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Thioredoxin-Related Mechanisms in Hyperoxic Lung Injury in Mice

¹ Division of Neonatology, Department of Pediatrics, Columbus Children's Hospital, The Ohio State University College of Medicine, Center for Perinatal Research, Columbus Children's Research Institute, Columbus, Ohio; ² Center for Developmental Pharmacology and Toxicology, Children's Hospital & Regional Medical Center, Seattle, Washington, ³ Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas; and ⁴ College of Pharmacy, Washington State University, Pullman, Washington

Correspondence and requests for reprints should be addressed to Trent E. Tipple, M.D., Columbus Children's Research Institute, Columbus Children's Hospital, Department of Pediatrics, The Ohio State University, 700 Children's Drive, Columbus, OH 43205. E-mail: tipplet{at}pediatrics.ohio-state.edu

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% O₂ (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.

Key Words: hyperoxia • glutathione • thioredoxin • auranofin • aurothioglucose

CLINICAL RELEVANCE The initiation of hyperoxic lung injury is not closely correlated with alterations in global thiol/disulfide ratios, and modulation of Trx/TrxR systems might provide therapeutically useful alterations of cellular resistance to oxidant stresses.