarisxis

imunodepresiaa damaxasiaTebeli, rac vlindeba T - helperebis

ujredebis Semcvelobis SemcirebiT (34m4%-mde), T –supresorebis

raodenobis momatebiT (19,3%-mde) da imunoregulaciis indeqsis

mkveTri daqveiTebiT (1,78-mde) janmrTeli araorsuli

qalebisaTvis damaxasiaTebel maCveneblebTan SedarebiT. A

gamovlenilia agreTve neitrofilebis fagocituri

aqtivobis (φh=68,4%, φb=4,6%. φ1=57,6=mde) Semcireba,

interferonebis (IFNα da IFNγ) donis mkveTri daqveiTeba.

orsulobis paTologiuri mimdenareobisas sisxlis

imunologiuri maxasiaTeblebis cvlilebebi kidev ufro

Zlierdeba, rac imunodeficitis gaRrmavebaze miuTiTebs.

aRsaniSnavia, rom imunodeficitis xarisxi korelirebs

orsulobis vadasTan.

Catarebuli kvlevis Sedegebis analizis safuZvelze

SeiZleba davaskvnaT: antifosfolipiduri sindromiT

garTulebuli orsulobis dros sisxlis limfoiduri

ujredebis subpopulaciis Semadgenlobis Seswavlisas

dafiqsirebulia am ujredebis funqciuri aqtivobisa da

fenotipis gadanawilebis Taviseburi cvlileba.

dadginda: sisxlSi T - limfocitebis saerTo raodenobisa

da maTi aqtiuri fraqciis (Ta), B-limfocitebis raodenobis

mkveTri Semcireba; Ggamovlinda T- limfocitebis supresoruli

populaciis raodenobrivi zrda.

71

cxrili 8

orsuli qalebis periferiuli sisxlis imunologiuri maCveneblebi

T

(%)

Ta

(%)

Th

(%)

Ts

(%)

ii B

(%)

fr

(φh)

(%)

Ffi

(φb)

(%)

Ffd

(φi)

(%)

INFα

(erT/ml)

INFγ

(erT/ml)

kontroli

52,6±

0,3

33,4±

0,4

36,6

±0,3

14,6

±0,4

2,5±

0,3

24,5

±0,4

75,5±

0,4

6,3±0,3

72,6±

0,5

43,4±0,6

31,8±0,7

Ffizio-

logiuri

orsuloba

(21-27 kvira)

51,7±0,

3

28,3±

0,3

33,9

±0,4

17,3

±0,5

1,78

±0,2

*

24,1

±0,3

72,1±

0,9

*

5,5±0,3

66,3±

0,3

*

28,3±0,5

*

20,4±0,6

*

Ffizio-

logiuri

orsuloba

(27-36 kvira)

53,8±0,

5

29.1±

0,4

34,4

±0,3

19,3

±0,4

1,78

±0,5

*

23,1

±0,5

68,4±

0,8

*

4,6±0,3

*

57,6±

0,3

*

26,3±0,3

*

18,5±0,5

*

AFA

garTule-

buli

preeklam-

fsia(21-27

kvira)

50,4±0,

4

26,5±

0,3

33,2

±0,3

19,3

±0,5

*

1,88

±0,3

*

20,7

±0,4

*

**

66,7±

0,9

*

**

3,8±0,3

*

**

59,1±

0,4

*

23,2±05

*

15,3±0,3

*

**

AFA

garTule-

buli pree-

klamfsia

(27-36 kvira)

51,4±0,

3

27,0±

0,2

34,0

±0,6

22,0

±0,3

*

**

1,90

±0,3

*

21,0

±0,3

*

**

66,0±

0,8

*

3,6±0,3

*

60,1±

0,3

*

24,5±0,3

*

16,4±0,3

*

* - sarwmuno cvlilebebi sakontrolo maCveneblebTan SedarebiT.

72

** - sarwmuno cvlilebebi fiziologiuri orsulobisaTvis

Sesabamis maCveneblebTan SedarebiT.

0

20

40

60

80

0

20

40

60

80

0

20

40

60

80

73

0

20

40

60

80

0

20

40

60

80

4. kvlevis Sedegebis ganxilva

(gansja)

Cveni kvlevebis SedegebiT dadginda, rom preeklamfsiiT

garTulebuli orsulobis mimdinareobiT gamokvleuli 60

orsuli qalidan, 42 qals aRmoaCnda kardiolipinis mimarT

antisxeulebis maRali Semcveloba, (antikardiolipinuri

antisxeulebi (ACA)), aqedan, 5 qalSi paralelurad gamovlinda

mgluras antikoagulanti (Lupus index), 10 orsul qals aRmoaCnda

antifosfotidilserinis antisxeulebi (APA), xolo 6 qals -

mxolod mgluras antikoagulanti (Lupus index) (cxrili 1).

cnobilia, rom sisxlSi autoimunuri antifosfolipiduri

antisxeulebis gamoCena mniSvnelovan zegavlenas axdens

organizmis hormonul da oqsidaciur homeostazze.

