期刊
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
卷 41, 期 6, 页码 742-755出版社
AMER THORACIC SOC
DOI: 10.1165/rcmb.2008-0157OC
关键词
inflammation; lung injury; neutrophils; proteinase; mitochondria
资金
- Canadian Institutes of Health Research
- National Institutes of Health [R01 HL090669]
- National Jewish Health
Leukocyte elastase induces apoptosis of lung epithelial cells via alterations in mitochondrial permeability, but the signaling pathways regulating this response remain uncertain. Here we investigated the involvement of proteinase-activated receptor-1 (PAR-1), the transcription factor NF-kappa B, and the protooncogene p53 in this pathway. Elastase-induced apoptosis of lung epithelial cells correlated temporally with activation of NF-kappa B, phosphorylation, and nuclear translocation of p53, increased p53 up-regulated modulator of apoptosis (PUMA) expression, and mitochondrial translocation of Bax resulting in enhanced permeability. Elastase-induced apoptosis was also prevented by pharmacologic inhibitors of NF-kappa B and p53 and by short interfering RNA knockdown of PAR-1, p53, or PUMA. These inhibitors prevented elastase-induced PUMA expression, mitochondrial translocation of Bax, increased mitochondrial permeability, and attenuated apoptosis. NF-kappa B inhibitors also reduced p53 phosphorylation. We conclude that elastase-induced apoptosis of lung epithelial cells is mediated by a PAR-1-triggered pathway involving activation of NF-kappa B and p53, and a PUMA- and Bax-dependent increase in mitochondrial permeability leading to activation of distal caspases. Further, p53 contributes to elastase-induced apoptosis by both transcriptional and post-transcriptional mechanisms.
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