RRC ID 64912
Author Shimada I, Kubota A, Katoh M, Suzuki F.
Title Hyperoxia causes diffuse alveolar damage through mechanisms involving upregulation of c-Myc/Bax and enhanced production of reactive oxygen species.
Journal Respir Investig
Abstract BACKGROUND:Hyperoxia is a known cause of diffuse alveolar damage (DAD). We previously reported the transcript profiling of DAD induced by hyperoxia exposure in mouse lungs and showed that the gene expression of myelocytomatosis oncogene (c-Myc) was significantly upregulated whereas that of surfactant-associated protein (SP)-C was downregulated. However, the mechanism underlying hyperoxia-induced DAD is not well understood.
METHODS:The hyperoxia-induced changes in SP-A/B/C/D, c-Myc, B-cell chronic lymphocytic leukemia/lymphoma (Bcl)-2, and Bcl-2-associated X protein (Bax) expression in mouse lungs were examined by cDNA microarray analysis. The expression levels of the above mentioned genes, cell viability, caspase activity, and reactive oxygen species (ROS) production were also examined in the human lung adenocarcinoma cell line A549 and mouse fibroblast-like cell line NIH/3T3.
RESULTS:Hyperoxia induced a decrease in SP-C/A expression in mouse lungs, and SP-C downregulation was also confirmed in A549 cells. In addition to enhanced c-Myc expression, Bax expression also increased following exposure of the mice to hyperoxia. In vitro analysis showed that expression of these genes is regulated in a cell-type-dependent manner, i.e., upregulation of c-Myc in NIH/3T3 cells and Bax in A549 cells occurred regardless of whether there was a similar decrease in cell viability and increase in caspase-3/7 activation in response to hyperoxia. ROS production and caspase-8 activation were also observed in both cells.
CONCLUSIONS:We concluded that hyperoxia induces ROS production and cell death in lung tissues through a cell-type specific mechanism involving the upregulation of c-Myc/Bax, and caspase-8 and -3/7 activation-dependent pathways, thereby leading to the development of DAD.
Volume 54(1)
Pages 59-68
Published 2016-1-1
DOI 10.1016/j.resinv.2015.08.006
PII S2212-5345(15)00107-0
PMID 26718146
MeSH Animals Caspase 8 / metabolism Cell Death* Cells, Cultured Gene Expression* Humans Hyperoxia / genetics* Hyperoxia / metabolism* Hyperoxia / pathology Mice, Inbred C57BL Proto-Oncogene Proteins c-myc / genetics* Proto-Oncogene Proteins c-myc / metabolism Pulmonary Alveoli / cytology Pulmonary Alveoli / pathology* Reactive Oxygen Species / metabolism* Signal Transduction / genetics Signal Transduction / physiology Up-Regulation* bcl-2-Associated X Protein / genetics* bcl-2-Associated X Protein / metabolism
Human and Animal Cells NIH/3T3(RCB2767)