literaturuli monacemebi mowmoben, rom auto-

antifosfolipiduri antisxeulebis warmoqmnis erT-erTi mizezia

lipidebis Tavisufalradikaluri Jangvis intensifikacia da

lipoperoqsiduli radikalebis dagroveba (Prafico D., et al., 1999).

kardiolopinis mimarT antisxeulebis warmoqmna (ACA) sisxlis

plazmaSi lipidebis peroqsidaciis intensifikaciis aRiarebuli

markeris, F2-izoprostanebis Semcvelobis momatebasTan

korelirebs (Morrow J.D., Roberts L.J., 1996, Iuliano L., et al., 1997). Tavis

mxriv, antifosfolipiduri antisxeulebi Jangbadis reaqciuli

naerTebis generatorebis, membranoSekavSirebuli fermentebis,

МАР-kinazebis (Simoncini S., et al., 2005), maT mier regulirebadi

transkripciuli faqtorebis (Kyriakis J.M., Avruch J., 2001)

saSualebiT xels uwyobs proanTebiTi ujredebis aqtivobas, am

ujredebis mier Jangbadisa da azotis reaqciuli naerTebis

Tavisufalradikaluri formebis generacias.

74

dadgenilia uaryofiTi korelacia antifosfolipiduri

antisxeulebis Semcvelobas da HDL-damokidebuli

antioqsidanturi fermentis, paraoqsanazas aqtivobas Soris

(Alves vJ., Grima B., 2003, Durrington P.N., et al., 2001).

araorsul qalebSi sistemuri mgluras antikoagulantis

(lupus erythematosus) dros gamovlenilia IL-2-is da IL-12-is

produqciis Semcireba T- limfocitebis, periferiuli sisxlis

mononuklealuri ujredebis (Horowitz D.A., et al., 1998, Liu T.F., Jones

B.M., 1998) da B limfocitebis (Liu T.F., et al., 1997) mier, rac

sxvadasxva faqtoris zemoqmedebiTaa ganpirobebuli, Th2

citokinebis damTrgunveli moqmedebis CaTvliT. mgluras

antikoagulantis gamoCenisas gamovlenilia Th2 citokinis, IL-10-

is, produqciis mniSvnelovani zrda (Liorente L., et al., 1993, Llorente

L., et al., 1994, Lauwerys B.R., et al., 2000). sistemuri mgluras

antikoagulantis dros pacientebis sisxlis SratSi dadgenilia

korelacia IL-10-is maRal Semcvelobas, daavadebis klinikur da

serologiur aqtivobas da anti-dnm-is antisxeulebis

koncentracias Soris (Haussiau F.A., 1995, Park Y.B., et al., 1998, Grondal

G., et al., 2000). dadgenilia, rom IL-12 ainhibirebs IL-10-is mier

spontanurad stimulirebuli imunoglobulinebis da anti-dnm

antisxeulebis produqcias (Houssiau F.A., et al., 1997).

aqedan gamomdinare, IL-10/IL-12 balansi mniSvnelovan rols

asrulebs ujredebis araadekvaturi imunuri pasuxis

regulaciaSi sistemuri mgluras antikoagulantis gamoCenis

dros.

janmrTeli orsuli qalebis organizmSi imunoregulaciis

cvlilebebis inducireba xorcieldeba feto-placentaruli

urTierTqmedebis doneze da ar xasiaTdeba sistemuri efeqtiT.

75

sistemuri mgluras antikoagulantis gamoCenisas orsuli qalis

imunuri sistema ganicdis cvlilebas da zemoqmedebas axdens

orsulobis mimdinareobaze. Aam TvalsazrisiT gansakuTrebiT

mniSvnelovania progresteronis da estrogenebis monawileoba

Th1/Th2 balansis regulaciaSi, romelic vlineba rogorc feto-

placentarulad, aseve zogadad mTels organizmSi. orsulobis

dros estrogenebis da progesteronis maRali koncentraciebi

ujreduli imunuri pasuxis (Th1 citokinebi) inhibicias Dda Th2

citokinebis produqciis induqcias uzrunvelyofen. arsebuli

literaturis (Doria A., et al., 2002) da Cveni kvlevebis monacemebidan

(cxrili 1) naTlad Cans, rom sistemuri mgluras

antikoagulantis gamoCenis dros dedis organizmSi hormonuli

statusi cvlilebas ganicdis. kerZod, orsulobis meore da

mesame trimestrSi, rodesac hormonopoezi ZiriTadad

placentaSi mimdinareobs, xdeba sisxlis plazmaSi estradiolis

da progesteronis koncentraciis Semcireba (janmrTeli orsuli

qalebisaTvis damaxasiaTebel Sesabamis maCveneblebTan

SedarebiT), rac ganpirobebuli SeiZleba iyos placentis

hormonopoezuli funqciis daqveiTebiT. es ukanaskneli

humoruli (Th2) pasuxis daqveiTebas da pacientTa mdgomareobis

gauaresebas ganapirobebs. (Houssiau F.A., et al., 1997).

maSasadame, sistemuri lupus erythematosus-is dros steroiduli

hormonebis Semcvelobis Semcireba Th2 citokinebis daqveiTebis

mizezs warmoadgens. gestaciis periodSi recidivebis maRali

sixSiris gamo, sistemuri mgluras antikoagulantis gamoCenisas,

orsuloba yovelTvis dakavSirebulia riskTan rogorc dedis,

aseve nayofis organizmisaTvis.

