Thioredoxin Prevents Loss of UCP2 in Hyperoxia via MKK4-p38 MAPK-PGC1α Signaling and Limits Oxygen Toxicity

Administration of high concentrations of oxygen (hyperoxia) is one of few available options to treat acute hypoxemia-related respiratory failure, as seen in the current coronavirus disease (COVID-19) pandemic. Although hyperoxia can cause acute lung injury through increased production of superoxide anion (O-2(center dot-)), the choice of high-concentration oxygen administration has become a necessity in critical care. The objective of this study was to test the hypothesis that UCP2 (uncoupling protein 2) has a major function of reducing O-2(center dot-) generation in the lung in ambient air or in hyperoxia. Lung epithelial cells and wild-type; UCP2(-/)(-); or transgenic, hTrx overexpression-bearing mice (Trx-Tg) were exposed to hyperoxia and O-2(center dot-) generation was measured by using electron paramagnetic resonance, and lung injury was measured by using histopathologic analysis. UCP2 expression was analyzed by using RT-PCR analysis, Western blotting analysis, and RNA interference. The signal transduction pathways leading to loss of UCP2 expression were analyzed by using IP, phosphoprotein analysis, and specific inhibitors. UCP2 mRNA and protein expression were acutely decreased in hyperoxia, and these decreases were associated with a significant increase in O-2(center dot-) production in the lung. Treatment of cells with rhTrx (recombinant human thioredoxin) or exposure of Trx-Tg mice prevented the loss of UCP2 protein and decreased O-2(center dot-) generation in the lung. Trx is also required to maintain UCP2 expression in normoxia. Loss of UCP2 in UCP2(-/-) mice accentuated lung injury in hyperoxia. Trx activates the MKK4-p38MAPK (p38 mitogenactivated protein ldnase)-PGCla (PPAR-gamma [peroxisome proliferator-activated receptor -gamma] coactivator 1 alpha) pathway, leading to rescue of UCP2 and decreased O-2(center dot-) generation in hyperoxia. Loss of UCP2 in hyperoxia is a major mechanism of O-2(center dot-) production in the lung in hyperoxia. rhTrx can protect against lung injury in hyperoxia due to rescue of the loss of UCP2.

Automated summary

The study aimed to investigate the role of UCP2 in reducing O-2(center dot-) production in the lung under normal or hyperoxia conditions. The results showed that high-concentration oxygen caused a decrease in UCP2 expression and an increase in lung O-2(center dot-) production. However, treatment with recombinant human thioredoxin or overexpression of Trx prevented the loss of UCP2 and reduced O-2(center dot-) generation in the lung.