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Raghavan S, Kundumani-Sridharan V, Kumar S, et al. Thioredoxin Prevents Loss of UCP2 in Hyperoxia via MKK4-p38 MAPK- PGC1α Signaling and Limits Oxygen Toxicity. Am J Respir Cell Mol Biol. 2021;doi: 10.1165/rcmb.2021-0219OC.
Raghavan, S., Kundumani-Sridharan, V., Kumar, S., White, C. W., & Das, K. C. (2021). Thioredoxin Prevents Loss of UCP2 in Hyperoxia via MKK4-p38 MAPK- PGC1α Signaling and Limits Oxygen Toxicity. American journal of respiratory cell and molecular biology, . https://doi.org/10.1165/rcmb.2021-0219OC
Raghavan, Somasundaram, et al. "Thioredoxin Prevents Loss of UCP2 in Hyperoxia via MKK4-p38 MAPK- PGC1α Signaling and Limits Oxygen Toxicity." American journal of respiratory cell and molecular biology vol. (2021). doi: https://doi.org/10.1165/rcmb.2021-0219OC
Raghavan S, Kundumani-Sridharan V, Kumar S, White CW, Das KC. Thioredoxin Prevents Loss of UCP2 in Hyperoxia via MKK4-p38 MAPK- PGC1α Signaling and Limits Oxygen Toxicity. Am J Respir Cell Mol Biol. 2021 Dec 10; doi: 10.1165/rcmb.2021-0219OC. Epub 2021 Dec 10. PMID: 34890296.
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Am J Respir Cell Mol Biol. 2021 Dec 10; doi: 10.1165/rcmb.2021-0219OC. Epub 2021 Dec 10.

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

American journal of respiratory cell and molecular biology

Somasundaram Raghavan, Venkatesh Kundumani-Sridharan, Sudhir Kumar, Carl W White, Kumuda C Das

Affiliations

  1. Texas Tech University Health Sciences Center, 12343, Internal Medicine, Lubbock, Texas, United States.
  2. University of Colorado Denver School of Medicine, 12225, Pediatrics, Aurora, Colorado, United States.
  3. Texas Tech University Health Sciences Center, 12343, Internal Medicine, Lubbock, Texas, United States; [email protected].

PMID: 34890296 DOI: 10.1165/rcmb.2021-0219OC

Abstract

Administration of high concentrations of oxygen (hyperoxia) is one of few available options to treat acute hypoxemia-related respiratory failure as in current Covid-19 pandemic. Although hyperoxia can cause acute lung injury due to increased production of superoxide anion (O2·-), the choice of high concentration oxygen administration has become a necessity in critical care. Test the hypothesis that UCP2 has a major function of reducing O2·- generation in the lung in ambient air or in hyperoxia. Lung epithelial cells, WT, UCP2-/- or Trx-Tg mice were exposed to hyperoxia and O2·- generation by EPR, and lung injury was measured by histopathology analysis. UCP2 expression was analyzed using RT-PCR, western analysis, RNA interference. The signal transduction pathways leading to loss of UCP2 expression was analyzed by immunoprecipitation, phosphoprotein analysis and, using specific inhibitors. UCP2 mRNA and protein expression were acutely decreased in hyperoxia, which were associated with significant increase in O2·- production in the lung. Treatment of cells with rhTrx or exposure of Trx-Tg mice prevented the loss of UCP2 protein and decreased O2·- 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 MKK4-p38MAPK-PGC1α pathway leading to rescue of UCP2 and decreased O2·- generation in hyperoxia. Loss of UCP2 in hyperoxia is a major mechanism of O2·- production in the lung in hyperoxia. rhTrx can protect lung injury in hyperoxia due to rescue of loss of UCP2.

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