2002 Fiscal Year Final Research Report Summary
To investigate the molecular mechanisms of pulmonary fibrosis and the development of treatment strategy
| Project/Area Number |
13470127
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Respiratory organ internal medicine
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| Research Institution | Kyushu University |
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Principal Investigator |
HARA Nobuyuki Kyushu University, Graduate School of Medical Sciences, professor, 大学院・医学研究院, 教授 (90038802)
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| Co-Investigator(Kenkyū-buntansha) |
FUJITA Masaki Kyushu University, Graduate School of Medical Sciences, assistant, 医学部附属病院, 助手 (50325461)
HAGIMOTO Naoki Kyushu University, Graduate School of Medical Sciences, assistant, 大学院・医学研究院, 助手 (50315074)
KUWANO Kazuyoshi Kyushu University, Graduate School of Medical Sciences, lecturer, 医学部附属病院, 講師 (40205266)
SUEISHI Katsuo Kyushu University, Graduate School of Medical Sciences, professor, 大学院・医学研究院, 教授 (70108710)
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| Project Period (FY) |
2001 – 2002
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| Keywords | pulmonary fibrosis / apoptosis / lung epithelium / lung fibroblast / Fas / TGF-beta / p21 / mitochondria |
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| Research Abstract |
1. Resistance to Fas-mediated apoptosis in lung fibroblasts
Fas-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 fibrosis
We 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 p27
Adenoviral 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 fibrosis
We 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
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