title: Thioredoxin-deficient mice, a novel phenotype sensitive to ambient air and hypersensitive to hyperoxia-induced lung injury.
abstract: Pulmonary oxygen toxicity is a major clinical problem for patients undergoing supplemental oxygen therapy. Thioredoxin (Trx) is an endogenous antioxidant protein that regenerates oxidatively inactivated proteins. We examined how Trx contributes to oxygen tolerance by creating transgenic mice with decreased levels of functional thioredoxin (dnTrx-Tg) using a dominant-negative approach. These mice showed decreased Trx activity in the lung although the expression of mutant protein is three times higher than the wild-type mice. Additionally, we found that these mice showed increased oxidation of endogenous Trx in room air. When exposed to hyperoxia (>90% O2) for 4 days, they failed to recover and showed significant mortality. Even in normal oxygen levels, these mice displayed a significant decrease in aconitase and NADH dehydrogenase activities, decreased mitochondrial energy metabolism, increased p53 and Gadd45α expression, and increased synthesis of proinflammatory cytokines. These effects were further increased by hyperoxia. We also generated mice overexpressing Trx (Trx-Tg) and found they maintained lung redox balance during exposure to high oxygen and thus were resistant to hyperoxia-induced lung injury. These mice had increased levels of reduced Trx in the lung in normoxia as well as hyperoxia. Furthermore, the levels of aconitase and NADH dehydrogenase activities were maintained in these mice concomitant with maintenance of mitochondrial energy metabolism. The genotoxic stress markers such as p53 or Gadd45α remained in significantly lower levels in hyperoxia compared with dnTrx-Tg or wild-type mice. These studies establish that mice deficient in functional Trx exhibit a phenotype of sensitivity to ambient air and hypersensitivity to hyperoxia.
authors.affiliation: Department of Anesthesiology and Center for Excellence in Cardiovascular Research, Texas Tech University Health Sciences Center, Lubbock, Texas kumuda.das@ttuhsc.edu.
authors.forename: Kumuda C
authors.initials: KC
authors.lastname: Das
mesh_terms: D000154:Aconitate Hydratase / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000388:Air; D000818:Animals; D017209:Apoptosis; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation; D019069:Cell Respiration; D002645:Chickens; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D018496:Hyperoxia / Q000150:complications* / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000201:enzymology / Q000473:pathology; D055370:Lung Injury / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D009245:NADH Dehydrogenase / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010084:Oxidation-Reduction; D010100:Oxygen; D010101:Oxygen Consumption; D010641:Phenotype; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000473:pathology; D016019:Survival Analysis; D013879:Thioredoxins / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000097642:GADD45 Proteins
chemical_list: D000154:Aconitate Hydratase; D000255:Adenosine Triphosphate; D018797:Cell Cycle Proteins; D016207:Cytokines; D018836:Inflammation Mediators; D009245:NADH Dehydrogenase; D009687:Nuclear Proteins; D010100:Oxygen; D013879:Thioredoxins; D016159:Tumor Suppressor Protein p53; C499072:Gadd45a protein, mouse; D000097642:GADD45 Proteins
keywords: hyperoxia; lung injury; redox; thioredoxin-deficient mice