Am J Respir Cell Mol Biol . The Role of Glutathione Reductase in Influenza Infection

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Am J Respir Cell Mol Biol


. 2022 Jun 29.
doi: 10.1165/rcmb.2021-0372OC. Online ahead of print.
The Role of Glutathione Reductase in Influenza Infection


Kyung Sook Hong ^{1 2} , Kassandra Pagan ³ , William Whalen ³ , Rebecca Harris ³ , Jianjun Yang ³ , Heather Stout-Delgado ³ , Soo Jung Cho ⁴



Affiliations

• PMID: 35767671
• DOI: 10.1165/rcmb.2021-0372OC

Abstract

Influenza infection induces lung epithelial cell injury via programed cell death. Glutathione, a potent antioxidant, has been reported to be associated with influenza infection. We hypothesized that lung epithelial cell death during influenza infection is regulated by glutathione metabolism. 8-week-old male and female BALB/c mice were infected with influenza (PR8: A/PR/8/34(H1N1)) via intranasal instillation. Metabolomic analysis were performed on whole lung lysate after influenza infection. For in vitro analysis, Beas-2B cells were infected with influenza. RNA was extracted and QuantiTect Primer Assay was used to assess gene expression. Glutathione levels were assessed by colorimetric assay. Influenza infection resulted in increased inflammation and epithelial cell injury in our murine model, leading to increased morbidity and mortality. In both our in vivo and in vitro models, influenza infection was found to induce apoptosis and necroptosis. Influenza infection furthermore led to decreased glutathione metabolism and reduced glutathione reductase activity in lung epithelial cells. Genetic inhibition of glutathione reductase suppressed apoptosis and necroptosis of lung epithelial cells. Pharmacologic inhibition of glutathione reductase reduced airway inflammation, lung injury and cell death in our murine influenza model. Our results demonstrate that glutathione reductase activity is suppressed during influenza. Glutathione reductase inhibition prevents epithelial cell death and morbidity in our murine influenza model. Our results suggest that glutathione reductase-dependent glutathione metabolism may play an important role in the host response to viral infection by regulating lung epithelial cell death.