The thioredoxin system in neonatal lung disease

Abstract

Significance: Fetal lung development takes place in hypoxia meaning that premature birth is hyperoxia for the prematurely born infant. The most common respiratory morbidity afflicting premature infants is bronchopulmonary dysplasia (BPD). Pathophysiologically, BPD represents the impact of injury, including O2 toxicity, to the immature developing lung that causes arrested lung development.

Recent advances: The thioredoxin (Trx) system, which is predominantly expressed in pulmonary epithelia in the newborn lung, acts as an antioxidant system; however, it is increasingly recognized as a key redox regulator of signal transduction and gene expression via thiol-disulfide exchange reactions.

Critical issues: This review focuses on the contribution of Trx family proteins toward normal and aberrant lung development, in particular, the roles of the Trx system in hyperoxic responses of alveolar epithelial cells, aberrant lung development in animal models of BPD, O2-dependent signaling processes, and possible therapeutic efficacy in preventing O2-mediated lung injury.

Future directions: The significant contribution of the Trx system toward redox regulation of key developmental pathways necessary for proper lung development suggests that therapeutic strategies focused on preserving pulmonary Trx function could significantly improve the outcomes of prematurely born human infants.

FIG. 1.

Trx-mediated reduction of protein mixed disulfides. Mechanism by which the thioredoxin (Trx) system (Trx+TrxR) can reduce protein mixed disulfides (PSSX) resulting in a net reduction of PSSX by NADPH.

FIG. 2.

Trx-mediated processes in neonatal lung development. Processes likely to be governed by the Trx system that are pertinent to lung development include transcription factor regulation, apoptosis, DNA synthesis, reduction of H₂O₂ and protein disulfides, and protein denitrosylation.

FIG. 3.

Txnip localization in the developing lung. Txnip immunopositivity in (A) fetal ovine (TII=type 2 and TI=type 1 alveolar epithelial cells) and (B) newborn murine lungs (arrow, type 2 alveolar epithelial cells). From (A) Filby et al. (27) and (B) Farrell et al. (26). To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 4.

Effects of hyperoxic exposure on murine neonatal lung development. Histology of mouse pup lung tissues (H&E, 100×) following exposure to room air or 85% O₂ for 7 or 14 days. From Rogers et al. (65). To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 5.

Effects of postnatal hyperoxic exposure on lung Trx1 redox state in newborn mice. Lung Trx1 redox state in newborn mice exposed to room air or 85% O₂ for 1, 3, or 7 days as assessed by redox Western blot. From Tipple et al. (81).

FIG. 6.

Effects of hyperoxic exposure on Trx redox state in baboon lungs. Effect of O₂ on baboon lung Trx redox state in vivo and in explant culture as assessed by redox Western blot. From Das et al. (19).

FIG. 7.

Relationship between lung Txnip and VEGF expression in embryonic and newborn murine lungs. (A) Regression analyses of lung Txnip and vascular endothelial growth factor (VEGF) contents in embryonic day 19 and 1-day-old newborn mice. From Farrell et al. (26). (B) Regression analyses of lung Txnip and VEGF contents in newborn mice exposed to room air or 85% O₂ for 1, 3, or 7 days. From Tipple et al. (81).

FIG. 8.

Hypothesized effects of preterm birth on lung Trx-dependent processes. Upon premature delivery into the relatively hyperoxic extrauterine environment, the Trx pool becomes oxidized. The resultant impairment in Trx-mediated antioxidant function results in elevated H₂O₂ levels. Increased protein oxidation and nitration lead to impaired protein function resulting in disruption of protein-mediated signaling pathways. Disruption of redox-dependent transcription, decreased DNA synthesis, enhanced apoptosis, Txnip release, and Trx secretion are also likely to occur.