Pre-eclampsia and the in¯ammatory response M.M. Faas a,* , G.A. Schuiling b a Reproductive Immunology, Medical Biology Branch, Department of Pathology and Laboratory Medicine, University of Groningen, P.O. Box 30.001, 9700 Groningen, The Netherlands b Department of Obstetrics and Gynaecology, University of Groningen, Groningen, The Netherlands Keywords: Pre-eclampsia; In¯ammatory response; Leukocytes; Blastocyst; Implantation; Pregnancy 1. Introduction Pre-eclampsia, a human disease of pregnancy, is the leading cause of maternal morbidity in the western world. Despite the ubiquity of the disease and the plethora of studies concerning its aetiology and pathogenesis no com- prehensive theory concerning its aetiology and pathogenesis have been put forward until now and so far there are no adequate therapies other than bed rest and, if necessary, early delivery. We recently developed an animal model for pre- eclampsia [1,2], whereby activation of the in¯ammatory response by low dose endotoxin resulted in pregnant rats, and not in non-pregnant rats, in a pre-eclampsia-like syn- drome. Analysis of the in¯ammatory reaction induced by low dose endotoxin in pregnant Ð and non-pregnant rats revealed that this reaction was much more persistent and intense in pregnant rats as compared with non-pregnant rats; this is in line with the vast literature showing that pregnant individuals are much more sensitive to endotoxin than non- pregnant individuals [3±5]. Based on the animal model, we have thus put forward the hypothesis that also human pre- eclampsia results from activation of the in¯ammatory sys- tem [6,7]. Here, we raise and try to answer, from a biological point of view, various questions such as ``why is pregnancy a pro-in¯ammatory condition?'', ``what triggers the in¯am- matory response leading to human pre-eclampsia?'' and ``why is pre-eclampsia so relatively common in humans?''. 2. Pre-eclampsia In our society, pre-eclampsia is the most common and serious antenatal complication of pregnancy, characterised by hypertension, proteinuria and sometimes abnormal ¯uid retention. It affects about 2±3% of all pregnancies [8]. The disease may also be associated with abnormalities of the liver and the central nervous system [9], as well as with disseminated intravascular coagulation [10]. Because the placenta of patients with pre-eclampsia is often under- developed, there generally is a poor placental circulation [11] and accordingly a poor exchange of nutrients and gasses. As a result, the foetus may suffer from severe intra-uterine growth retardation [12]. Pre-eclampsia appears to be a typical human disease, although it has been observed in two other primates, i.e. the patas monkey [13] and the lowland gorrila [14]. 3. Pathophysiology of pre-eclampsia Unfortunately, the pathophysiology of pre-eclampsia is relatively unknown. The current, generally accepted concept regarding the pathophysiology of pre-eclampsia is that it is a disease due to endothelial cell dysfunction [15,16]. This endothelial cell dysfunction is apparent from both morpho- logical parameters, endotheliosis in the glomeruli of the kidney and ultrastructural changes in the placentabed [17,18], as well as from biochemical parameters, such as aberrations in endothelin-1 and elastase [19] and increased levels of factor VIII [20]. This, however, raises the question of how the endothelial cell dysfunction is brought about. Some authors claim that sera of pre-eclamptic patients contain factors cytotoxic to endothelial cells [15,16], while others suggest that pre-eclampsia is a maternal response to a pathogenic factor of trophoblastic origin [21,22]. More recently, we and others have suggested that pre-eclampsia is the result of an activated maternal in¯ammatory response, including activa- tion of in¯ammatory cells, such as monocytes and granu- locytes, as well as activation of endothelial cells, which are indeed part of the in¯ammatory system [2,7,22]. 4. Activation of the maternal inflammatory response in pregnant rats results in a pre-eclampsia-like syndrome We recently demonstrated that activation of the in¯am- matory response by infusion of an ultra low dose of European Journal of Obstetrics & Gynecology and Reproductive Biology 95 (2001) 213±217 * Corresponding author. Tel.: 31-50-3613045; fax: 31-50-3611694. E-mail address: m.m.faas@med.rug.nl (M.M. Faas). 0301-2115/01/$ ± see front matter # 2001 Elsevier Science Ireland Ltd. All rights reserved. PII:S0301-2115(00)00493-0