Nonhematopoietic Developmental Functions of EPO

University Of Washington, Seattle WA

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Abstract

Erythropoietin receptors are present on intestinal cells of the human fetus and neonate. Cells in contact with the developing intestinal lumen are exposed to erythropoietin (Epo) in swallowed amniotic fluid prenatally, and in human milk postnatally. When infants are born prematurely this exposure to Epo is interrupted. Pilot studies suggest that Epo may enhance the growth and development of neonatal intestine, and may also protect the neonatal intestine from injury. We hypothesize that Epo has an important role in the growth and development of the gastrointestinal tract, and that Epo will improve neonatal intestinal survival following injury. A combination of animal models will be used to test this hypothesis. The role of Epo in early intestinal development will be determined by studying intestinal growth in the presence and absence of Epo using Epo and Epo receptor knockout mouse models. These null mutation are, however, lethal at day 13.5 of gestation, so neonatal rats will be used for experiments designed to determine the effects of Epo in the post-natal intestine. Two experimental paradigms will be used. The first will be dam-raised neonatal rats, which receive Epo enterally via gavage, or parenterally, by SQ injection. These experiments will allow us to quantify the effects of exogenous Epo during normal development in a nursing pup, and to determine whether the route of administration is important. To determine the effect of mothers milk in conjunction with Epo, we will artificially rear rat pups using gastrostomy feedings of rat milk substitute to which specific total daily doses of Epo are added. As mothers' milk alone may be an important factor in bowel development, both experimental paradigms are important in evaluating the effects of Epo in the GI tract. To determine the effects of Epo on bowel injury, rat pups will be exposed to cold stress plus hypoxia in the presence or absence of Epo. It will be determined whether Epo protects the bowel from such injury, the timing of such protection, whether the route of administration is important, and the dose-response curve of such response in the presence and absence of mothers' milk. We feel these experiments will provide important specific insights into the regulation of neonatal intestinal growth and injury.