Consequences of redox imbalance in preterm parturition

子宫内（如绒毛膜炎）和各种母体系统性感染被认为是由保护性炎症反应（基于细胞因子升高的发现）触发的早产的原因，该炎症反应变得对妊娠不适应。在所有炎症过程中都会形成大量的自由基和活性氧（FR/ROS）。FR是具有半满轨道的高活性化学物种。引发一个电子转移反应的效力解释了它们的氧化作用以及微生物杀灭效率。细胞FR/ROS浓度受到抗氧化防御机制的精心调节，以防止对内源性细胞成分的非特异性损伤。有利于FRIROS的氧化剂/抗氧化剂（氧化还原）平衡的改变留下了它们与各种形态学或信号传导靶标相互作用的印记。最近，有人提出氧化还原平衡是炎症级联反应的重要调节剂，包括细胞因子水平。我们的工作假设是，在母体（全身和/或子宫内）感染和炎症过程中，母体和胎儿室中都有自由基的溢出。然而，FR/ROS形成的后果（以及因此的临床影响）是不同的，并且取决于形成的FR/ROS的量以及胎儿-母体还原能力。氧化还原平衡的净变化是导致不良胎儿/新生儿结局和早产的事件的重要调节剂。为了测试这一工作假设的各个方面，在特定目标1下进行的实验被设计为在小鼠模型中将由炎症诱导的不同水平的氧化还原转变与FR/ROS形成、胎儿结局和早产相关联。如果如假设的那样连接，则通过改变硫醇水平来靶向自由基/活性氧物质（FR/ROS）形成将通过减少硫醇表达来减少FR/ROS的直接损伤和间接作用。因此，在特定目标2中进行的实验中，对限制导致不良胎儿结局和/或早产胎膜早破（PPROM）和早产的病理生理学事件链的治疗干预进行了检测。最后，我们在特定目标3中记录了在妊娠合并绒毛膜炎的人胎儿中是否发生巯基水平的改变。这一建议可以启动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.