Maternal corticosteroid use is accepted as a means to decrease the incidence of respiratory distress syndrome in the preterm infant, and thyrotropin releasing hormone (TRH) is being evaluated in clinical trials as a lung maturational agent. Recent clinical experience suggests that surfactant treatments will decrease the incidence and severity of respiratory distress syndrome. While corticosteroids are thought to influence fetal lung maturation to a large degree via the stimulation of surfactant synthesis, the goals of the proposed experiments are to extend our observations that the effects of both corticosteroids and TRH are probably on other properties of the developing lung as evaluated by measuring effects of these agents on postnatal lung functions such as compliance, protein leak characteristics, and rupture pressures. A striking effect of maternal corticosteroid treatment is the large improvement in response to exogenous surfactant. Three questions will be asked by the proposed research. 1) Do lung maturational agents alter surfactant phospholipid and protein metabolism in the postnatal lung? This question will be explored using a preterm ventilated rabbit model to evaluate the effects of maternal hormone treatments on surfactant phosphatidylcholine synthesis, secretion and clearance as well as possible effects of these agents on the amounts of the surfactant specific proteins in the alveoli. 2) How do corticosteroid and/or TRH treatments alter protein leaks and lung water clearance in the preterm ventilated lamb? Fetal sheep will be treated with corticosteroids and/or TRH and subsequent lung function, response to surfactant, protein leaks and water clearance will be evaluated following delivery and ventilation. Protein leaks will be measured with radiolabeled proteins to evaluate alveolar to vascular and vascular to alveolar protein leaks. Lung water clearance will be assessed using an airway occluded lung segment in surfactant treated and ventilated preterm lambs. 3) What is the mechanism of action of TRH on the fetal lung? Pulsatile TRH infusions will be given to thyroidectomized or control lambs and a variety of hormones known to influence lung maturation will be measured together with assessments of lung maturation following delivery and ventilation. The goal is to develop a sound basis for the use of maternal hormone treatments in conjunction with postnatal surfactant treatments for preterm infants.
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