Pathophysiology of preeclampsia

Preeclampsia and eclampsia are important causes of maternal death worldwide. Preeclampsia/eclampsia constİtotes the syndrome of vasoconstriction with elevated artedal blooel pressure, eelema, proteinuria and convulsions. Preeclampsia reduces uteroplacental perfusion, which places the fetus at high risk of (actıte and/or chronic) hypoxemia, malnutrition, fetal growth retardation, preterm birth, and perinatal morbidity and mortalily. In contrasl, hypertemion arising Iate in pregnancy, and not accompanied by proteintıria is neHher associated with any inerease in perinatal mol'tality or morbidity nor with a decreased birthweight.
Although preeelampsia has been studied extensively, its true cause remains unknown. Hypotheses have focussed on endogenous hormones, mıtrition, and immunologic and genetic factors. There is increasing evidenee that genetic and immune mechanisms are involved in the etiology of preecIampsia. Severe preeelampsia and eclampsia have a familinl tendeney. The development of preeelampsia-eclampsia may be based on a single reeessive gene or a dominant gene with ineomplete penetrance. Penetranee may be dependent on the fetal genotype. Multifaetorial inheritanee is another possibility. Future moleeular genetic method s will provide information on the exaet mode of inheritanee. The possible involvement of the immune system in the pathogenesis of preeelampsia has attraeted inereasing attention. The feıoplaeental unİt serves as an allograft because it eontains paternal anıigenie tissue which is foreign to its matemal host. Pregnaney repl'esents an unique state of mu tual immunologic tolerance.
The decidua has been reeognized as a mainly lymphoid tissue. Certain types of immune response, may be benefical to pregnancy and prevent 'rejeetion' by natural effeetors such as Iymphokine acıivated killer eells. Cytokines such as granuloeyte-maerophage eolony stimulating faetor derived from T-eells or macrophages can sıinıulate ırophobıasl growth. Plenty of eireumstantial evidenee suggests that immune meehanisms ought to be involved in the etiology of preeelampsia. lnvolvement of immune aIterations in the early development of preeclampsia, show a significantly lower proportion of T-helper eells than those who remain normotensive, aıready early in the second trimester. ln addition, it was found that neutrophil activation occurs İn preeclampsia, loeaIİzeel in part to the plaeental bed. Immune maladaptation is an attractİve, although stili hypothetieal, explanation for the disturbecl endovascular troplıoblast invasion in preeelampsia. In normotensive pregnancy the invasion of the uteroplacental arteries by non-villoııs trophoblast results in a significant reduction in peripheral vascular resistanee in ıhe ııteroplacental vascıılar circulation allowing sııbstantial blood flow under low pressure through the intervillous spaces of the plncenta. In preeclampsia the physiologic changes in the ııteroplacental arteries are eonfined to the decidual arteries, the myomeırial segments remain anatomically ıntacı and do not dilate. Adrenergic nerve supply to these arteries remains intael. The inhibiıion of trophoblastic invasion of the myometrial segments of the spiral arteries, anel secondaı'y lesions such as aeute atherosis and thrombosis, may have the effeet of curtailiııg the increased blood sııpply required by ıhe fetoplacental uııit in the later stages of pregnaney and eause further aeute dearangements of uteroplacental perfusion.
In reeent years evidence has been adduced to support the concept that the eicosanoid system plays an imporıant part in the pathophysiology of pre-eclampsia. The imbalance between vaseıdilator prosıaglandins anel vasoeonstrictors such as thromboxane-A2 and angiotensin-ıı, especially in the uteroplacental circulation and the kidney allows an explanation for many of the clinical manifestations of preeclampsia. The absence of the normal sıimu!ation of the rerıinangiotensin-aldosterone system, despite signifieant hypovolemia, and the increased vasculm serısiıivity to angiotensin-n and norepinephrine can be explained by a single mechanism: endothelial eell injury, resulting in a prostaeyclinl thromboxaneA2 imbalance.
In addition, the increased thromboxane-A2/prostacyclin ratio may be ıhe eaLlse of the seleclive platelet destruction, sometimes aecompanied by microangiopathie haemolysis resulting in the syndrome of haemolysis, elevated liver enzymes, and low platelet count (HELLP syndrome), and ıhe reduceCı uteroplacenıal bloCJc! flow with arterial thrombosis and placental infarction. Because the platelet is the principal SOlll'ce of cireulating serotonin, the increased platelet aggregation in preeelampsia may be the eause of the higlıer levels of serotonin reporteel in blood and plaeentas of women with preeclampsia as compared to normçıtensive pregnancies. The increased level of free eirculating platelet-derived serotonin further faciliıates platelet aggregation, but mayalso ampJify the vasocol1strictor aetion of eerlain neurohumoral mediators, in partieular eateeholamines and angiotensin-I1, and may eausc direct contraetion via S2-reeeptors on vascular smooth muscle itsdf.
Although the concept of a prostacyclin/ıhromboxane-A2 imbalanee, as a major pathcıgenetic mechanism, al10ws an explanation for many of the elinical manifesmtions of pregnancy-induced hypertensive disorCıers ancl provides a framework for further investigations, the hypothesis remains unproven.
Endothelial cell injury and altered endorhelial cell funerion play an important role in the pathogenesis of preeclamp,ia. Serum from preeclamptic women injures endothelial cells in vitro. Preeclampsia is characterized by a generalizeel disturbanee in normal endothelial physiology. and not merely by an isolated elefeeı in vaseular pfostacyelin synıhesi,. it might be that the physiologic vasodilation in pregnaney is mediated by other autoeoicls instead of prostaeyclin. Recent animal and in-vitro studies support the hypothesis that endothelium-derived relaxing faetor (EDRF) is the majo!' "antihypertensive factor" in normal pregnaney rather than prostaeyelin. If this hypothesis is correct, prostaeyelin synthesi, in the uteroplaeental eireulation may be "just" a rescue meehanism in those pregnaneies where uteroplaeental perfusion is endangered beeause of inadequate eonversion of spiral arteries to uteroplaeental arterie, and a deerease in uteroplacental EDRF release. The adequaey of the uteroplaeental reseue meehanism (S1 -reeeptors, prostaeyclin EDRF, uterophıeental renin-angiotensin system) may detemline the final clinical and perinatal outeome.
Neutrophil aetivation oeeurs in preeclampsia, loealized in part to the plaeental bed. Plasma neutrophil elastase, a marker for neutrophil aetivation, is significantly higher in plasma from preeelamptie patients than in normotensive controls. The number of elastase eontaining neutrophils in the fibrin of the decidua is signifieantly greater in preeclampsia than in normal pregnancies, and correlates with plasma urate. Coneentration of ııeutrophil elastase in umbilical venous plasma is simHar in normotensive and hypertensive pregnaneies, which implies thaı neutrophil aetivation in preeclampsia is eontined to the maternal circulation
. What might be the connection between these activated neurrophils anel endothelial eell dysfunction in preeelampsia? Neutrophils have been implicated in the pathogenesis of vascular damage in the non-pregnant situation. Aeıİvaıed neutrophils release a variety of substanees, capable of mediatİng vascular damage. These inelude the contems of neutroplıil granules such as elastase and other proteases whieh can destroy the inregrity of endothelial ceHs. vasl'ular basement membrane and subendotheEal matrix. Endothelial cells eonvert leukotriene-A4 generated by neutrophils to leukotriene-C4, a molecule eapable of smooth-muscle eonslrictor aetivity. Leukotriene-C4 is known to eause a sustained formation of platelet activating faetor (PAF). In addition, toxic oxygen free radieals are released whieh results İn membrane lipid peroxidation, lysis of endothelial eells, disruption of the enclothelium and inereased vascular permeability and reaetivity. Oxygen free radkals inhibit endothelium-dependent reiaxation in vitro and in vivo by ehemieal inaetivation of EDRF and inhibition of the produetion and release of relaxing faetors due to oxiclanı injury of endothelial eeııs. Lipid peroxides aetivate cyclo-oxygenase and impair endothelial prostaeyelin synthewse. Therefore the inereaseLi lipid peroxide levels in preeelampsia favour prodııetion of platelet-clerived thromboxane-A2 above vaseular prostaeyelin produetion. Also, an increased produetion of oxygen free radieals may cause "Up" regulation of endothelin reeeptors with a subsequent inereased reaetivity to endothelin.
Oxygen free radieals and lipid hydroperoxides are increased in preeelampsia. Erythrocytc glutathione peroxidase activity and erythroeyte glutathion Tevels, major lipid hydroperoxide seavenger systems, are increased in preeelampsia.This inerease is probably compensatory. The inereased production of oxygen free radieals, or other produet, released by aetivated Iymphoid eells in the pregnant deeidua may be the link between the hypothetieal immunologic maladaptation and the generalized endothehal injury oceurring in preeelampsia.

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