Down-regulation of thyroid transcription factor-1 gene expression in fetallung hypoplasia is restored by glucocorticoids

The thyroid transcription factor (TTF)-1 has an essential role in lung morp hogenesis and development. It is involved in the transcription of surfactan t proteins (SP), which are critical in respiratory function. Neonates with congenital diaphragmatic hernia die of respiratory failure caused by pulmon ary hypoplasia with associated biochemical immaturity. To gain new insights into the causes of this disorder and the effect of prenatal hormonal treat ment on reducing mortality in these infants, we evaluated the expression of TTF-1 as marker of lung morphogenesis and SP-B as marker of lung maturity. Using a rat model of lung immaturity, we show that TTF-1 and SP-B messenge r RNA (mRNA) levels are drastically reduced in congenital lung hypoplasia. Interestingly, prenatal dexamethasone (Dex) treatment increased both TTF-1 and SP-B mRNAs over control levels when administered to rats with lung hypo plasia, but it had no effect on TTF-1 or a moderate effect on SP-B mRNA whe n administered to control rats. TRH alone also increases TTF-1 and SP-B mRN A levels but to a lesser extent than Dex. When administered together with D ex, TRH counteracts the induction observed with the glucocorticoid. The dec rease in TTF-1 mRNA levels in lung hypoplasia is paralleled by a down-regul ation of TTF-1 protein levels, as well as by a decrease in the TTF-1/DNA co mplex when the TTF-l-binding site of the SP-B promoter was used as a probe. Both parameters were reestablished after glucocorticoid treatment. Moreove r, the regulation of TTF-1 gene expression described in this report is acco mpanied by the same regulation in its promoter activity, as demonstrated in transfection experiments performed in H-441 human lung-derived adenocarcin oma cells. In conclusion, our data demonstrate, for the first time, that lu ng hypoplasia and the associated respiratory dysfunction caused by SP-B def iciency are caused, in part, by down-regulation of TTF-1 gene expression. T he observations that prenatal glucocorticoid treatment induces the expressi on of TTF-1 supports routine in utero glucocorticoid treatment of patients expected to have lung hypoplasia.