1998 WHRG Grant Program

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Symposia

Interactions Between Free Radicals in Pathogenesis of Pre-term Birth
Irina Buhimschi, M.D.
School of Medicine, University of Maryland, Baltimore

We hypothesize that reactive oxygen species (ROS) are involved in the initiation of parturition at both term and pre-term and that the interaction between ROS and nitric oxide (NO) during pregnancy may be more important than each alone in determining whether the uterus remains quiescent and the cervix closed or whether uterine contractions and cervical dilation are initiated. The integrity of connective tissues is determined by the balance of resorption and repair of the extracellular matrix components. There is considerable evidence that, among other proteinases, the matrix metalloproteases (MMPs) have a major role in collagen remodeling. Selective activation of MMPs is implicated in cervical ripening and rupture of membranes during parturition. Moreover, cervical ripening per se is considered the result of a controlled inflammatory reaction modulated by changes in steroid hormones. In a preliminary series of experiments, we have examined MMP activity in human fetal membranes by substrate-gel electrophoresis (zymography). MMP2 (gelatinase A) and MMP9 (gelatinase B) activities were detected. We found a 1.4 fold increase in total gelatinolytic activity after exposure to ROS which was dramatically decreased by the antioxidant N-acetyl cysteine, a gluthatione precursor. MMP activation is a feature of spontaneous term labor and pre-term labor associated with occult intrauterine and inflammatory response syndrome. There is evidence that inflammatory cells produce ROS. If the hypothesis is correct and ROS are involved in MMP activation, targeting ROS formation with antioxidants or spin trapping compounds would block the expansion of the inflammatory process. However, since MMPs might be only one of the targets for ROS, we propose in vivo experiments on the endotoxin-injected murine model of pre-term labor to evaluate the effect of certain classes of antioxidants that might extend the duration of gestation and also aid the fetus and its defense mechanisms in arresting the inflammatory response syndrome that has been associated with high infant morbidity.