Consequences of redox imbalance in preterm parturition

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Both intrauterine (e.g. chorioamnionitis) and various matemal systemic infections are proposed causes of preterm labor triggered by a protective inflammatory response (based on the finding of elevated cytokines) that becomes maladaptive for the pregnancy. A large amount of free radicals and reactive oxygen species (FR/ROS) are formed during all inflammatory processes. FR are highly reactive chemical species with half-filled orbitals. The potency to initiate one electron transfer reactions explains their oxidizing action as well as microorganism killing efficiency. Cellular FR/ROS concentration is carefully regulated by antioxidant defense mechanisms to prevent nonspecific damage against endogenous cell constituents. An alteration in the oxidant/antioxidant (redox) balance in favor of FRIROS leaves an imprint of their interaction with various morphological or signaling targets. Recently, it was suggested that the redox balance is an.important modulator of the inflammatory cascade, including cytokine levels. Our working hypothesis is that during maternal (systemic and/or intrauterine) infection and inflammation there is an outpouring of free radicals in both the maternal and fetal compartments. However, the consequences (and hence the clinical impact) of FR/ROS formation are varied and depend on the amount of FR/ROS formed as well as upon the fetal-maternal reducing abilities. A net shift in redox balance is an important modulator of events leading to adverse fetal/neonatal outcome and preterm birth. To test aspects of this working hypothesis the experiments performed under Specific Aim 1 are designed to correlate different levels of redox shift induced by inflammation with FR/ROS formation, fetal outcome and preterm birth in a mouse model. If linked as postulated, targeting free radical /reactive oxygen species (FR/ROS) formation by altering thiol levels will reduce both the direct damage and the indirect effects of FR/ROS by reducing cytokjne expression. Thus, therapeutic interventions that would limit the pathophysiological chain of events leading to adverse fetal outcome and /or preterm premature rupture of membranes (PPROM) and preterm birth are tested under experiments performed in Specific Aim 2. Finally, we document in Specific Aim 3 whether alterations in thiol levels occur in human fetuses in pregnancies complicated by chorioamnionitis. This proposal could initiate a new area of therapeutic intervention targeted to prevent prematurity and its impact on postnatal life.