Consequences of redox imbalance in preterm parturition

宫内感染（例如绒毛膜羊膜炎）和各种母体全身感染均被认为是早产的原因，这些感染是由保护性炎症反应（基于细胞因子升高的发现）引发的，该反应对妊娠产生不良反应。在所有炎症过程中都会形成大量自由基和活性氧（FR/ROS）。 FR 是具有半填充轨道的高反应性化学物质。引发一种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仔细调节，以防止针对内源性细胞成分的非特异性损伤。氧化剂/抗氧化剂（氧化还原）平衡的改变有利于 FRIROS，从而留下了它们与各种形态或信号靶点相互作用的印记。最近，有人提出氧化还原平衡是炎症级联反应（包括细胞因子水平）的重要调节剂。我们的工作假设是，在母体（全身和/或宫内）感染和炎症期间，母体和胎儿室中都会大量涌出自由基。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，并且取决于 FR/ROS 形成的量以及胎儿-母体的减少能力。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因素。为了测试这一工作假设的各个方面，在特定目标 1 下进行的实验旨在将炎症诱导的不同水平的氧化还原位移与小鼠模型中的 FR/ROS 形成、胎儿结局和早产相关联。如果按照假设联系起来，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表达来减少直接损伤和 FR/ROS 的间接影响。因此，在特定目标 2 中进行的实验中测试了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措施。最后，我们在特定目标 3 中记录了妊娠并发绒毛膜羊膜炎的人类胎儿中硫醇水平是否发生变化。该提案可能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.