Bcl-2 Family Gene Expression during Severe Hyperoxia Induced Lung Injury

Abstract

SUMMARY:Exposure of the lung to severe hyperoxia induces terminal transferase dUTP end-labeling (TUNEL) indicative of DNA damage or apoptosis and increases expression of the tumor suppressor p53 and of members of the Bcl-2 gene family. Because cell survival and apoptosis are regulated, in part, by the relative abundance of proteins of the Bcl-2 family, we hypothesized that lung cells dying during exposure would show increased expression of pro-apoptotic members, such as Bax, whereas surviving cells would have increased expression of anti-apoptotic members, such as Bcl-X L . The hypothesis is tested in the current study by determining which Bcl-2 genes are regulated by hyperoxia, with specific focus on correlating expression of Bax and Bcl-X L with morphologic evidence of apoptosis or necrosis. Adult mice exposed to greater than 95% oxygen concentrations for 48 to 88 hours had increased whole-lung mRNA levels of Bax and Bcl-X L , no change in Bak, Bad, or Bcl-2, and decreased levels of Bcl-w and Bfl-1. In situ hybridization revealed that hyperoxia induced Bax and Bcl-X L mRNA in uniform and overlapping patterns of expression throughout terminal bronchioles and parenchyma, coinciding with TUNEL staining. Electron microscopy and DNA electrophoresis, however, suggested relatively little classical apoptosis. Unexpectedly, Western analysis demonstrated increased Bcl-X L , but not Bax, protein in response to hyperoxia. Bax and Bfl-1 were not altered by hyperoxia in p53 null mice; however, oxygen toxicity was not lessened by p53 deficiency. These findings suggest that oxygen-induced lung injury does not depend on the relative expression of these

Effect of Short-term Exposure of Different Concentrations of Hyperoxia on Fetal Alveolar Type II Cell Death

“…However, hyperoxia can generate lung injury [3][4][5][6][7] , which is known well as a major contributing factor to the development of BPD. Importantly, hyperoxia has a main biological effect of cell death 8) .…”

The Role of Angiopoietin 2 in Hyperoxia-Inuduced Acute Lung Injury

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“…27,39,40 The dose and/or duration of hyperoxia exposure can cause different cell types in the lung to undergo death via distinct or overlapping mechanisms. Recent studies from our laboratory and others have added to this pathogenic paradigm by demonstrating that ROS mediate their effects, in part, by inducing an endothelial and epithelial cell death response with features of apoptosis and necrosis 6,20,21,25,36,41,42 and that a variety of exogenously administered regulators inhibit these toxic events by regulating local cell death responses. 5,6,20 In addition, although structural cell apoptosis (such as that seen in HALI) can stimulate tissue inflammation, 43,44 hyperoxia-induced inflammation cannot be attributed solely to the nearby cell death response.…”

Comparison of mammary gland involution between 129S1 and C57BL/6 inbred mouse strains: differential regulation of Bcl2a1, Trp53, Cebpb, and Cebpd expression

“…In view of the changed tissue composition on day 3 compared to days 0 and 1, this expression may reflect highly induced levels in epithelial cells and/or in adipocytes of either strain. Bcl2a1 also suppresses apoptosis induced by the tumor suppressor Trp53 (D' Sa-Eipper et al, 1996) and its expression may itself be regulated by Trp53 (O'Reilly et al, 2000). This observation prompted us to investigate expression of the proapoptotic Trp53 gene.…”