Journal article
Thioredoxin Reductase Inhibition Elicits Nrf2-Mediated Responses in Clara Cells: Implications for Oxidant-Induced Lung Injury
Antioxidants & redox signaling, Vol.17(10), pp.147-1416
11/15/2012
Handle:
https://hdl.handle.net/2376/110943
PMCID: PMC3437047
PMID: 22607006
Abstract
Aims:
Pulmonary oxygen toxicity contributes to lung injury in newborn and adult humans. We previously reported that thioredoxin reductase (TrxR1) inhibition with aurothioglucose (ATG) attenuates hyperoxic lung injury in adult mice. The present studies tested the hypothesis that TrxR1 inhibition protects against the effects of hyperoxia via nuclear factor E2-related factor 2 (Nrf2)-dependent mechanisms.
Results:
Both pharmacologic and siRNA-mediated TrxR1 inhibition induced robust Nrf2 responses in murine-transformed Clara cells (mtCC). While TrxR1 inhibition did not alter the susceptibility of cells to the effects of hyperoxia, glutathione (GSH) depletion after TrxR1 inhibition markedly enhanced the hyperoxic susceptibility of cultured mtCCs. Finally,
in vivo
data revealed dose-dependent increases in the expression of the Nrf2 target gene NADPH:quinone oxidoreductase 1 (NQO1) in the lungs of ATG-treated adult mice.
Innovation:
TrxR1 inhibition activates Nrf2-dependent antioxidant responses in mtCCs
in vitro
and in adult murine lungs
in vivo
, providing a plausible mechanism for the protective effects of TrxR1 inhibition
in vivo
.
Conclusion:
GSH-dependent enzyme systems in mtCCs may be of greater importance for protection against hyperoxic exposure than are TrxR-dependent systems. The induction of Nrf2 activation
via
TrxR1 inhibition represents a novel therapeutic strategy that attenuates oxidant-mediated lung injury. Similar expression levels of TrxR1 in newborn and adult mouse or human lungs broaden the potential clinical applicability of the present findings to both neonatal and adult oxidant lung injury.
Antioxid. Redox Signal.
17, 1407–1416.
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Details
- Title
- Thioredoxin Reductase Inhibition Elicits Nrf2-Mediated Responses in Clara Cells: Implications for Oxidant-Induced Lung Injury
- Creators
- Morgan L Locy - 1Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Columbus, OhioLynette K Rogers - 2Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OhioJustin R Prigge - 3Department of Immunology and Infectious Diseases, Montana State University, Bozeman, MontanaEdward E Schmidt - 3Department of Immunology and Infectious Diseases, Montana State University, Bozeman, MontanaElias S.J Arnér - 4Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, SwedenTrent E Tipple - 2Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, Ohio
- Publication Details
- Antioxidants & redox signaling, Vol.17(10), pp.147-1416
- Academic Unit
- UNKNOWN
- Publisher
- Mary Ann Liebert, Inc
- Identifiers
- 99900547298201842
- Language
- English
- Resource Type
- Journal article