TISSUE DISTRIBUTION OF ALPHA(1)-PROTEINASE INHIBITOR MESSENGER-RIBONUCLEIC-ACID AND ITS REGULATION BY GLUCOCORTICOIDS IN FETAL AND NEONATAL SHEEP

Alpha1-proteinase inhibitor (alpha1-PI) controls several proteinases that play important roles during inflammation and tissue remodeling, but its function during mammalian development remains obscure. We have therefore studied the ontogeny of alpha1-PI mRNA in selected fetal and newborn sheep tissues by Northern blotting. Furthermore, because glucocorticoids play important roles in fetal maturation and parturition in sheep, we measured the relative amounts of glucocorticoid receptor (GR) mRNA in the same tissues and compared the effect of dexamethasone (DEX) administration on alpha1-PI mRNA levels in liver and kidney of fetal and adult sheep. In the ontogeny study, a 1.8-kb alpha1-PI mRNA was found in fetal adrenal gland and lung at Days 60-70 but was low or undetectable in these tissues at later gestational ages. By contrast, the abundance of hepatic alpha1-PI mRNA did not vary between Days 60 and 130 of gestation, but decreased significantly (p < 0.05) at term (Days 145-147) and in newborn lambs. In the fetal kidney, it was also present between Days 60 and 130, and its relative abundance increased significantly (p < 0.05) in term and newborn lambs. These changes did not correlate with GR mRNA abundance, which was relatively stable in all tissues except the kidney, where a significant (p < 0.05) decrease was observed in neonates. Compared to saline treatment, DEX infusion (2 mug/min for 15 min every 2 h for 96 h) to fetal sheep beginning on Day 130 of gestation resulted in a significant decrease in fetal liver alpha1-PI mRNA abundance in the fetal liver, but no corresponding change in the fetal kidney. In adult sheep liver, a similar effect was seen after administration of 10 mg DEX per day in comparison to saline controls. We therefore conclude that 1) the widespread tissue distribution of alpha1-PI mRNA during mid-gestation becomes more restricted to the liver and kidney during late gestation; 2) glucocorticoids decrease the relative amount of alpha1-PI mRNA in the liver but not in the kidney. These results suggest that the decrease in liver alpha1-PI mRNA abundance in term fetuses and neonates may be induced by increases in fetal plasma cortisol concentrations during the last few days of gestation.