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. The overall goal of this proposal is to ultimately use the new information gained from this body of work to help lower morbidity rates from RDS in premature infants. Pre-B-Cell Colony-Enhancing Factor (PBEF) is a promising candidate for intervention in neonatal lung disease. PBEF is a relatively novel cytokine which has been shown to be expressed in many tissues and across many species. Work has demonstrated an increase in expression of the PBEF gene when amniotic epithelial-like cells and explants of fetal membranes were distended. Labor also increases its expression in the myometrium and fetal membranes and the inflammatory stimuli;LPS, TNF?, IL-1?, and IL-6 all increase PBEF gene expression. Although PBEF lacks a secretion sequence, its secretion from transfected lymphocytes, human amniotic epithelial cells, neutrophils and adipocytes has been shown. Thus, it is likely that this novel molecule acts as a pro-inflammatory cytokine in many situations. In keeping with this role in inflammation, PBEF expression has been identified in the lung where it is suggested to be a biological marker for acute lung injury. It has also been shown to be anti-apoptotic and to be involved in the cell cycle. From the body of work developing on PBEF, its importance in the maturation of the lung's cytoarchitecture and its role in infection in the neonatal lung are exciting questions. Therefore, by using a series of experiments, I plan to determine the role of PBEF in the maturation of the lung. In this project I will use amniotic fluids, in order to observe changes in PBEF secretion and relate this to the known degree of lung maturation and the presence of inflammation in cases of ventilator dependent RDS and CLD. This project will provide the opportunity to demonstrate how this protein could be altered in neonatal disease states. It will also help to asses the potential of a blocking therapy for this protein, with the aim of minimizing inflammation-driven neonatal lung damage. Collecting these samples will demonstrate any relationship between PBEF and lung disease in human infants. Amniotic fluid samples will be obtained from all pregnancies that undergo genetic amniocentesis either for genetic studies, to exclude chorioamnionitis, or to assess for fetal lung maturity. These fluid samples will be centrifuged to separate the cells from the fluid and the levels of PBEF protein will be measured in the supernatant by the commercially available EIA. Clinical information to be obtained from mothers undergoing amniocentesis will include: demographic information, gestational age at time of procedure, and presence of maternal medical disease like diabetes. Completing this series of experiments will allow us to gain important insights on the relevance of PBEF in pregnancy and in neonatal lung disease and thus to predict its therapeutic potential.
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