76

zemoT moyvanili literaturuli monacemebis da Cveni

kvlevis Sedegebis analizis safuZvelze SegviZlia davaskvnaT,

rom orsul qalebSi antifosfolipiduri sindromiT (kerZod,

sistemuri mgluras antikoagulantiT) garTulebuli

preeklamfsiis dros imunuri balansis darRvevisa da ujreduli

imunitetis (Th1) aqtivobis ZiriTad mizezs warmoadgens

hormonuli statusis cvlilebebi (progesteronis da

estradiolis Semcvelobis daqveiTeba).

rogorc ukve aRvniSneT, antifosfolipiduri

antisxeulebis gamoCena organizmSi oqsidaciuri stresis

ganviTarebis Sedegs da, amave dros, fermentebisa da

transkripciuli faqtorebis aqtivobaze zemoqmedebis

meSveobiT, misi intensifikaciis mizezs warmoadgens.


preeklamfsiis dros Cvens mier orsuli qalebis sisxlSi

gamovlenilia Jangbadis (O2-) da lipidebis (LOO.) reaqciuli

naerTebis gaZlierebuli warmoqmna, rac Sesabamisi epr

signalebis maRali intensivobiT vlindeba (cxrili 7).


preeklamfsiis dros dros orsulTa placentaSi gamovlenilia

proanTebiTi ujredebis da makrofagebis maRali Semcveloba

(Stone S., 2005), romlebic axdenen Janbadis reaqciuli naerTebis

didi raodenobiT generacias, rac xels uwyobs oqsidaciuri

stresis ganviTarebas. placentaSi Aaqtivirebuli makrofagebis

infiltracia da anTebis ganviTareba mniSvnelovan rols

asrulebs trofoblastebis invaziis, spiraluri arteriebis

transformaciis darRvevis, apoptozis iniciaciis da

77

placentis disfunqciis ganviTarebaSi (Mor G., Abrahams V.M..

2003).

maSasadame, antifosfolipiduri antisxeulebi organizmSi

oqsidaciuri stresis Sedegs da amave dros misi gaRrmavebis

da qsovilebis oqsidaciuri dazianebis mizezs warmoadgenen.

placenta orsulobis II da III trimestrSi organizmis

ZiriTad hormonmaproducirebul organos warmoadgens.

maSasadame, antifosfolipiduri sindromiT garTulebuli

preeklamfsiis dros orsuli qalebis organizmSi Cvens mier

gamovlenili hormonuli statusis darRveva dakavSirebuli

unda iyos placentis metabolizmis da funqciebis

cvlilebebTan. fiziologiuri orsulobis dros steroiduli

hormonebis Semcvelobis cvlilebebi uzrunvelyofen

organizmSi imunuri, anTebiTi pasuxis da imunoregulaciuri

molekulebis (citokinebis) koncentraciis modifikacias, xels

uwyoben dedis organizmSi nayofis mimarT imunotolerantobis

ganviTarebas da uzrunvelyofen orsulobis SenarCunebas.

Aaqedan gamomdinare, Zalze mniSvnelovania hormonuli

regulaciis darRvevebis molekuluri meqanizmebis Seswavla

orsulobis garTulebis dros. Cven gamovikvlieT mSobiare

qalebis placentis paramagnituri centrebis cvlilebebi

fiziologiuri orsulobis da antifosfolipiduri sindromiT

garTulebuli preeklamfsiis dros.

rogorc cnobilia, drouli placentis mitoqondriebSi

arsebobs eleqtronebis satransporto jaWvis ori tipi –

pirveli pasuxisgebelia atf-is sinTezze, xolo meore

monawileobs steroidogenezis procesebSi (Klimek J., et al., 1998).

ETavisi daniSnulebis mixedviT placentis mitoqondriebis

78

eleqtronebis satranporto jaWvebi Seicaven citoqromebis

sxvadasxva tips (citoqrom c-s da citoqrom P-450-s), xolo am

jaWvebSi monawile FeS-Semcveli centrebi miekuTvneba

sxvadasxva ferments (NADH-dehidrogenazas da adrenodoqsins).

mitoqondriebis sunTqviTi jaWvis NADH-dehidrogenaza

monawileobs eleqtronebis flavoproteidebidan qinonebze

gadatanaSi.

