To investigate the molecular mechanisms of pulmonary fibrosis and the development of treatment strategy

探讨肺纤维化的分子机制及制定治疗策略

• 批准号: 13470127
• 负责人: HARA Nobuyuki
• 金额: $ 9.41万
• 依托单位: Kyushu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470127/
• 关键词: pulmonary fibrosis; apoptosis; lung epithelium; lung fibroblast; Fas; TGF-beta; p21; mitochondria; p27; アデノウイルス; FLIP

1. Resistance to Fas-mediated apoptosis in lung fibroblastsFas-mediated apoptosis was upregulated in pulmonary fibrosis. However, Fibroblasts are not sensitive against this pathway. We found that IAP and FLIP upregulation may be involved in this resistance.2. Apoptosis and TGF-beta in pulmonary fibrosisWe found that TFG-beta can induce apoptosis in lung epithelial cells and also synergistic effects with Fas. This result is very important because BALF from patients with IPF induced apoptosis in lung epithelial cells in vitro, which is dependent on TGF-beta and Fas. We also found that TGF-beta and Fas have synergistic effects on epithelial cell apoptosis and survival in mice.3. Anti-apoptotic effect of p21 , but not p27Adenoviral transfer of CDKI p21 inhibited apoptosis induced by TGF-beta or FasL in lung epithelial cells through inhibition of the caspase-3 activation. However, p27 did not inhibited apoptosis in epithelial cells. Adenoviral transfer of p21 attenuated apoptosis, inflammation, and pulmonary fibrosis in bleomycin-induced pneumopathy in mice. Adenoviral gene transfer of p21 may be a new strategy against pulmonary fibrosis in human.4. Mitochondria-mediated apoptosis and pulmonary fibrosisWe examined whether mitochondria-mediated apoptosis Is involved in the pathogenesis of pulmonary fibrosis. We round that release of cytochrome c from mitochondria and the caspase-9 activation is present in lung tissues from patients with IPF. We conclude that not only death receptor-mediated but alaso mitochondria-mediated apoptosis is involved in the pathophysiology of pulmonary fibrosis

1. 肺成纤维细胞对fas介导的细胞凋亡的抵抗fas介导的细胞凋亡在肺纤维化中上调。然而，成纤维细胞对这一途径并不敏感。我们发现IAP和FLIP的上调可能参与了这种抗性。我们发现tgf - β可诱导肺上皮细胞凋亡，并与Fas有协同作用。这一结果非常重要，因为来自IPF患者的BALF在体外诱导肺上皮细胞凋亡，这依赖于tgf - β和Fas。我们还发现tgf - β和Fas对小鼠上皮细胞凋亡和存活具有协同作用。腺病毒转染CDKI后，p21通过抑制caspase-3的激活，抑制tgf - β或FasL诱导的肺上皮细胞凋亡。然而，p27不抑制上皮细胞的凋亡。p21的腺病毒转移减轻了博莱霉素诱导的小鼠肺炎的细胞凋亡、炎症和肺纤维化。腺病毒p21基因转移可能是治疗人肺纤维化的新策略。线粒体介导的细胞凋亡和肺纤维化我们研究了线粒体介导的细胞凋亡是否参与肺纤维化的发病机制。我们发现线粒体中细胞色素c的释放和IPF患者肺组织中caspase-9的活化存在。我们得出结论，不仅死亡受体介导，线粒体介导的细胞凋亡也参与肺纤维化的病理生理过程

项目成果

Kuwano K, Hagimoto N, et al.: "Oxidative stress in lung epithelial cells from patients with idiopathic interstital pneumonias"European Respitratory Journal. 21. 232-240 (2003)

Kuwano K、Hagimoto N 等人：“特发性间质性肺炎患者肺上皮细胞的氧化应激”欧洲呼吸杂志。

Tanaka T, Kuwano K, et al.: "Resistance to Fas-mediated apoptosis in human lung fibroblast"Europen Respiratory Journal. 20. 359-368 (2002)

Tanaka T、Kuwano K 等人：“人肺成纤维细胞对 Fas 介导的细胞凋亡的抵抗”欧洲呼吸杂志。

Hagimoto N, Kuwano K, et al.: "TGF-beta1 as an enhancer of Fas-mediated apoptosis of lung epithelial cells"Journal of Immunology. 168. 6470-6478 (2002)

Hagimoto N、Kuwano K 等人：“TGF-β1 作为 Fas 介导的肺上皮细胞凋亡的增强剂”免疫学杂志。

Kuwano K, Hagimoto N, et al.: "Mitochondria-mediated apoptosis of lung epithelial cells in idiopathic interstitial pneumonias"Laboratory Investigation. 82. 1695-1706 (2002)

Kuwano K、Hagimoto N 等人：“特发性间质性肺炎中线粒体介导的肺上皮细胞凋亡”实验室研究。

Hagimoto N, Kuwano K, et al.: "TGF-beta1 as enhancer of Fas-mediated apoptosis of lung epithelial"Journal of Immunology. 168. 6470-6478 (2002)

Hagimoto N、Kuwano K 等人：“TGF-β1 作为 Fas 介导的肺上皮细胞凋亡的增强剂”免疫学杂志。