Investigation of p21 in the molecular mechanisms of lung injury and pulmonary fibrosis

p21在肺损伤和肺纤维化分子机制中的研究

基本信息

批准号：
15590813
负责人：
FUJITA Masaki
金额：
$ 1.92万
依托单位：
KYUSHU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590813/
关键词：
lung injury pulmonary fibrosis apoptosis p21 肺腺維症ブレオマイシン

项目摘要

1.Transforming Growth Factor-β1 as an Enhancer of Fas-mediated Apoptosis of Lung Epithelial CellsTransforming growth factor-β1(TGF-β1) has important roles in lung fibrosis and the potential to induce apoptosis in several types of cells. We previously demonstrated that apoptosis of lung epithelial cells induced by Fas ligation may be involved in the development of pulmonary fibrosis. Here we show that TGF-β1 induces apoptosis of primary cultured bronchiolar epithelial cells via caspase-3 activation and downregulation of cyclin-dependent kinase inhibitor p21. Concentrations of TGF-β1 that were not sufficient to induce apoptosis alone could enhance agonistic anti-Fas antibody or recombinant Fas ligand-mediated apoptosis of cultured bronchiolar epithelial cells. Soluble Fas ligand in the bronchoalveolar lavage fluid(BALF) from patients with idiopathic pulmonary fibrosis(IPF) also induced apoptosis of cultured bronchiolar epithelial cells that was significantly attenuated by anti-TGF-β anti … More body. Otherwise, BALF from patients with hypersensitivity pneumonitis(HP) could not induce apoptosis on bronchiolar epithelial cells despite its comparable amounts of soluble Fas ligand. The concentrations of TGF-β1 in BALF from patients with IPF were significantly higher compared with those in BALF from patients with HP or controls. Furthermore, co-incubation with the low concentration of TGF-β1 and HP BALF created pro-apoptotic effects comparable to the IPF BALF. In vivo, the administration of TGF-β1 could enhance Fas-mediated epithelial cell apoptosis and lung injury via caspase-3 activation in mice. Our results demonstrate a novel role of TGF-β1 in the pathophysiology of pulmonary fibrosis as an enhancer of Fas-mediated apoptosis of lung epithelial cells.2.In vivo gene transfer of mutant MCP-1 attenuates pulmonary fibrosisAlveolar epithelial cells are known to be present at the primary site of lung damage in pulmonary fibrosis. Apoptosis has been implicated as being involved in epithelial cell damage and pulmonary fibrosis. Since the cyclin-dependent kinase inhibitor p21 induces G1 arrest and DNA repair, and since it also prevents apoptosis in some cells, we hypothesized that p21 gene transfer may attenuate bleomycin-induced pulmonary fibrosis in mice, the pathogenesis of which likely involves epithelial cell apoptosis. Human p21 protein was expressed in mouse alveolar epithelial cells at 1 to 7 days in vitro and was detected predominantly in lung epithelial cells at 1 to 7 days in vivo after adenoviral transfer of the human p21 gene. Inflammatory cell infiltration and fibrosis had already begun at 7 days in this model. Adenoviral transfer of the human p21 gene at 7days after intratracheal instillation of bleomycin led to a decrease in the number of apoptotic cells, lung inflammation and fibrosis at 14 days. Therefore, the forced expression of p21 exerted both anti-apoptotic and anti-fibrotic effects, which would facilitate the ultimate goal of treatment for pulmonary fibrosis. Less

1.转化生长因子-β1作为Fas介导的肺上皮细胞凋亡的增强剂转化生长因子-β1(TGF-β1)在肺纤维化中具有重要作用，并且具有诱导多种类型细胞凋亡的潜力。 Fas连接诱导的肺上皮细胞凋亡可能参与肺纤维化的发生，本研究表明TGF-β1可诱导原代培养的肺上皮细胞凋亡。细支气管上皮细胞通过 caspase-3 激活和细胞周期蛋白依赖性激酶抑制剂 p21 的下调，单独不足以诱导细胞凋亡的 TGF-β1 浓度可以增强激动性抗 Fas 抗体或重组 Fas 配体介导的培养细支气管上皮细胞的细胞凋亡。特发性肺病患者支气管肺泡灌洗液（BALF）中可溶性 Fas 配体纤维化（IPF）还诱导培养的细支气管上皮细胞凋亡，抗TGF-β抗体可显着减弱这种凋亡，而来自过敏性肺炎（HP）患者的BALF尽管数量相当，但不能诱导细支气管上皮细胞凋亡。 IPF 患者 BALF 中的可溶性 Fas 配体的浓度显着高于 HP 患者或对照患者的 BALF 中的浓度。此外，低浓度的 TGF-β1 和 HP BALF 共孵育产生了与 IPF BALF 相当的促凋亡作用。在体内，给予 TGF-β1 可以通过 caspase- 增强 Fas 介导的上皮细胞凋亡和肺损伤。 3 在小鼠中的激活。我们的结果表明 TGF-β1 作为 Fas 介导的肺上皮细胞凋亡的增强剂在肺纤维化的病理生理学中具有新的作用。突变型 MCP-1 的体内基因转移可减轻肺纤维化已知肺泡上皮细胞存在于肺纤维化中肺损伤的主要部位，因为细胞周期蛋白依赖性激酶导致细胞凋亡参与上皮细胞损伤和肺纤维化。抑制剂 p21 诱导 G1 停滞和 DNA 修复，并且由于它还可以防止某些细胞的凋亡，因此我们发现 p21 基因转移可能会减弱博莱霉素诱导的小鼠肺纤维化，其发病机制可能涉及上皮细胞凋亡。体外 1 至 7 天时，人 p21 蛋白在小鼠肺泡上皮细胞中表达，而体内 1 至 7 天时，主要在肺上皮细胞中检测到。在该模型中，在腺病毒转移7天后，炎症细胞浸润和纤维化已经开始。气管内滴注博莱霉素7天后人p21基因导致14天时凋亡细胞数量减少、肺部炎症和纤维化，因此p21的强制表达同时发挥抗凋亡和抗纤维化作用。促进肺纤维化治疗的最终目标。

项目成果

期刊论文数量（43）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Serum CC-10 in Inflammatory Lung Diseases

炎症性肺病中的血清 CC-10

DOI：
发表时间：
2004
期刊：
Respiration 71
影响因子：
0
作者：
Ye Q;et al.
通讯作者：
et al.

Apoptosis signaling pathways in lung diseases.

DOI：
10.2174/1573406053402497
发表时间：
2005
期刊：
Medicinal chemistry (Shariqah (United Arab Emirates))
影响因子：
0
作者：
K. Kuwano;M. Yoshimi;T. Maeyama;N. Hamada;M. Yamada;Y. Nakanishi
通讯作者：
K. Kuwano;M. Yoshimi;T. Maeyama;N. Hamada;M. Yamada;Y. Nakanishi

Induction of CDK inhibitor p21 gene as a new therapeutic strategy against pulmonary fibrosis pulmonary fibrosis

诱导CDK抑制剂p21基因作为抗肺纤维化的新治疗策略肺纤维化

DOI：
发表时间：
2004
期刊：
Am J Physiol Lung Cell Mol Physiol 286
影响因子：
0
作者：
Kuwano K;Yoshimi M;Maeyama T;Hamada N;Yamada M;Nakanishi Y;Inoshima I et al.
通讯作者：
Inoshima I et al.

Anti-monocyte chemoattractant protein-1 gene therapy attenuates pulmonary fibrosis in mice