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Gene Expression Profiling of the Early Pulmonary Response to Hyperoxia in Mice

Department of Clinical Studies-Philadelphia, School of Veterinary Medicine, and Department of Medicine, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and Center for Environmental Genetics, University of Cincinnati, Cincinnati, Ohio

Address correspondence to: Sandra Perkowski, V.M.D., Ph.D., Dept. of Clinical Studies-Philadelphia, School of Veterinary Medicine, University of Pennsylvania, 3850 Spruce Street, Philadelphia, PA 19104-6010. E-mail: perksz{at}mail.vet.upenn.edu

To identify molecular events occurring during the early response to hyperoxia, we measured changes over time in total lung gene expression in C57BL/6 mice during prolonged exposure to > 95% O₂. Specifically, differential gene expression of > 8,734 sequence-verified murine complementary DNAs was analyzed after 0, 8, 24, and 48 h of O₂ exposure, with additional genes of interest analyzed at 24 h. Of the 385 genes differentially expressed, hyperoxia increased expression of 175 genes (2.0%) and decreased expression of 210 genes (2.3%). The majority of "classic" antioxidant enzymes, including catalase, MnSOD, and Cu-Zn SOD, showed no change in expression during hyperoxia, with a number of other antioxidant enzymes, including glutathione peroxidase, glutathione-S-Transferase (GST) 1, GST µ2, and heme oxygenase-1 showing relatively moderate increases. The exception was the heavy metal–binding protein metallothionein, which increased expression over 7-fold after 48 h of O₂. We found no change in the expression of a number of known proinflammatory genes after 24 or 48 h of hyperoxia. A large increase in p21 expression was demonstrated, suggesting overall inhibition of cell cycle progression. Increases of the antiapoptotic gene Bcl-X_L were counterbalanced by similar increases of the proapoptotic gene BAX. New findings included significant increases in expression of cysteine-rich protein 61(cyr61) at 48 h, suggesting a potential role for this factor in angiogenesis or remodeling of the extra cellular matrix during recovery from hyperoxia. In addition, downregulation of thrombomodulin expression occurred by 24 h and was further decreased at 48 h. Given the importance of thrombomodulin/thrombin interaction in regulating protein C activity, decreases in thrombomodulin may contribute to activation of the coagulation and inflammatory cascades and development of lung injury with hyperoxia.

Abbreviations: activator protein-1, AP-1 • activator protein C, APC • antioxidant response element, ARE • complementary DNA, cDNA • cysteine-rich protein 61, cyr61 • expressed sequence tags, ESTs • glyceraldehyde-3-phosphate dehydrogenase, GAPDH • glutathione peroxidase, GPx • glutathione reductase, GRed • oxidized glutathione, GSSG • glutathione-S-transferase, GST • heme oxygenase-1, HO-1 • intercellular adhesion molecule-1, ICAM-1 • interferon, IFN • interleukin, IL • IFN-–inducible protein 10, IP-10 • ribosomal protein L32, L32 • lipopolysaccharide, LPS • macrophage inflammatory protein, MIP • messenger RNA, mRNA • metallothionein, MT • nitric oxide synthase, NOS • nuclear factor B, NF-B • plasminogen activator inhibitor-1, PAI-1 • platelet endothelial cell adhesion molecule-1, PECAM-1 • reactive oxygen species, ROS • RNAse protection assay, RPA • reverse transcriptase-polymerase chain reaction, RT-PCR • superoxide dismutase, SOD • transforming growth factor, TGF • thrombomodulin, TM • tumor necrosis factor, TNF

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