Thioredoxin-Related Mechanisms in Hyperoxic Lung Injury in Mice

Abstract

Reduction of glutathione disulfide (GSSG) to glutathione (GSH) by glutathione reductase (GR) enhances the efficiency of GSH-dependent antioxidant activities. However, GR-deficient (a1Neu) mice are less susceptible to acute lung injury from continuous exposure to > 95% O(2) (96 h: 6.9 +/- 0.1 g right lung/kg body versus room air 3.6 +/- 0.3) than are C3H/HeN control mice (10.6 +/- 1.3 versus 4.2 +/- 0.3, P < 0.001). a1Neu mice have greater hepatic thioredoxin (Trx)1 and Trx2 levels than do C3H/HeN mice, suggesting compensation for the absence of GR. a1Neu mice exposed to hyperoxia for 96 hours showed lower levels of inflammatory infiltrates in lungs than did similarly exposed C3H/HeN mice. Pretreatment with aurothioglucose (ATG), a thioredoxin reductase (TrxR) inhibitor, exacerbated the effects of hyperoxia on lung injury in a1Neu mice (11.6 +/- 0.8, P < 0.001), but attenuated hyperoxic lung edema and inflammation in C3H/HeN mice (6.3 +/- 0.4, P < 0.001). No consistent alterations were observed in lung GSH contents or liver GSH or GSSG levels after ATG pretreatment. The data suggest that modulation of Trx/TrxR systems might provide therapeutically useful alterations of cellular resistance to oxidant stresses. The protective effects of ATG against hyperoxic lung injury could prove to be particularly useful therapeutically.

Thioredoxin Reductase Inhibition Elicits Nrf2-Mediated Responses in Clara Cells: Implications for Oxidant-Induced Lung Injury

“…Our studies also indicate that TrxR1 is highly enriched in newborn human and mouse airway epithelia, though these findings require confirmation in a greater number of samples. The activation of Nrf2-dependent antioxidant responses on TrxR1 inhibition provides a plausible mechanism for our previous findings of attenuated hyperoxic lung injury in vivo after the TrxR1 inhibition by ATG (38). We speculate that the protective effects of TrxR1 inhibition on hyperoxia-induced lung injury in vivo are likely GSH dependent and mediated via Nrf2.…”

“…Experimental models utilize the hyperoxic exposure of newborn or adult mice to investigate the pathogenesis of BPD or ARDS, respectively. In hyperoxia-exposed adult mice, we have previously shown that ATG pretreatment persistently inhibits TrxR1 and attenuates lung edema and inflammation (38). Though the mechanisms responsible for these effects were unclear, our data suggested that TrxR1 inhibition could be therapeutically beneficial in protecting against oxidant-induced lung injury.…”

“…We previously found that the TrxR1 inhibitor ATG attenuated hyperoxic lung injury in adult mice (38). Therefore, we sought to determine whether Nrf2 activation could be involved by studying the effects of TrxR1 inhibitors AFN and dinitrochlorobenzene (DNCB) and the well-characterized Nrf2 inducer sulforaphane (SFN).…”

Involvement of Epithelial Cell Apoptosis in Interstitial Lung Diseases

“…Bcl-2 protein and mRNA levels in the lung were more significantly increased in transgenic mice than in wild type mice (72). (68,78).…”

DNA Replication in Animal Systems Lacking Thioredoxin Reductase I

“…Some recent advances have come from the development of mouse models bearing targeted "conditional" alleles of the gene encoding thioredoxin reductase I (TrxR1, also called Txnrd1 or TR1), which can be disrupted in a cell type-or developmental stage-specific manner. Whereas these models are yielding some exciting insights into the Trx and GSH systems in embryonic development, stress responses, toxicology, cancer, and other processes (Bondareva et al, 2007;Branco et al, 2011;Carvalho et al, 2008;Jakupoglu et al, 2005;Mandal et al, 2010;Rogers et al, 2004;Suvorova et al, 2009;Tipple et al, 2007;Zhang and Lu, 2007), the current treatise will emphasize the interplay of these pathways in supporting DNA replication in animal systems. The enormity of the body of literature on the Trx, GSH, and RNR systems precludes an exhaustive review of these materials, and it is my intention to cover these subjects in only a cursory manner to set the backdrop for understanding these systems in the context of DNA replication in animals.…”