Induction of thioredoxin and thioredoxin reductase gene expression in lungs of newborn primates by oxygen

Thioredoxin (TRX) is a potent protein disulfide oxidoreductase important in antioxidant defense and regulation of cell growth and signal transduction processes, among them the production of nitric oxide. We report that lung T RX and its reductase, TR, are specifically upregulated at birth by O-2. Thr oughout the third trimester, mRNAs for TRX and TR were expressed constituti vely at low levels in fetal baboon lungs. However. after premature birth (1 25 or 140 of 185 days gestation), lung TRX and TR mRNAs increased rapidly w ith the onset of O-2 or air breathing. Lung TRX mRNA also increased in lung s of term newborns with air breathing. Premature animals (140 days) breathi ng 100% O-2 develop chronic lung disease within 7-14 days. These animals ha d greater TRX and TR mRNAs after 1, 6, or 10 days of life than fetal contro l animals. In 140-day animals given lesser O-2 concentrations (as needed) w ho do not develop chronic lung disease, lung TRX and TR mRNAs were also inc reased on days 1 and 6 but not significantly on day 10. In fetal distal lun g explant culture, mRNAs for TRX and TR were elevated within 4 h in 95% O-2 relative to 1% O-2, and the response was similar at various gestations. In contrast, TRX protein did not increase in lung explants from premature ani mals (125 or 140 days) but did in those from near-term (175-day) fetal babo ons after exposure to hyperoxia. However, lung TRX protein and activity, as well as TR activity, eventually did increase in vivo in response to hypero xia (6 days). Increases in TRX and TR mRNAs in response to 95% O-2 also wer e observed in adult baboon lung explants. When TRX redox status was determi ned, increased O-2 tension shifted TRX to its oxidized form. Treatment of l ung explants with actinomycin D inhibited TRX and TR mRNA increases in 95% O-2, indicating transcriptional regulation by O-2. The acute increase in ge ne expression for both TRX and TR in response to O-2 suggests an important role for these proteins during the transition from relatively anaerobic fet al life to O-2 breathing at birth.