Organ system immaturity significantly blunts adaptive potential in the premature newborn. Induced pulmonary maturation through maternal steroid administration has proven beneficial, and steroids in combination with thyroid hormone (T3), thyrotropin releasing hormone (TRH) or epidermal growth factor (EGF) offer significant promise in promoting functional pulmonary maturation. Although severe fluid and electrolyte imbalances secondary to renal immaturity also are observed in premature newborns, the coincident and possibly synergistic effects of maturational agent treatments on neonatal kidney function have not been assessed. Cortisol, T3, TRH and/or EGF affect secretion of, and/or renal responses to a variety of endocrine factors important to renal modulation including arginine vasopressin (AVP), atrial natriuretic factor (ANF) and the catecholamines epinephrine and norepinephrine. Our hypothesis is: fetal hormone treatment (single dose steroids alone or in combination with T3, TRH or EGF), will induce premature lamb kidney maturation through effects on key endocrine systems; providing a model for developing clinically relevant modes of treating prematurity. Thus, our objective is to assess maturational effects of steroids alone and in combination with other maturational agents (T3, TRH or EGF). To minimize the effects of stress and endogenous steroid production, fetal lambs will be treated by direct intravenous or intramuscular injection. Moreover, the experience and expertise in the use of the preterm ventilated lamb model available in the Harbor-UCLA Perinatal Research Laboratories will provide the unique opportunity to investigate renal adaptation in the premature newborn, and directly assess prior maturational agent treatment effects.
The specific aims are: 1) To compare renal function (GFR, distribution of sodium reabsorption, total and intra-renal blood flow distribution) in control and maturation-induced preterm lambs, 2) To assess the impact of induced maturation on preterm lamb renal AVP, ANF and catecholamine receptor binding characteristics and second messenger systems and 3) To compare renal tubular Na-K-ATPase activities in control and maturation-induced preterm neonatal lambs. These studies will demonstrate the efficacy of the various maturational agents and will provide information critical to future prospective strategies for managing neonatal outcome in prematurity.
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