Aadrenodoqsini 11β steroidebis hidroqsilirebis

reaqciaSi asrulebs eleqtronebis donoris rols.

adrenodoqsini aRdgeba NADPH-damokidebuli adrenodoq-

sinreduqtazas mier da Semdeg gadascems eleqtronebs or

citoqrom P-450-s, romlebic 11β steroidebis hidroqsilirebis

da qolesterolis pregnenalonamde daSlT axdenen reaqciebis

katalizebas.

Cveni kvlevis Sedegad dadginda, rom antifosfolipiduri

sindromiT garTulebuli preeklamfsiis dros adrenodoqsinis

FeS – Semcveli centrebis epr signalis intensivoba 50%-iT

mcirdeba, xolo citoqrom Р-450-is epr signali 39%-iT izrdeba

fiziologiurad mimdinare orsulobisaTvis damaxasiaTebel

Sesasabamis maCveneblebTan SedarebiT (cxrili 3). rogorc

cnobilia, (Strauss I.H., et al., 1995), citoqrom Р-450 paramagnituria

daJangul dabalspinur mdgomareobaSi. steroidogenezis

intensifikaciis dros fericitoqrom Р-450-is epr signalis

intensivoba (g1=2,42; g2=2,25; g3=1,92) mcirdeba, rac

ganpirobebulia an substratis mierTebiT da fermentis

maRalspinur mdgomareobaSi gadasvliT (g=8,0), an misi

erTeleqtroniani aRdgenis Sedegad araparamagnituri

kompleqsebis warmoqmniT (Пулатова М.К., и др., 1989). Aam dros

79

aRdgenili adrenodoqsinis FeS-centrebis epr signalis

intensivoba mcirdeba. maSasadame, antifosfolipiduri

sindromiT garTulebuli preeklampsiis dros Cvens mier

gamovlenili FeS-centrebis da citoqrom Р-450-is epr

signalebis cvlilebebi placentaSi steroidogenezis procesis

(qolesteroli-pregnenaloni) daRrvevis Sesaxeb metyvelebs,

rac orsuli qalebis sisxlis plazmaSi progesteronis

Semcvelobis SemcirebiT vlindeba (ix. cxrili 4).

progesteronis sinTezis blokireba preeklampsiis dros

ujreduli imunuri pasuxis darRvevis erT-erT mizezs

warmoadgens. proanTebiTi citokinebis hiperproduqcia

SemdgomSi icvleba antianTebiTi citokinebis IL-4, IL-10, TGF-β

donis matebiT. es citokinebi axdenen imunuri pasuxis

supresias _ Trgunaven Th1 ujredul pasuxs da iwveven

monocitebis deaqtivacias. Aamitom preeklamfsiis gvian

stadiebze yalibdeba imunotolerantobis, anu “imunodamblis”

mdgomareoba, rac sakmaod saSiSia, vinaidan SesaZlebelia

poliorganuli ukmarisobis sindromis gaRrmaveba.


preeklamfsiis dros placentis epr speqtrSi

Tavisufalradikaluri epr signalis naxevarganis (ΔH)

Semcireba (cxrili 3) mitoqondriuli sunTqvis jaWvis

darRvevis, energogenezis procesis daqveiTebis,

superoqsidradikalebis generatorebis, semiubiqinonebis

dagrovebis Sesaxeb metyvelebs. maSasadame,Eenergiis

ukmarisobis pirobebSi placentaSi Zlierdeba Jangbadis

Tavisufalradikaluri formebis generacia.

80


preeklamfsiis dros placentis epr speqtrSi Cvens mier

gamovlenilia Mn2+–Semcveli kompleqsebis intensiuri epr

signali (cxrili 3), rac membranuli struqturebis dazianebis

da mitoqondriuli superoqsiddismutazas inaqtivaciaze

miuTiTebs (Пулатова М.К., и др., 1989). Mn2+ ionebi Jangbadis

reaqciuli naerTebis (superoqsidradikalebis) warmoqmnis

mZlavri promotorebi arian. superoqsidradikalebis

gaZlierebul generaciaSi monawileobs agreTve, placentis

mitoqondriebis eleqtronuli satransporto jaWvis

fermentebi, citoqromi C da citoqromi P-450.

Jangbadis Tavisufalradikaluri formebis gaZlierebuli

generaciis pirobebSi placentaSi SesaZlebelia

Tavisufalradikaluri Jangvis procesebis intensifikacia, rac

cilebis, nukleinuri mJaveebis da lipidebis dazianebas uwyobs

xels. Uukanaskneli placentis epr spqtrSi lipoperoqsdebis

(LOO.) intensiuri epr signaliT vlindeba (cxrili 3).

