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Assessment for the mechanisms of anti-apoptotic effects of transcription factor MafB in alveolar macrophages of emphysematous lungs induced by cigarette smoke exposure

转录因子MafB对香烟烟雾诱导的肺气肿肺肺泡巨噬细胞抗凋亡作用的机制评估

基本信息

批准号：
18590835
负责人：
SHIBATA Yoko
金额：
$ 2.53万
依托单位：
Yamagata University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590835/
关键词：
alveolar macrophage transcription factor MafB cigarette smoking pulmonary emphysema 肺胞マクロフィージ

项目摘要

Cigarette smoking is the most common risk factor for the development of chronic obstructive pulmonary disease (COPD), a severe worldwide medical problem. COPD is characterized physiologically by various levels of airflow obstruction, and pathologically by findings of pulmonary emphysema. In the lungs of smokers, oxidative stress rises due to increase of free radicals and oxidants. The functions of alveolar macrophages (Ams) are altered in such an environment, and their survival is prolonged against toxicities of cigarette smoke (CS) by an unknown mechanism. We previously demonstrated that transcriptional factor MafB was upregulated in Ams from CS-exposed mice. DNA binding capacity of MafB for Maf recognition element was also increased in Ams from those mice. Furthermore, we established a macrophage cell line that can overexpress MafB, and thereby clarified the role of MafB. Forced expression of MafB heightened cell viability and attenuated the occurrence of apoptosis in cells treated w … More ith CS-extract. After CS exposure Caspase-3 activity was inhibited in MafB overexpressing cells compared to control cells, while the release of cytochrome c in MafB overexpressing cells was not different from those of control cells. mRNA expression of caspase-3 was not altered by MafB overexpression. On the other hand, modulator of apoptosis 1 (Moap1) gene expression was significantly reduced by MafB overexpression. The expressions of other genes which are regulating caspase-3 activity, such as activated factor 1 (Apaf1), p21^<CIP1/WAF1>, BclX_L, and Bax, remained unchanged. These results suggest that enhanced MafB expression by oxidative stress inhibits AM cell death through caspase pathway, not through mitochondrial pathway.In order to evaluate the role of MafB further, we currently establish dominant-negative MafB expressing mice under the control of human scavenger receptor promoter that enables specific gene expression only in macrophages (manuscript under preparation). Using this mouse, we are assessing the role of MafB in vivo. Less

吸烟是慢性阻塞性肺疾病（COPD）发展的最常见危险因素，COPD是一个严重的全球性医学问题。COPD在生理上的特征在于不同程度的气流阻塞，在病理上的特征在于肺气肿的发现。在吸烟者的肺中，由于自由基和氧化剂的增加，氧化应激上升。肺泡巨噬细胞（Ams）的功能在这样的环境中被改变，并且它们的存活通过未知的机制被延长以对抗香烟烟雾（CS）的毒性。我们以前证明，转录因子MafB上调从CS暴露的小鼠的Ams。在这些小鼠的Ams中，MafB对Maf识别元件的DNA结合能力也增加。此外，我们建立了一个巨噬细胞系，可以过表达MafB，从而阐明MafB的作用。MafB的强制表达提高了细胞活力，并减弱了用抗肿瘤药物处理的细胞中凋亡的发生。 ...更多信息 CS-浸提液。CS曝光后，Caspase-3活性被抑制在MafB过表达细胞相比，对照细胞，而释放的细胞色素c在MafB过表达细胞与对照细胞没有什么不同。MafB过表达不改变caspase-3的mRNA表达。另一方面，凋亡调节因子1（Moap 1）基因表达显着降低MafB过表达。其他调节caspase-3活性的基因如活化因子1（Apaf 1）、p21^<CIP 1/WAF 1>、BclX_L和Bax的表达保持不变。这些结果表明，MafB的表达增强通过caspase途径抑制AM细胞死亡，而不是通过线粒体途径。为了进一步评估MafB的作用，我们目前建立了显性负性MafB表达小鼠，该小鼠在人清道夫受体启动子的控制下，使特定的基因仅在巨噬细胞中表达（手稿正在编写中）。使用这种小鼠，我们正在评估MafB在体内的作用。少