The Thioredoxin Reductase-1 Inhibitor Aurothioglucose Attenuates Lung Injury and Improves Survival in a Murine Model of Acute Respiratory Distress Syndrome

Britt, Rodney D.; Velten, Markus; Locy, Morgan L.; Rogers, Lynette K.; Tipple, Trent E.

doi:10.1089/ars.2013.5332

Cited by 36 publications

(43 citation statements)

References 41 publications

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“…These results were in agreement with previous studies showing that hyperoxia leads to increased TNF-α levels in the lung [52–55]. The role of cytokines in hyperoxic acute lung injury has been extensively studied [56] and other mediators such as IL-1, IL-8, IFN-γ, MIP-2 and MCP-1 play a role in this disease process.…”

Section: Discussionsupporting

confidence: 92%

Disruption of cytochrome P4501A2 in mice leads to increased susceptibility to hyperoxic lung injury

Wang

Lingappan

Jiang

et al. 2015

Free Radical Biology and Medicine

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Hyperoxia contributes to acute lung injury (ALI) in diseases such as acute respiratory distress syndrome (ARDS). Cytochrome P450 (CYP)1A enzymes have been implicated in hyperoxic lung injury, but the mechanistic role(s) of CYP1A2 in pulmonary injury is not known. We hypothesized that mice lacking the gene for Cyp1a2 (which is predominantly expressed in the liver) will be more sensitive to lung injury and inflammation mediated by hyperoxia, and that CYP1A2 will play a protective role by attenuating lipid peroxidation and oxidative stress in the lung. Eight to ten week old WT (C57BL/6) or Cyp1a2(−/−) mice were exposed to hyperoxia (>95% O2) or maintained in room air for 24–72 h. Lung injury was assessed by determining the ratios of lung weight/body weight (LW/BW), and by histology. Extent of inflammation was determined by measuring the number of neutrophils in the lung as well as cytokine expression. The Cyp1a2(−/−) mice under hyperoxic conditions showed increased LW/BW ratios, lung injury, neutrophil infiltration, IL-6 and TNF-α levels, and augmented lipid peroxidation, as evidenced by increased formation of malondialdehyde (MDA)- and 4-hydroxynonenal (4-HNE)-protein adducts, and pulmonary isofurans compared to those of WT mice. In vitro experiments showed that the F2-isoprostane PGF2-α is metabolized by CYP1A2 to a dinor metabolite, providing evidence for a catalytic role for CYP1A2 in the metabolism of F2-isoprostanes. In summary, our results support the hypothesis that hepatic CYP1A2 plays a critical role in the attenuation against hyperoxic lung injury by decreasing lipid peroxidation and oxidative stress in vivo.

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Section: Discussionsupporting

confidence: 92%

Disruption of cytochrome P4501A2 in mice leads to increased susceptibility to hyperoxic lung injury

Wang

Lingappan

Jiang

et al. 2015

Free Radical Biology and Medicine

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“…Aurothioglucose (ATG) and auranofin (AFN) are Food and Drug Administration-approved antirheumatic drugs that potently inhibit TrxR1 (24,25). We have shown previously in vivo that ATG inhibits TrxR1, induces Nrf2-dependent gene transcription, and prevents lung injury in adult murine models (26,27). Moreover, in vitro data from our laboratory suggest that the protective effects of TrxR1 inhibition are mediated by Nrf2 activation (28).…”

mentioning

confidence: 62%

“…We have shown previously that TrxR1 disruption increases Nrf2 activation and Nrf2-mediated antioxidant responses in airway epithelial cells in vitro. TrxR1 inhibition also induces pulmonary Nrf2 activation and protection against hyperoxic and inflammatory lung injury in adult mice in vivo, suggesting the possible clinical usefulness of TrxR1 inhibitors in conditions such as acute respiratory distress syndrome (26)(27)(28). By demonstrating that TrxR1 inhibitors increase Nrf2 activation in alveolar epithelial cells in vitro and in the lungs of hyperoxia-exposed neonatal mice in vivo, the current studies extend our previous findings and support the possible clinical use of TrxR1 inhibition to prevent and/or treat BPD.…”

Section: Discussionmentioning

confidence: 99%

“…Treatment of adult mice with a single dose of 25 mg/kg ATG is well tolerated and prevents lung injury in adult models (24,26,27). To determine the effect of ATG administration on hyperoxia-induced lung developmental deficits in newborn C3H/HeN mice, pups were treated with a single dose of ATG (25 mg/kg administered i.p.)…”

