Thioredoxin-related mechanisms in hyperoxic lung injury in mice.
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.
Tipple
Trent E
TE
Columbus Children's Research Institute, Columbus Children's Hospital, Department of Pediatrics, The Ohio State University, Columbus, OH 43205, USA. tipplet@pediatrics.ohio-state.edu
Welty
Stephen E
SE
Rogers
Lynette K
LK
Hansen
Thomas N
TN
Choi
Young-Eun
YE
Kehrer
James P
JP
Smith
Charles V
CV
D000818:Animals; D001835:Body Weight; D005978:Glutathione / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D018496:Hyperoxia / Q000378:metabolism* / Q000473:pathology*; D008099:Liver / Q000201:enzymology; D008168:Lung / Q000201:enzymology / Q000473:pathology; D008171:Lung Diseases / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D009929:Organ Size; D013880:Thioredoxin-Disulfide Reductase / Q000378:metabolism; D013879:Thioredoxins / Q000378:metabolism*
D013879:Thioredoxins; D005980:Glutathione Reductase; D013880:Thioredoxin-Disulfide Reductase; D005978:Glutathione