literaturuli monacemebi (Kauma S.W., et al., 1999, Huppertz B,

2003, Mackova M, et al., 2003) da Cveni kvlevis Sedegebi mowmoben

imis Sesaxeb, rom placentas orsulTa paTologiebisaTvis

damaxasiaTebeli oqsidaciuri stresis ganviTarebaSi

mniSvnelovani roli eniWeba. Cveni kvlevebis Sedegad dadgina,

rom antifosfolipiduri sindromiT garTulebuli

preeklamfsiis dros placentaSi grovdeba Jangbadis

reaqciuli naerTebis generatorebis (daJanguli citoqrom P-

450, semiubiqinonebi, Mn2+ ionebi) Warbi raodenoba, rac

membranuli struqturebis rRvevas (LOO.-s dagroveba),

fermentebis da fermentuli kompleqsebis (adrenodoqsini-

81

citoqrom P-450, NADH-ubiqinon-oqsidoreduqtaza) inaqtivacias,

steroidogenezis darRvevas uwyobs xels.

sainteresoa placentaSi Tavisufali azotis Jangis

Semcvelobis Semcireba Uantifosfolipiduri sindromiT

garTulebuli orsulobis III trimestris ganmavlobaSi (ix.

cxrili 6). Tavisufali azotis Jangis Semcvelobis Semcirebas

Tan axlavs hemSemcveli cilebis (citoqrom C oqsidaza,

citoqrom P-450, adrenodoqsini, NADH-dehidrogenaza,

citoqrom P-450-aromataza da a.S.) nitrozilireba, rac

hemSemcveli cilebis nitroziluri kompleqsebis gamoCeniT

vlindeba (cxirili 3).

rogorc cnobilia, NO da molekuluri Jangbadi (O2)

mitoqondriuli hemSemcveli cilebis konkuretuli

substratebia (Lamas S., et al., 1998). fiziologiur pirobebSi am

molekulebis mitoqondriul cilebTan Seqcevadi

konkurentuli urTierTqmedeba qsovilebSi Jangbadis

moxmarebis regulacias uzrunvelyofs. NO-s xangrZlivi, Warbi

gamoyofis da Jangbadis dabali parcialuri wnevis pirobebSi

azotis Jangs SeuZlia mitoqondriuli cilebis Seuqcevadi

inhibireba kritikuli Tiolebis da fermentuli kompleqsebis

nitrozilirebis meSveobiT (Clementi E., et al., 1997) da es fenomeni

warmodgens misi fiziologiuri mediatoridan

paTofiziologiur faqtorad gardaqmnis erT-erT meqanizms

(Moncada S., et al., 1993). Uukanaskneli Cveni kvlevis SedegebiT

mtkicdedeba: antifosfolipiduri sindromiT garTulebuli

orsulobis dros placentas mitoqondriuli cilebis

nitrozilireba (cxrili 4) eleqtronuli tranportis

82

darRvevas, energogenezis da steroigenezis intensivobis

daqveiTebas gaapirobebs.

arsebobs monacemebi, rom azotis Jangi adrenodoqsinis da

citoqrom-Р-450-aromatazas nitrozilirebis Sedegad

placetaSi steroidogenezis daTrgunvas uzrunvelyofs (Pate

J.L., Keyes P.L., 2001, Van Voorhis B., et al., 1994). rogorc ukve

aRvniSneT, adrenodoqsini axdens qolesterolis

progesteronis winamorbedaT _ pregnenalonad gardaqmnis

katalizebas; estradioli warmoiqmneba testosteronisagan

ferment citoqrom-Р-450-aromatazas monawileobiT. citoqrom-Р-

450-aromatazas inaqtivoba orsuli qalebis sisxlSi

estadiolis donis Semcirebas da testosteronis momatebas

uwyobs xels. maSasadame, antifosfolipiduri sindromiT

garTulebuli preeklamfsiis dros orsuli qalebis sisxlSi

progesteronis, estradiolis da testosteronis Semcvelobis

cvlilebebi placentis redoqs-homeostazis da NO-s

Semcvelobis cvlilebebiTaa ganpirobebuli.

Lliteraturuli monacemebi mowmobs preeklamfsiis dros

placentaSi azotis Jangis sinTezis intensifikaciis Sesaxeb.

zogierTi avtoris mier gamovlenili azotis Jangis sinTezis

intensifikacia ganpirobebuli SeiZleba iyos, rogorc JangviTi

stresiT inducirebuli iNOS gaZlierebuli eqspresiiT, aseve

placentis qsovilis dabali perfuziis, hipoqsiis da

sisxlZarRvebis momatebuli rezistentobis sapasuxo eNOS

eqspresiis adaptaciuri intensifikaciiT (Noddad E.K., et al.,

1997).

