Nitric oxide-dependent activation of p53 suppresses bleomycin-induced apoptosis in the lung.
Nitric oxide-dependent activation of p53 suppresses bleomycin-induced apoptosis in the lung.
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DOI：
10.1084/jem.192.6.857
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发表时间：
2000-09-18
期刊：
影响因子：
--
通讯作者：
McConkey DJ
中科院分区：
文献类型：
--
作者：
Davis DW;Weidner DA;Holian A;McConkey DJ
Chronic inflammation leading to pulmonary fibrosis develops in response to environmental pollutants, radiotherapy, or certain cancer chemotherapeutic agents. We speculated that lung injury might be mediated by p53, a proapoptotic transcription factor widely implicated in the response of cells to DNA damage. Intratracheal administration of bleomycin led to caspase-mediated DNA fragmentation characteristic of apoptosis. The effects of bleomycin were associated with translocation of p53 from the cytosol to the nucleus only in alveolar macrophages that had been exposed to the drug in vivo, suggesting that the lung microenvironment regulated p53 activation. Experiments with a thiol antioxidant (N-acetylcysteine) in vivo and nitric oxide (NO) donors in vitro confirmed that reactive oxygen species were required for p53 activation. A specific role for NO was demonstrated in experiments with inducible nitric oxide synthase (iNOS)−/− macrophages, which failed to demonstrate nuclear p53 localization after in vivo bleomycin exposure. Strikingly, rates of bleomycin-induced apoptosis were at least twofold higher in p53−/− C57BL/6 mice compared with heterozygous or wild-type littermates. Similarly, levels of apoptosis were also twofold higher in the lungs of iNOS−/− mice than were observed in wild-type controls. Consistent with a role for apoptosis in chronic lung injury, levels of bleomycin-induced inflammation were substantially higher in iNOS−/− and p53−/− mice compared with wild-type controls. Together, our results demonstrate that iNOS and p53 mediate a novel apoptosis-suppressing pathway in the lung.
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影响因子：
11.4
作者：
Asada, M;Yamada, T;Mizutani, S
通讯作者：
Mizutani, S
影响因子：
11.4
作者：
Asada, M;Yamada, T;Mizutani, S
通讯作者：
Mizutani, S
影响因子：
8
作者：
Griffiths, SD;Clarke, AR;Greaves, M
通讯作者：
Greaves, M
DOI：
10.1164/ajrccm.158.2.9711075
发表时间：
1998-08-01
影响因子：
24.7
作者：
Jones, HA;Schofield, JB;Haslett, C
通讯作者：
Haslett, C
DOI：
10.1083/jcb.119.3.493
发表时间：
1992-11
期刊：
The Journal of cell biology
影响因子：
--
作者：
Gavrieli Y;Sherman Y;Ben-Sasson SA
通讯作者：
Ben-Sasson SA