This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Prematurity, and its consequences, remain the most important problem in obstetrics. The 12% of neonates born prematurely account for 80% of neonatal deaths not attributable to congenital malformations. Intrauterine infections are an important, and potentially preventable, cause of preterm delivery. The long-term objectives of this research are: a) to elucidate the pathophysiologic mechanisms of infection-induced preterm labor; b) to establish the cellular and molecular links among intrauterine infection and preterm labor; and c) to test the efficacy of rational interventional strategies for preterm labor in the setting of infection. It is our belief that if successful, these studies will facilitate the rapid development of appropriate human interventional trials. We have developed the first experimental model in a nonhuman primate using chronically catheterized pregnant rhesus monkeys (both placentation and the hormonal control of parturition are similar to humans) in which intrauterine infection is established by the intraamniotic inoculation of known concentrations of a specific microorganism (Group B Streptococcus). Following experimental intraamniotic infection, there is sequential production of the proinflammatory cytokines, prostaglandins, and matrix metalloproteinases (MMPs). This is then followed in all cases by uterine contraction, labor and delivery, usually within 72 hours. Recently, we demonstrated that infection-induced preterm labor can be inhibited, and gestation prolonged, by systemic and/or intraamniotic treatment with non-specific immunomodulators (interleukin-10 or dexamethasone) or prostaglandin syntase inhibitors (indomethacin) and appropriate antibiotics.
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