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
(gestaciis 27-36 kvira) 2
7
2 -
antifosfolipiduri sindromiT
garTulebuli Oorsuloba
(gestaciis 21-27 kvira) 3
20 8 2
antifosfolipiduri sindromiT
garTulebuliOorsuloba
(gestaciis 27-36 kvira) 4
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.
antifosfolipiduri sindromiT garTulebuli
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
fiziologiuri orsuloba
(gestaciis 27-36 kvira) 2
1610±77
P12>0,1
410±48
P12>0,1
130±36
P12>0,1
antifosfolipiduri sindromiT
garTulebuli orsuloba
(gestaciis 21-27 kvira) P 3
1100±85
P13<0,01
239±59
P13>0,1
224±42
P13>0,1
antifosfolipiduri sindromiT
garTulebuli orsuloba
(gestaciis 27-36 kvira) 4
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
(gestaciis 27-36 kvira) 2
32,0±2,5
P12>0,1
Oantifosfolipiduri sindromiT
garTulebuliOorsuloba
(gestaciis 21-27 kvira) 3
25,6±2,0
P13<0,01
Oantifosfolipiduri sindromiT
garTulebuliOorsuloba
(gestaciis 27-36 kvira) 4
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
(gestaciis 27-36 kvira) 2
14,0±0,8
P12>0,1 2,5±0,9
antifosfolipiduri sindromiT
garTulebuli Oorsuloba
(gestaciis 21-27 kvira) 3
10,0±0,8
P13<0,01
15,0±1,6
P23<0,01
antifosfolipiduri sindromiT
garTulebuliOorsuloba
(gestaciis 27-36 kvira) 4
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.
fiziologiuri orsuloba
(gestaciis 21-27 kvira) 125,9±0,1 - 0,8±0,1
fiziologiuri orsuloba
(gestaciis 27-36 kvira) 224,9±0,1 - 1,0±0,1
antifosfolipiduri sindromiT
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
antifosfolipiduri sindromiT
garTulebuli orsuloba
(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
antifosfolipiduri sindromiT garTulebuli
preeklamfsiis dros, organizmis imunologiuri rezistentobis
donis Sefasebis mizniT, Cven SeviswavleT periferiuli
sisxlis limfoiduri ujredebis funqciuri da raodenobrivi
cvlilebebi.
antifosfolipiduri sindromiT garTulebuli
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).
antifosfolipiduri sindromiT garTulebuli
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.
antifosfolipiduri sindromiT garTulebuli
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).
antifosfolipiduri sindromiT garTulebuli
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.
antifosfolipiduri sindromiT garTulebuli
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
antifosfolipiduri sindromiT garTulebuli
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.
antifosfolipiduri sindromiT garTulebuli
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
antifosfolipiduri sindromiT garTulebuli
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.
4. antifosfolipiduri sindromiT garTulebuli
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.
7. antifosfolipiduri sindromiT garTulebuli
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.
8. antifosfolipiduri sindromiT garTulebuli
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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