title: 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.
authors.affiliation: 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
authors.forename: Trent E
authors.initials: TE
authors.lastname: Tipple
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Welty
authors.forename: Lynette K
authors.initials: LK
authors.lastname: Rogers
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Hansen
authors.forename: Young-Eun
authors.initials: YE
authors.lastname: Choi
authors.forename: James P
authors.initials: JP
authors.lastname: Kehrer
authors.forename: Charles V
authors.initials: CV
authors.lastname: Smith
mesh_terms: 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*
chemical_list: D013879:Thioredoxins; D005980:Glutathione Reductase; D013880:Thioredoxin-Disulfide Reductase; D005978:Glutathione