HMD and BPD remain the major causes of neonatal mortality and norbidity. Maternal Thyrotropin Releasing Hormone (TRH) treatment enhances fetal lung maturation, but inhibits antioxidant enzyme (AOE). Nevertheless, there is an increasing use of prenatal TRH=corticosteroids (CS) for the prevention of HMD & BPD. The mechanism of TRH effects on fetal lung are unclear, it may be due to its neuroendocrine or neurotransmitter actions. To investigate these possibilities, we will use the HYT/HYT mouse where primary hypothyroidism occurs due to a mutation (ProyieldsLeu,a.a.556) in the TM4 domain of the beta subunit of the TSH receptor, & is transmitted as an autosomal recessive trait. We will test alternative hypotheses that TRH mediates its effect through 1 of 3 pathways: 1) Fetal pituitary-thyroid (TH), 2) Fetal CNS autonomic sympathetic or parasympathetic neurotransmission, or 3) Fetal adrenal medullary release of Epinephrine (beta-a drenergic effect). We will perform fetal lung ultrastructural analysis, quantitate disaturated phosphatidylcholine (DSPC), the rate of 3H-choline incorporation into phosphatidaylcholine (PC) & DSPC, & AOE activity, as indices of TRH effects. Clinically TRH is used with CS, & TRH=CS therapy increases fetal ling SP-A in animals. We have observed altered protein (SP-A & C) & gene expression (SP-C) in HYT/HYT mouse fetal lungs. We will study the effect of prenatal CS, TRH or CS+TRH on fetal lung SP-A & SP-C mRNA (Northern) & protein expression (Western & immunostaining), along with other indices of TRH effects. Plasma TSH & free T4 levels (RIA) will determine the TH status of the Mice. The role of each pathway will be determined as follows: 1) Pituitary-thyroid-lung axis: Comparison of the effect on the fetal lung of maternal TRH treatment in the HYT/HYT & Balb-C mouse; presence of TRH effects in Balb-C & their absence in the HYT/HYT mouse will indicate a role for the pituitary-thyroid axis. 2) CNS sympathetic or adrenal medullary Epinephrine (beta adrenergic) stimulation: Comparison of the effect in the fetal lung of maternal TRH therapy in the HYT/HYT mouse with & without prior treatment with 6- hydroxydopamine (6-OHDA, chemical sympathectomy) or Propranolol (beta- adrenergic blockade) respectively: Absence of TRH effects on the lung in 6-OHDA or Propranolol treated fetuses will suggest a role for the Cnz sympathetic or beta-adrenergic system respectively. 3) CNS parasympathetic stimulation: Comparison of the effect on fetal lung of maternal TRH treatment in the HYT/HYT & Balb-C mouse with & without prior atropine treatment for cholinergic blockade: A lack of TRH effect on lungs of Atropine treated fetuses will indicate a role for the cholinergic system. TRH (24mug/dose) will administered (IP, d16 & 17, b.i.d.) & 18 (1 h prior to killing) of pregnancy. The vehicle, 6-OHDA, Propranolol or Atropine will be infused by Alzet pumps starting on d 14. For TRH+CS studies, vehicle+saline, TRH (24mug/dose) in saline+vehicle, TRH+Beta. (0.6 mg/dose), or saline+Beta. will be injected on d 16 & 17 (b.i.d.) & 18 of pregnancy. All pregnant mice will be killed on d 18, (term about 20 d). These studies will further establish the efficacy, & clarify the mechanism of TRH & TRH+CS~s effect on the fetal lung, & may provide clues for the prevention of AOE inhibition after TRH treatment & improved management of neonates prenatally treated with CS+TRH.
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