title: Gene expression profiling of the early pulmonary response to hyperoxia in mice.
abstract: 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) Pi1, GST mu2, 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-XL 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.
authors.affiliation: Department of Clinical Studies-Philadelphia, School of Veterinary Medicine, University of Pennsylvania, 3850 Spruce Street, Philadelphia, PA 19104-6010, USA. perksz@mail.vet.upenn.edu
authors.forename: Sandra
authors.initials: S
authors.lastname: Perkowski
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.forename: Sunil
authors.initials: S
authors.lastname: Singhal
authors.forename: Jose
authors.initials: J
authors.lastname: Santiago
authors.forename: George D
authors.initials: GD
authors.lastname: Leikauf
authors.forename: Steven M
authors.initials: SM
authors.lastname: Albelda
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics; D002374:Catalase / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D004727:Endothelium / Q000166:cytology / Q000502:physiology; D004798:Enzymes / Q000235:genetics / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D005979:Glutathione Peroxidase / Q000235:genetics; D018496:Hyperoxia / Q000235:genetics* / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000502:physiology* / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D020411:Oligonucleotide Array Sequence Analysis; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000235:genetics; D013997:Time Factors
chemical_list: D000975:Antioxidants; D004798:Enzymes; D016326:Extracellular Matrix Proteins; D018836:Inflammation Mediators; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase