Lipid peroxides and oxygen radicals are highly reactive and very damaging compounds. In normal pregnancy lipid peroxides increase, but antioxidants also increase to offset their toxic actions. However, this is not the case in preeclampsia. In women with preeclampsia, circulating levels of lipid peroxides are increased, but net antioxidant activity is decreased as compared to normally pregnant women. A source of circulating levels of lipid peroxides in pregnancy is the placenta because the placenta produces and secretes lipid peroxides, and lipid peroxide levels decrease after delivery of the placenta. Other sources are activated neutrophils, radical-initiated propagation, and self-propagation. Although some lipid peroxides are unstable, those present in oxidized low-density lipoproteins have a half-life of 3 h in the circulation and so function as circulating compounds. In preeclampsia, placental production of lipid peroxides is significantly increased, and this is correlated with significantly increased production of thromboxane. Placental production rates of lipid peroxides and thromboxane may be coupled by the PGH synthase enzyme because when PGH synthase is activated, it generates, not only thromboxane, but also oxygen radicals that could lead to conversion of placental lipids into lipid peroxides. Evidence for this is that low-dose aspirin, by inhibiting PGH synthase, inhibits production of both thromboxane and lipid peroxides, whereas stimulation of PGH synthase with exogenous peroxide results in increased production of both. In addition, peroxide stimulation of PGH synthase increases placental thromboxane production to cause placental vasoconstriction. The vasoconstriction is blocked by low-dose aspirin or thromboxane receptor blockade. Lipid peroxides also enhance vascular responsiveness of the systemic circulation independent of thromboxane. The cause of the increased placental production of lipid peroxides and thromboxane in preeclampsia is not known, but it may be related to a deficiency in the placental levels of glutathione peroxidase activity. Glutathione peroxidase is one of the primary antioxidants present in tissues that limit the amount of lipid peroxides. In preeclampsia, the placental tissue levels of glutathione peroxidase activity are significantly lower than normal, which could lead to increased tissue levels of peroxides, leading to increased stimulation of PGH synthase that could result in increased production of thromboxane and lipid peroxides. Because of the physiologic and biochemical actions of lipid peroxides, including their ability to stimulate thromboxane and inhibit prostacyclin synthesis, many of the clinical and pathophysiological features of preeclampsia might be explained by the abnormal increase of lipid peroxides in women with preeclampsia.
