期刊
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
卷 28, 期 6, 页码 682-696出版社
AMER THORACIC SOC
DOI: 10.1165/rcmb.4692
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资金
- NCCIH NIH HHS [AT-00428] Funding Source: Medline
- NHLBI NIH HHS [R01-HL65612, KO8 HL 67913-01A1, P50-HL60290, HL656213] Funding Source: Medline
- NIEHS NIH HHS [P30-ES06096] Funding Source: Medline
- PHS HHS [R01-10562] Funding Source: Medline
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% O-2. Specifically, differential gene expression of > 8,734 sequence-verified murine complementary DNAs was analyzed after 0, 8, 24, and 48 h Of 02 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) II1, 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 O-2. 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.
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