Consequences of redox imbalance in preterm parturition

早产中氧化还原失衡的后果

• 批准号: 6319543
• 负责人: IRINA A BUHIMSCHI
• 金额: $ 0.93万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6319543
• 关键词: birth; cytokine; disease /disorder etiology; embryo /fetus death; embryo /fetus membrane; enzyme linked immunosorbent assay; female; free radical oxygen; free radicals; gene expression; high performance liquid chromatography; histology; human subject; inflammation; laboratory mouse; lipopolysaccharides; oxidation reduction reaction; oxidative stress; patient oriented research; pregnancy infection; premature labor; radioimmunoassay; thiols; western blottings; women's health

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.

宫内感染(例如绒毛膜羊膜炎)和各种母体系统感染都被认为是早产的原因，早产是由保护性炎症反应(基于细胞因子升高的发现)触发的，这种反应变得不适应妊娠。在所有的炎症过程中都会产生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能力解释了它们的氧化作用和微生物杀灭效率。细胞的FR/ROS浓度受到抗氧化防御机制的仔细调节，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，有人认为氧化还原平衡是炎症级联反应的重要调节器，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，母体和胎儿体内的自由基都会涌出。然而，FR/ROS形成的后果(以及临床影响)是不同的，取决于FR/ROS形成的数量以及胎儿-母体的减少能力。氧化还原平衡的净变化是导致不良胎儿/新生儿结局和早产事件的重要调节因素。为了检验这一工作假说的各个方面，在特定目标1下进行的实验旨在将炎症引起的不同程度的氧化还原转移与FR/ROS的形成、胎儿结局和早产联系起来。如果如假设的那样，通过改变硫醇水平来靶向自由基/活性氧物种(FR/ROS)的形成，将通过减少细胞因子的表达来减少FR/ROS的直接损害和间接影响。因此，将限制导致不良胎儿结局和/或胎膜早破(PPROM)和早产的病理生理事件链的治疗干预措施是在特定目标2下进行的实验测试。最后，我们在特定目标3中记录在妊娠合并绒毛膜羊膜炎的胎儿中是否发生硫醇水平的变化。这项提议可能会开创一个新的治疗干预领域，旨在预防早产及其对出生后生活的影响。