| Project/Area Number |
14570568
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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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 | Nihon University |
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Principal Investigator |
HASHIMOTO Shu Nihon University, School of Medicine, Assistant Professor, 医学部, 講師 (30159090)
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| Co-Investigator(Kenkyū-buntansha) |
HORIE Takashi Nihon University, School of Medicine, Professor, 医学部, 教授 (60090081)
SHIMIZU Kazufumi Nihon University, School of Medicine, Professor, 医学部, 教授 (50004677)
権 寧博 日本大学, 医学部, 助手 (80339316)
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| Project Period (FY) |
2002 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2004: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2003: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2002: ¥1,200,000 (Direct Cost: ¥1,200,000)
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| Keywords | COPD / bronchial asthma / MAP kinase / ASK1 / airway epithelial cell / oxidative stress / 気道平滑筋 / 気道炎症 / 気道リモデリング / 肺血管内皮細胞 / MAPキナーゼ / アポトーシス / 喫煙 / MMP9 / TIMP |
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| Research Abstract |
Airway epithelial cells(AEC) participate in the production of airway inflammation by expressing various cytokines. Many extracellular stimuli elicit specific biological responses through activation of mitogen-activated protein kinase(MAPK), ERK, p38 MAPK and c-Jun-NH2-terminal kinase(JNK), cascades. Each MAPK is activated by distinct upstream kinase. MEKK1-4, ASK1 and TAK1 were identified as a member of the MAPK kinase kinase(MAPKKK) family that activates SEK1/MKK7-JNK and MKK3/MKK6-p38 MAPK pathways. We have examined the role of MAPK cascades in transcription activation, cytokine expression and cell apoptosis in AEC in response to various stimuli, including cigarette smoking extract(CSE), hydrogen peroxide. In addtion, the role of ASK1 in the induction of AP-1 activation in human airway smooth muscle cells(ASMC). The results shoed that 1)CSE activate ASK1-p38 MAPK to express MMP-9 in AEC, 2)hydrogen peroxide activates ASK1 to induce cell apoptosis via caspase-3,and 3)LTD4 activates ASK1 to induce AP-1 activation in ASMC. These results indicate that ASK1 plays a crucial role in the production of airway inflammation of COPD and bronchial asthma. The analysis of signaling pathway leading to transcription factor activation and cytokine expression, and its regulation may be beneficial in therapeutic strategy of airway inflammation.
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