T.H. Hung-i da Tanaavtorebi miiCneven (2001) (Hung T.H., et al.,

2001), rom placentaSi azotis Jangis Semcvelobis Semcireba

83

gamowveuli SeiZleba iyos preeklamfsiisaTvis damaxasiaTebeli

Tavisufalradikaluri Jangvis procesebis intensifikaciiT,

NO-s da superoqsidradikalebs (O2-) Soris balansis

darRveviTa da azotis Jangis peroqsinitritad

transformaciiT.

am mosazrebis sasargeblod metyvelebs monacemebi

preeklamfsiis dros placentaSi nitroTirozinis naSTebis

arsebobis Sesaxeb (Myatt L., et al., 1996). peroqsinitriti Zlieri

toqsiuri naerTia, monawileobs biologiuri membranebis

peroqsidaciuli daJangvis, cilebis aminomJavuri naSTebis

nitrirebis procesebSi, rac ganapirobebs membranebis, maTze

ganlagebuli fermentuli kompleqsebis struqturis da

funqciebis Secvlas. mitoqondriebSi eleqtronebis

satransporto cilebis nitrozilireba xels uwyobs

bususovani epiTeliumis gluvkunTovani ujredebis

destruqcias, sincitiotrofoblastebis apoptozis da

nekrozis intensifikacias, placentis perfuziis, energo- da

steroidogenezis darRvevas (Hung T.H., et al., 2001, Kossenjans W.,

et al., 2000, Ayuk, 2002). peroqsinitriti SemdgomSi iwvevs

birTvuli faqtoris NFkB-s inhibicias, iNOS eqspresiis

daTrgunvas (Alves J.D., et al., 2005) da organizmSi NO-s warmoqmnis

Semcirebas (cxrili 3, cxrili 6). Lliteraturis da Cveni

kvlevis Sedegebze dayrdnobiT vvaraudobT, rom

antifosfolipiduri sindromiT garTulebuli preeklamfsiis

dros placentaSi Tavisufali azotis Jangis Semcvelobis

Semcireba mitoqondriuli satransporto cilebis

nitrozilirebis da NO-s peroqsinitritad oqsidaciuri

transformaciis Sedegs warmoadgens. sisxlSi Tavisufali NO-

84

s dabali Semcveloba (cxrili 6) orsulobis dros NO-

inducirebuli dilataciis ukmarisobis, sisxlZarRvebis

reaqciulobis momatebis da dedis organizmSi hipertenziis

ganviTarebis erT-erT mizezs warmoadgens. paTologiuri

orsulobis paTogenezSi NO-s mniSvnelovani rolis Sesaxeb

mowmoben monacemebi NO-sinTazas inhibitoris, LNAME-s (Nω-L-

arginine metylesther), zemoqmedebiT make cxovelebSi

preeklamfsiisaTvis damaxasiaTebeli niSnebis ganviTarebis

Sesaxeb (Buhimschi I., et al., 1995). A

sisxlZarRvebis tonusis regulaciaSi mniSvnelovan rols

asruleben agreTve vazoaqtiuri hormonebi Pprogesteroni da

estradioli. orsulebis sisxlSi progesteronis maRali

Semcveloba sisxlis plazmaSi K+ ionebis Semcvelobis

SenarCunebas uzrunvelyofs (Ehrlish E.N., Lindheimer M. D., 1972),

romlebic Tavis mxriv xels uwyoben membranuli potencialis

da sisxlZarRvebis reaqciulobis SenarCunebas (Furesta C., et al.,

1993, Patrat C., 2000). Fantifosfolipiduri sindomiT

garTulebuli preeklamfsiis dros orsuli qalebis sisxlSi

progesteronis donis Semcireba sisxlZarRvebis gluvi

muskulaturis ujredebSi K+-is homeostazis darRvevis,

membranuli potencialis cvlilebis, neli Са2+ arxebis gaxsnis

da arteriuli wnevis momatebis erT-erT mizezs warmoadgens

(Barbagallo M., et al., 2001). Buhimschi (1995), Q. P. Liao (1996) da

Tanaavtorebma aCvenes, rom progesteronis ineqciebi xels

uwyobs virTagvebSi LNAME-inducirebuli hipertenziis

daqveiTebas (Buhimschi I., et al., 1995, Liao Q.P., et al., 1996).

kvlevebi mowmoben sisxlZarRvebis tonusis da arteriuli

wnevis regulaciaSi estradiolis mniSvnelovani rolis Sesaxeb

85

(Svedas E., et al., 2002). miCneulia, rom es regulacia xorcieldeba

NO-damokidebuli meqanizmiT (MacRitchie A.N., et al., 1997)

estradiolis receptorebis monawileobiT, romlebic

aregulireben NO-sinTazas (eNOS) aqtivobas (Shaul P.W., 1999,

Darblade B., et al., 2002).K

rogorc cnobilia, organizmis redoqs homeostazis

cvlilebebi mniSvnelovan zegavlenas axdenen imunuri sistemis

aqtivobaze, romelic Tavis mxriv organizmis sxvadasxva

faqtoris (infeqciuri, dieturi da a. S.) mimarT tolerantobas

gansazRvravs. antifosfolipiduri sindromiT garTulebuli

preeklamfsiis dros organizmis imunologiuri rezistentobis

donis Sefasebis mizniT Cven SeviswavleT periferiuli sisxlis

limfoiduri ujredebis funqciuri da raodenobrivi

cvlilebebi.


preeklamfsiis dros limfoiduri ujredebis subpopulaciis

Seswavlisas dafiqsirda am ujredebis funqciuri aqtivobisa da

fenotipis gadanawilebis Taviseburi cvlilebebi: Ddadgenda T-

limfocitebis saerTo raodenobisa (50,4%-mde) da misi aqtiuri

fraqciis (26,5%-mde) Semcirebis faqti. Semcirda T-

limfocitebis helperebis raodenoba (26%-mde) da

imunoregulaciis indeqsi (1,93-mde) (cxrili 8).

