Modeling Preeclampsia: The True Model for the Uniquely Human Disease Preeclampsia Is the Human Female Not the Pregnant Rat
To the Editor:
Gadonski et al1 describe a series of elegant experiments in which they used a rodent (rat) model to show that chronic reduction in uterine perfusion pressure was associated with an elevation of arterial pressure and that this elevation in AP was associated with a rise in serum levels of interleukin-6. They further showed that this rise in arterial pressure occurs after chronic elevation of interleukin-6 in pregnant but not in nonpregnant rats and is associated with increase in renal vascular resistance and reduction in renal plasma flow, as well as glomerular filtration rate. They conclude that interleukin-6 may play a role in mediating the hypertension and reduction in renal hemodynamics observed in the reduction in uterine perfusion pressure in pregnant rats. All of this is fine until the authors allude to the possibility that their observations could reflect the pathophysiology of that uniquely human disease of pregnancy, that is, preeclampsia (PE).
First, it is clear that no adequate laboratory model of PE exists. Stated another way, no animal model develops a condition during pregnancy that remotely resembles PE. This is in part because of the evolutionary diversity in placentation, and although the hemochorial placentation seen in the human also occurs in rodents, there are important differences between the 2 species. Specifically, rodents do not spontaneously develop PE. Occluding uterine arteries to create a reduction in uterine perfusion pressure could hardly be compared with the high resistance that is found in the fetoplacental circulation in PE. Moreover, studies have shown that trophoblast at the level of the maternofetal interface is not ischemic in the way that might be expected after uterine artery occlusion.2 Indeed, some evidence would suggest that defective oxygen transfer rather than ischemia, per se, in the placenta is associated with pathologies such as intrauterine growth restriction,3 which also occurs in association with PE.
Second, the reports of elevated proinflammatory cytokines in PE are conflicting, with some suggesting a rise in interleukin-6 and other cytokines4 and others failing to concur.5 This should not be surprising, because it is undoubtedly naive to study individual cytokines within such a vast and complex milieu of cytokines that are associated with human pregnancy within and outside the placenta. The advent of microarray technology, which allows the study of a vast array of cytokines simultaneously, is likely to yield more meaningful results with regard to the role and interaction of cytokines during normal and abnormal pregnancy.
We applaud the efforts of Gadonski et al1 and, indeed, other workers in the field, but we wish to emphasize that any significant progress in the field of PE research can only realistically come from studies of the human model. We, therefore, find it alarming when quantum leaps are made suggesting potential treatments with inhibitors of cytokines in women with preeclampsia: a false dawn if ever there was one!