Lung immaturity at birth is a major cause of mortality and morbidity in premature babies. Liggins findings that glucocorticoids (GC) administered to the mother accelerate lung maturation led to improved clinical management based on GC administration to pregnant women in premature labor. GC induced fetal lung maturation after weeks gestational age (GA) is not reproduced at 28 weeks (0.7 GA). Animal studies, mostly sheep and rabbits, suggest that combined therapies with thyrotropin releasing hormone (TRH) and GC may be of benefit at 0.7 GA. Combined therapy clinical trials provide conflicting data, in part because of confounds in patient populations (e.g. presence of infection). In addition, recent observations in human and animal pregnancy show that maternal GC administration has significant extra-pulmonary effects on fetal maturation affecting fetal breathing, movements, and cardiovascular function. Thus, further experimental studies are needed in nonhuman primates to evaluate effects of TRH alone and combined with GC, on critical features of maturation of fetal pulmonary systems. HYPOTHESES: There are six hypotheses 1) TRH and beta-M will rapidly cross the primate placenta; 2) TRH will alter maternal and fetal cardiovascular function; 3) TRH will stimulate both maternal and fetal thyroid function and prolactin (PRL) secretion; 4) Message and protein for surfactant proteins will increase, accompanied by lung lipid changes and improved pressure volume relationships. 5) Betamethasone (beta-M) administration alone will affect the fetal pituitary-adrenal axis; 6) beta-M will not alter placental TRH transfer but there will be differences in fetuses receiving beta-M in functions of the fetal pituitary adrenal axis. Importantly, combination of TRH with beta-M will be more effective at stimulating synthesis of various surfactant proteins, and accelerating the normal gestational age related lipid changes and other aspects of lung maturation. PROPOSED STUDIES: Chronically instrumented pregnant baboon preparations at 0.7 GA will be used to evaluate TRH and 3-M effects on: i) transplacental TRH and beta-M passage; ii) maternal and fetal cardiovascular system; iii) maternal and fetal endocrinology, plasma ACTH, cortisol, dehydroepiandrosterone sulfate, PRL, thyroxine (T4), triiodthyronine (T3), and reverse T3 (rT3); iv) fetal lung maturation indexed by; lung a) distensibility and stability; b) lipid metabolism; c) surfactant proteins. RATIONALE: Firm mechanistic knowledge is required to underpin combined therapies used to accelerate lung maturation at 0.7 GA. Clinical trials have begun despite lack of fundamental knowledge of TRH effects on fetal development. Our proposed studies will rectify this situation and provide firm data at plasma and tissue levels of mechanisms of action of TRH and GC on primate fetal lung maturation. The clinical value of these studies is that they will serve to indicate optimal therapeutic regimens and potential side effects. These data can never be obtained in 0.7 GA human fetuses and yet they are essential to optimal treatment.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Human Embryology and Development Subcommittee 1 (HED)
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Cornell University
Other Basic Sciences
Schools of Veterinary Medicine
United States
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