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Thioredoxin Prevents Loss of UCP2 in Hyperoxia via MKK4-p38 MAPK-PGC1α Signaling and Limits Oxygen Toxicity.
Raghavan, Somasundaram; Kundumani-Sridharan, Venkatesh; Kumar, Sudhir; White, Carl W; Das, Kumuda C.
  • Raghavan S; Department of Internal Medicine, School of Medicine, Texas Tech University Health Sciences Center, Texas Tech University, Lubbock, Texas; and.
  • Kundumani-Sridharan V; Department of Internal Medicine, School of Medicine, Texas Tech University Health Sciences Center, Texas Tech University, Lubbock, Texas; and.
  • Kumar S; Department of Internal Medicine, School of Medicine, Texas Tech University Health Sciences Center, Texas Tech University, Lubbock, Texas; and.
  • White CW; Department of Pediatrics, Children's Hospital, University of Colorado Health Sciences Center, University of Colorado, Aurora, Colorado.
  • Das KC; Department of Internal Medicine, School of Medicine, Texas Tech University Health Sciences Center, Texas Tech University, Lubbock, Texas; and.
Am J Respir Cell Mol Biol ; 66(3): 323-336, 2022 03.
Article in English | MEDLINE | ID: covidwho-1714501
ABSTRACT
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 (O2•-), 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 O2•- 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 O2•- 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 O2•- 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 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 the MKK4-p38MAPK (p38 mitogen-activated protein kinase)-PGC1α (PPARγ [peroxisome proliferator-activated receptor γ] coactivator 1α) 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 against lung injury in hyperoxia due to rescue of the loss of UCP2.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Oxygen / Thioredoxins / Uncoupling Protein 2 / Lung Limits: Animals / Humans Language: English Journal: Am J Respir Cell Mol Biol Journal subject: Molecular Biology Year: 2022 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Oxygen / Thioredoxins / Uncoupling Protein 2 / Lung Limits: Animals / Humans Language: English Journal: Am J Respir Cell Mol Biol Journal subject: Molecular Biology Year: 2022 Document Type: Article