The objectives of this Research Plan are to assess the efficacy of antibiotic and anti-inflammatory therapy on preterm labor and relevant sequelae of prematurity (i.e., fetal lung injury) in mobile, chronically catheterized pregnant rhesus monkeys infected intraamniotically with Ureaplasma parvum (formerly U. urealyticum serovar 1). It is our hypothesis that prenatal treatment of intrauterine ureaplasmal infection with an intravenous macrolide antibiotic combined with an anti-inflammatory agent and an immunomodulator will inhibit preterm labor, delay premature delivery, and ameliorate or prevent fetal/neonatal lung disease Physiological studies together with cellular and molecular studies of intrauterine and fetal tissues will address the following questions: (1) Does therapy with azithromycin combined with a prostaglandin synthesis inhibitor (indomethacin) and with dexamethasone inhibit intraamniotic microbial growth and downregulate the cytokine/prostaglandin cascade? (2) Do these interventions prevent preterm labor and fetal lung disease without adverse fetal side-effects? The effect of no treatment, antibiotic therapy, and combined antibiotic/anti-inflammatory therapy on preterm labor and fetal sequelae will be compared. A number of endpoints will be ascertained to establish links among ureaplasma infections, preterm labor, fetal lung injury and the response to therapy including potential fetal side-effects (e.g., intraventricular hemorrhage, enterocolitis). Continuous recordings of uterine contractility will be correlated with amniotic fluid levels of prostaglandins, cytokines, leukocytes, MMPs and maternal, fetal and amniotic fluid levels of azithromycin. Quantitative cultures and PCR for ureaplasmas will be performed on amniotic fluid, blood and fetal tissues. Tissue cytokine mRNA will be quantitated by real-time PCR. Fetal lung damage will be assessed by histopathologic and immunohistochemical methods and by lung morphometry. The gastrointestinal tract, meninges and brain will be examined for inflammation. Death of oligodendrocyte progenitors and other cell types in cerebral white matter will be evaluated by immunohistochemical methods and assays for apoptosis. The work proposed is unique in its use of combined interventional strategies in a well established nonhuman primate model of intrauterine infection. The results should illuminate the causal role of ureaplasma in prematurity and lead to advances in clinical management.
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