Of the 4.1 millions births annually in the USA, about 0.9 per cent (38,000) occur prior to 28 weeks of gestation. These extremely preterm neonates consume a disproportionately large share, over 50 per cent, of the total dollars expended for newborn intensive care unit (NBICU) services. Two of the factors that are known to significantly increase this cost are: 1) in utero fetal infections, and 2) repeated acquisition of nosocomial infections during the NBICU course. The applicant maintains that these two problems have considerable mechanistic interrelationship. Specifically, he postulates that they originate, at least in part, from limitations in the capacity of extremely preterm neonates to rapidly accelerate specific aspects of granulocytopoiesis. The long term aims of this laboratory are to better define the hematopoietic regulatory mechanisms operative in the human fetus and neonate and, based on those principles, to devise strategies for improving the outcome of prematurely delivered infants. To forward these goals the investigator designed the studies that constitute the present proposal. The proposed studies have been organized into five aims that deal with uncovering unique hematopoietic mechanisms of the fetus, and two aims that involve clinical trials. The five sections that relate to basic fetal hematopoietic mechanisms include aims to: 1) Describe the kinetics of production of Granulocyte Colony-Stimulating Factor (G-CSF) from liver and bone marrow macrophages and blood monocytes obtained from human fetuses between 14 and 24 weeks of gestation; 2) To quantify the neutrophil storage pool, the neutrophil proliferative pool, and the neutrophil progenitor cell pool in the liver and marrow of human fetuses; 3) To quantify the responsiveness to recombinant G-CSF of neutrophil progenitors obtained from the liver, marrow, and blood of human fetuses at various gestational ages; 4) To determine the mechanism responsible for the unique """"""""growth factor independence"""""""" observed in a sub-set of hematopoietic progenitors of fetal origin, and 5) To determine the mechanism responsible for the erythropoietin-induced down-modulation of neutrophil production from progenitors of fetal origin. Their two clinical studies involve: 1) quantification of G-CSF concentrations in the serum of pregnant women who have clinical chorioamnionitis, and in the umbilical cord serum of their infants, and 2) quantification of the effect of administering recombinant G-CSF to women about to deliver at 23-24 weeks of gestation, on fetal neutrophil production, fetal neutrophil pool sizes, and fetal neutrophil bactericidal capacity.
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