Oxidative stress in preeclampsia

Abstract

In this issue of the American Journal of Obstetrics and Gynecology, Dr Moretti and associates use a noninvasive strategy to demonstrate increased oxidative stress in preeclampsia. Oxidative stress has garnered a great deal of attention (and controversy) as a component of the pathophysiology of diseases ranging from heart disease to cancer, and in obstetrics, preeclampsia. What is oxidative stress? Why is it important? What is its origin, and why is its role in diseases such as preeclampsia, controversial? Oxidative stress is the presence of active oxygen species in excess of the available antioxidant buffering capacity. These products, reactive oxygen species, can damage proteins, lipids, and DNA, altering the organism's structure and function. Not surprisingly, the organism has an efficient system to buffer these products, and also not surprisingly, it will occasionally not be able to do so. When this happens, whether because of reduced antioxidant enzymes, insufficient intake of dietary antioxidants, or with excessive production of reactive oxygen species, oxidative stress ensues. A very common pathologic source of reactive oxygen species is the response to hypoxia/reperfusion, reduced organ blood flow followed by reperfusion.1.Lum H Roebuck K.A Oxidant stress and endothelial cell dysfunction.Am J Physiol Cell Physiol. 2001; 280: C719-C741PubMed Google Scholar In this setting, ATP breaks downs to products that when metabolized generate reactive oxygen species that deplete antioxidants. With reperfusion and reoxygenation oxidative stress ensues. This phenomenon is quite relevant to pregnancy, where placental perfusion is subject to the vagaries of uterine blood flow that decreases and increases with posture, meals, exercise, and uterine contractions. There are numerous protective mechanisms in place, and although some studies show a minimal increase in oxidative stress in normal pregnancy, many, such as in the Moretti study, are not able to detect significant differences. However, in a setting such as preeclampsia, with reduced placental perfusion, it is proposed that the reduction of oxygen delivery is sufficient to generate oxidative stress.2.Roberts J.M Hubel C.A Is oxidative stress the link in the two-stage model of preeclampsia?.Lancet. 1999; 354: 788-789Abstract Full Text Full Text PDF PubMed Scopus (303) Google Scholar Lipid markers of oxidative stress were the first to be measured in preeclampsia over 30 years ago.3.Hubel CA. Oxidative stress in the pathogenesis of preeclampsia. Proceedings of the Society For Experimental Biology and Medicine 1999;222:222-35.Google Scholar Much of the controversy about oxidative stress in preeclampsia is because of the nonspecificity of these markers.4.Regan C.L Levine R Baird D.D et al.No evidence for lipid peroxidation in severe preeclampsia.Am J Obstet Gynecol. 2001; 185: 572-578Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar Lipid markers can be generated after blood is drawn, and some can be produced by enzymes as part of normal metabolism and do not indicate oxidative stress. Less controversy is associated with protein products of oxidative stress. These are also present in preeclampsia.5.Roggensack A.M Zhang Y Davidge S.T Evidence for peroxynitrite formation in the vasculature of women with preeclampsia.Hypertension. 1999; 33: 83-89Crossref PubMed Scopus (197) Google Scholar, 6.Zusterzeel P.L Rutten H Roelofs H.M Peters W.H Steegers E.A Protein carbonyls in decidua and placenta of pre-eclamptic women as markers for oxidative stress.Placenta. 2001; 22: 213-219Abstract Full Text PDF PubMed Scopus (116) Google Scholar The study of Moretti measures oxidative stress “on line” in exhaled breath, and is not subject to in vitro artifacts. However, the authors do mention sources for these materials other than oxidative stress are possible, but feel that the analysis they use makes this unlikely. Nonetheless, the definitive test for the role of oxidative stress in preeclampsia is whether antioxidants can prevent preeclampsia. This approach was tested and the concept supported in a small study,7.Chappell L.C Seed P.T Briley A.L et al.Effect of antioxidants on the occurrence of pre-eclampsia in women at increased risk: a randomised trial.Lancet. 1999; 354: 810-816Abstract Full Text Full Text PDF PubMed Scopus (686) Google Scholar and is now the subject of large randomized controlled trials. The NICHD/NHLBI-sponsored trial of antioxidants to prevent preeclampsia has begun the enrollment of 10,000 women. If this trial is successful, studies such as Dr Moretti's should be extended to test before evident disease to perhaps direct more targeted therapy.