Tu fiziologiuri orsulobis III trimestris bolos B

limfovitebis Semcveloba praqtikulad ar gansxvavdeba

araorsuli qalebisaTvis damaxasiaTebeli analogiuri

maCveneblebisagan (24,1% da 24,5%), antifosfolipiduri

sindromiT garTulebuli preeklamfsiis dros es maCvenebeli

statistikurad sarwmunod mcirdeba 20,7%-mde (p<0,005).

86


preeklamfsiis dros neitrofilebis fagocituri aqtivobis

maCvenebeli (φh=67,3%, φb=3,8% φ1 =58,1%) mcirdeboda

fiziologiuri orsulobisaTvis damaxasiaTebel analogiur

maCveneblebTan SedarebiT (φh=72,1%, φb=5,5%, φ1=66,3%).

kvlevis Sedegad miRebuli monacemebis analizis

safuZvelze SegviZlia davaskvnaT, rom fiziologiuri

orsulobis III trimestris bolos garkveuli xarisxis

imunodepresiaa damaxasiaTebeli, romelic vlindeba T -

helperebis ujredebis Semcvelobis SemcirebiT (34m4%-mde), T –

supresorebis raodenobis momatebiT (19,3%-mde) da

imunoregulaciis indeqsis mkveTri daqveiTebiT (1,78-mde)

janmrTeli araorsuli qalebisTvis damaxasiaTebel

maCveneblebTan SedarebiT. Agamovlenilia agreTve neitr

ofilebis fagocituri aqtivobis (φh=68,4%, φb=4,6%. φ1=57,6=mde)

Semcireba, interferonebis (IFNα da IFNγ) donis mkveTri

daqveiTeba.

orsulobis paTologiuri mimdenareobisas sisxlis

imunologiuri maxasiaTeblebis cvlilebebi kidev ufro

Zlierdeba, rac imunodeficitis gaRrmavebaze miuTiTebs.

aRsaniSnavia, rom imunodeficitis xarisxi korelirebs

orsulobis vadasTan.

Catarebuli kvlevis Sedegebis analizis safuZvelze

SeiZleba davaskvnaT: antifosfolipiduri sindromiT

garTulebuli orsulobis dros sisxlis limfoiduri

ujredebis subpopulaciis Semadgenlobis Seswavlisas

dafiqsirebulia am ujredebis funqciuri aqtivobisa da

fenotipis gadanawilebis Taviseburi cvlileba: dadginda

87

sisxlSi T - limfocitebis saerTo raodenobisa da maTi aqtiuri

fraqciis (Ta), B-limfocitebis raodenobis mkveTri Semcireba;

Ggamovlinda T- limfocitebis supresoruli populaciis

raodenobrivi zrda.

maSasadame, antifosfolipiduri sindromiT garTulebuli

orsulobis dros mcirdeba organizmis imunologiuri

rezistentobis done.

kvlevis Sedegad gamovlinda, rom gamokvleuli 60

orsulidan umetesobas aRmoaCnda СMV da HSV mimarT

antisxeulebis Semcveloba (gestaciis 21-27 kvira: anti-СMV IgG _

20 orsuls, anti-HSV IgG _ 8 orsuls; gestaciis 27-36 kvira anti-

СMV IgG _ 25 orsuls, anti-HSV IgG _ 14 orsuls), rac gestaciis

am vadaze imunodepresiis gaRrmavebaze miuTiTebs.

Cveni kvlevis Sedegebis analizis safuZvelze SegviZlia

davaskvnaT, rom arsebobs mizez-Sedegobrivi damokidebuleba

orsulTa organizmSi antifosfolipiduri antisxeulebis

gamoCenas, Tavisufalradikaluri Jangvis procesebis

intensifikaciasa da preeklamfsiis ganviTarebas Soris.

