OXIDATIVE DAMAGE AND PREMATURE RUPTURE OF THE MEMBRANES

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Increasing evidence suggests that preterm premature rupture of the chorioamnion membranes (PPROM) is attributable to oxidative damage resulting from reactive oxygen species (ROS). In-vitro data from our laboratory demonstrate that, in physiologic concentrations, the ROS, hypochlorous acid and superoxide, do damage amnion epithelium and collagen I, the strongest component of chorioamnion. Pretreatment of chorioamnion with vitamins C and E blocks the destructive processes when membranes then are exposed to ROS. Vitamin antioxidant treatment after OS-exposure reduces the damage. We believe that increased intake of vitamins C and E through pregnancy will protect the chorioamnion and decrease PPROM. As a first step, we must show that obstetric patients who experience PPROM demonstrate increased evidence of systemic or regional oxidative damage. We then must prove that increased vitamins C and E when taken by pregnant women reach the chorioamnion and increase its antioxidant capacity. This project has two goals. 1) Our in-vitro studies (1 A-D) will map the sequelae of ROS- induced damage of chorioamnion membranes with special attention to the role of vitamins C and E to influence fibroblast and amnion epithelial cell damage, alterations in expression and release of the collagenolytic enzymes, metalloproteinases (MMPS) and their tissue inhibitors (TIMPS), collagen breakdown, membrane tensile strength and collagen repair. 2) Our clinical trials will test (specific aim 2A) whether patients with documented PPROM on admission exhibit nutritional alterations and increased biomarker evidence of systemic (increased DNA adducts, decreased total antioxidant capacity) or local oxidative damage (decreased total anti-oxidant capacity) when compared with patients of comparable gestational age admitted for preterm labor (PTL) alone (fetal fibronectin+), or with control patients. Patients with documented PPROM from specific aim 21 will be randomized to daily standard prenatal vitamins alone or daily prenatal vitamins alone or daily prenatal vitamins plays enhanced vitamins C and E. Outcome data during vitamin treatment will include serial measures of systemic and local oxidative stress, collagenolytic activity in cervical-vaginal fluid, and interval between PPROM to delivery. At delivery, measures of maternal and newborn blood (cord blood) oxidative damage and antioxidant status, and vitamin C and E levels, as well as chorioamnion tensile strength and membrane vitamin C concentrations and neonatal outcome will be obtained. These in-vitro studies and clinical trials will provide important new information on the value of enhanced vitamin therapy to protect the chorioamnion. It also would lay the foundation for a prospective study of antioxidant therapy to prevent PPROM.