Section: Atg Treatment Improves Alveolarization In Hyperoxia-exposed mentioning

confidence: 99%

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Thioredoxin Reductase Inhibition Attenuates Neonatal Hyperoxic Lung Injury and Enhances Nuclear Factor E2–Related Factor 2 Activation

Wall

Ren³

et al. 2016

Am J Respir Cell Mol Biol

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Oxygen toxicity and antioxidant deficiencies contribute to the development of bronchopulmonary dysplasia. Aurothioglucose (ATG) and auranofin potently inhibit thioredoxin reductase-1 (TrxR1), and TrxR1 disruption activates nuclear factor E2-related factor 2 (Nrf2), a regulator of endogenous antioxidant responses. We have shown previously that ATG safely and effectively prevents lung injury in adult murine models, likely via Nrf2-dependent mechanisms. The current studies tested the hypothesis that ATG would attenuate hyperoxia-induced lung developmental deficits in newborn mice. Newborn C3H/HeN mice were treated with a single dose of ATG or saline within 12 hours of birth and were exposed to either room air or hyperoxia (85% O2). In hyperoxia, ATG potently inhibited TrxR1 activity in newborn murine lungs, attenuated decreases in body weight, increased the transcription of Nrf2-regulated genes nicotinamide adenine dinucleotide phosphate reduced quinone oxidoreductase-1 (NQO1) and heme oxygenase 1, and attenuated alterations in alveolar development. To determine the impact of TrxR1 inhibition on Nrf2 activation in vitro, murine alveolar epithelial-12 cells were treated with auranofin, which inhibited TrxR1 activity, enhanced Nrf2 nuclear levels, and increased NQO1 and heme oxygenase 1 transcription. Our novel data indicate that a single injection of the TrxR1 inhibitor ATG attenuates hyperoxia-induced alterations in alveolar development in newborn mice. Furthermore, our data support a model in which the effects of ATG treatment likely involve Nrf2 activation, which is consistent with our findings in other lung injury models. We conclude that TrxR1 represents a novel therapeutic target to prevent oxygen-mediated neonatal lung injury.

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“…We and others have shown that cellular injury in the lung is the main pathophysiological event leading to death after hyperoxia and other experimental lung injury protocols (26)(27)(28). We asked whether endothelial TLR4 protects lungs against oxidant-induced injury.…”

Section: Endothelial Tlr4 Protects the Lung Against Oxidant-induced Imentioning

confidence: 99%

An endothelial TLR4‐VEGFR2 pathway mediates lung protection against oxidant‐induced injury

et al. 2015

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TLR4 deficiency causes hypersusceptibility to oxidant-induced injury. We investigated the role of TLR4 in lung protection, using used bone marrow chimeras; cell-specific transgenic modeling; and lentiviral delivery in vivo to knock down or express TLR4 in various lung compartments; and lung-specific VEGF transgenic mice to investigate the effect of TLR4 on VEGF-mediated protection. C57/BL6 mice were exposed to 100% oxygen in an enclosed chamber and assessed for survival and lung injury. Primary endothelial cells were stimulated with recombinant VEGF and exposed to hyperoxia or hydrogen peroxide. Endothelium-specific expression of human TLR4 (as opposed to its expression in epithelium or immune cells) increased the survival of TLR4-deficent mice in hyperoxia by 24 h and decreased LDH release and lung cell apoptosis after 72 h of exposure by 30%. TLR4 expression was necessary and sufficient for the protective effect of VEGF in the lungs and in primary endothelial cells in culture. TLR4 knockdown inhibited VEGF signaling through VEGF receptor 2 (VEGFR2), Akt, and ERK pathways in lungs and primary endothelial cells and decreased the availability of VEGFR2 at the cell surface. These findings demonstrate a novel mechanism through which TLR4, an innate pattern receptor, interacts with an endothelial survival pathway.

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The Thioredoxin Reductase-1 Inhibitor Aurothioglucose Attenuates Lung Injury and Improves Survival in a Murine Model of Acute Respiratory Distress Syndrome

Cited by 36 publications

References 41 publications

Disruption of cytochrome P4501A2 in mice leads to increased susceptibility to hyperoxic lung injury

Disruption of cytochrome P4501A2 in mice leads to increased susceptibility to hyperoxic lung injury

Thioredoxin Reductase Inhibition Attenuates Neonatal Hyperoxic Lung Injury and Enhances Nuclear Factor E2–Related Factor 2 Activation

An endothelial TLR4‐VEGFR2 pathway mediates lung protection against oxidant‐induced injury

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