gestaciis adreul etapebze sxvadasxva faqtoris (genetikuri,

infeqciuri, stresuli, ekologiuri da a. S.) zemoqmedebiT

trofoblastebis invaziisa da diferenciaciis darRveva

placentaSi iSemiis da JangviTi stresis ganviTarebis mizezs

warmoadgens. Mmembranuli fosfolipidebis peroqsidaciuli

dazianebis sapasuxod warmoqmnili auto-antifosfolipiduri

antisxeulebi xels uwyobs oqsidaciuri stresis

intensifikacias da placentis disfunqciis gaRrmavebas, energo-

da steroidogenezis darRvevas. oqsidaciuri stresis da

hipoqsiis pirobebSi izrdeba azotis Jangis peroqsinitritad

88

(romelic iNOS eqspresiis daTrgunvas ganapirobebs)

transformaciis da hemSemcveli cilebis nitrozilirebis

intensivoba, rac Tavisufali NO-s Semcvelobis Semcirebas

uwyobs xels. Tavisufali NO-s da vazoaqtiuri hormonebis

(progesteronis da estradiolis) ukmarisoba xels uwyobs

orsulebis organizmSi endoTeluri disfunqciis ganviTarebas,

rac Tavis mxriv ganapirobebs hipertenziisa da bolos _

preeklamfsiis Camoyalibebas.

89

daskvnebi

1. arsebobs pozitiuri korelaciuri kavSiri orsulebis

sisxlsSi antifosfolipiduri antisxeulebis gamoCenas,

Tavisufalradikaluri Jangvis procesebis intensifikacias da

preeklamfsiis ganviTarebas Soris.

2. orsulebSi antifosfolipiduri sindromiT

garTulebuli preeklamfsiis dros dedis organizmSi imunuri

balansis darRvevas, ujreduli imunitetis aqtivacias,

hormonuli statusis cvlilebebs (progesteronis da

estradiolis Semcvelobis daqveiTebas) mniSvnelovani roli

eniWeba.

3. antifosfolipiduri sindromiT garTulebuli

preeklamfsiis dros organizmSi viTardeba oqsidaciuri

stresi, rac mJRavndeba orsuli qalebis sisxlSi Jangbadis (O2-

) da lipidebis (LOO.) reaqciuli naerTebis gaCeniT.


preeklamfsiis dros placentaSi Jangbadis reaqciuli

naerTebis generatorebis (daJanguli citoqrom P-450,

semiubiqinonebi, Mn2+-ionebi) dagroveba xels uwyobs membranuli

struqturebis rRvevas (LOO., Mn2+-ionebi), agreTve fermentebisa

da fermentuli kompleqsebis (adrenodoqsini-citoqrom P-450,

NADH-ubiqinon-oqsidoreduqtaza) inaqtivacias da

steroidogenezis darRvevas.

5. Uantifosfolipiduri sindromiT garTulebuli

preeklamfsiis dros placentaSi Tavisufali azotis Jangis

Semcvelobis Semcireba NO-s peroqsinitritad,Doqsidaciuri

transformaciis da mitoqondriebis hemSemcveli cilebis

90

nitrozilirebis Sedegs warmoadgens. placentis

mitoqondriuli cilebis nitrozilireba ganapirobebs

eleqtronuli transportis Seferxebas, energogenezisa da

steroidogenezis darRvevas.

6. Uantifosfolipiduri sindromiT garTulebuli

preeklamfsiis dros orsuli qalebis sisxlSi oqsidaciuri

stresiT da NO-inducirebuli vazoaqtiuri hormonebis

Semcvelobis Semcireba sisxlZarRvebis vazoreaqtiulobis

daqveiTebis da hipertenziis ganviTarebis mizezs warmoadgens.


orulobis dros sisxlis limfoiduri ujredebis

subpopulaciis Semadgenlobis Seswavlisas dafiqsirebulia am

ujredebis funqciuri aqtivobisa da fenotipis gadanawilebis

Taviseburi cvlileba: sisxlSi T- limfocitebis saerTo

raodenobisa da maTi aqtiuri fraqciis (Ta), B-limfocitebis

raodenobis mkveTri Semcireba; T- limfocitebis supresoruli

populaciis raodenobrivi zrda. aRniSnuli cvlilebebi

organizmis imunologiuri rezistentobis donis daqveiTebaze

miuTiTebs.


orsulobis dros yvela orsul qals aRmoaCnda СMV da HSV

mimarT antisxeulebis Semcveloba, rac umetesad imatebs

gestaciis vadis momatebasTan erTad; aqedan ramdenime orsuls

daudginda antisxeulebis Semcveloba rogorc СMV, aseve HSV

mimarT, rac gestaciis am vadaze imunodepresiis gaRrmavebaze

miuTiTebs.

91

praqtikuli rekomendaciebi

1. antifosfolipiduri sindromis gamovlenis SemTxvevaSi

garTulebebis Tavidan asacileblad aucilebelia

pacientis monitoringi 21-dan 36 kv. orsulobis vadaze;

doplerografiuli, ultrabgeriTi gamokvleva, imunuri da

homeostazis sistemis kontroli.

2. antifosfolipiduri sindromis gamovlenis SemTxvevaSi 21-

dan 36 kv. orsulisaTvis iTvleba kritikul periodad.

amitom saWiroa medikamenturi koreqcia, rac gulisxmobs:

antikoagulaciur mkurnalobas imunoproteqtorebis

CarTviT.

92

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