Consequences of redox imbalance in preterm parturition

子宫内（如绒毛膜羊膜炎）和各种母体全身性感染都被认为是早产的原因，这是由保护性炎症反应（基于细胞因子升高的发现）引起的，这种炎症反应对怀孕不适应。在所有炎症过程中都形成了大量的自由基和活性氧（FR/ROS）。FR是具有半填充轨道的高活性化学物质。引发单电子转移反应的能力解释了它们的氧化作用以及杀灭微生物的效率。细胞FR/ROS浓度由抗氧化防御机制精心调节，以防止对内源性细胞成分的非特异性损伤。有利于FRIROS的氧化/抗氧化（氧化还原）平衡的改变会留下它们与各种形态或信号靶标相互作用的印记。最近，有人提出，氧化还原平衡是一个重要因素。炎症级联的重要调节剂，包括细胞因子水平。我们的工作假设是，在母体（全身和/或宫内）感染和炎症期间，母体和胎儿腔室中都有大量自由基。然而，FR/ROS形成的后果（以及由此产生的临床影响）是多种多样的，取决于FR/ROS形成的数量以及胎儿-母体的还原能力。氧化还原平衡的净转移是导致不良胎儿/新生儿结局和早产事件的重要调节因子。为了验证这一工作假设的各个方面，在Specific Aim 1下进行的实验旨在将炎症诱导的不同水平的氧化还原移位与FR/ROS形成、胎儿结局和早产的小鼠模型联系起来。如果如假设的那样，通过改变硫醇水平来靶向自由基/活性氧（FR/ROS）的形成将通过减少细胞因子的表达来减少FR/ROS的直接损伤和间接影响。因此，可以限制导致不良胎儿结局和/或早产的病理生理链事件的治疗干预措施在Specific Aim 2的实验中进行了测试。最后，我们在Specific Aim 3中记录了妊娠合并绒毛膜羊膜炎的人类胎儿中硫醇水平的改变是否发生。这一建议可以开创一个新的治疗干预领域，旨在预防早产及其对产后生活的影响。

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.