| Project/Area Number |
09670628
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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 | Keio University |
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Principal Investigator |
YAMAGUCHI Kazuhiro DEPARTMENT OF MEDICINE, SCHOOL OF MEDICINE, KEIO UNIVERSITY, ASSISTANT PROFESSOR, 医学部, 講師 (30129712)
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| Co-Investigator(Kenkyū-buntansha) |
KAZUMI Nishio DEPARTMENT OF MEDICINE, SCHOOL OF MEDICINE, KEIO UNIVERSITY, INSTRUCTOR, 内科, 医員 (10255458)
SATO Nagato DEPARTMENT OF MEDICINE, SCHOOL OF MEDICINE, KEIO UNIVERSITY, INSTRUCTOR, 内科, 医員 (20265797)
NAOKI Katsuhiko DEPARTMENT OF MEDICINE, SCHOOL OF MEDICINE, KEIO UNIVERSITY, INSTRUCTOR, 医学部・内科, 助手 (40265806)
鈴木 浩一 慶應義塾大学, 医学部, 助手 (40245486)
青木 琢也 慶應義塾大学, 医学部, 助手 (70255438)
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| Project Period (FY) |
1997 – 1999
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| Project Status |
Completed (Fiscal Year 1999)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 1999: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1998: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1997: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Keywords | hypercapnic acidosis / isocapnic acidosis / ecNOS / iNOS / COX-1 / COX-2 / hyperoxia-injured lung / vascular paralysis / 構造型NOS / 誘導型NOS / 構造型ミクオロキシゲナーゼ / 誘導型ミクロオキシゲナーゼ / 高濃度酸素暴露損傷肺 / 肺細某 / 共焦点レーザ顕微鏡 / Permissive hypercapnia / 細葉 / 細動脈 / 細静脈 / 毛細血管 / COX / NOS |
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| Research Abstract |
Impairment of the acinar microvessel response to profound acidosis in injured lungs has not been vigorously analyzed despite the importance of knowledge about it when treating patients with lung injury by permissive hypercapnia. Real-time confocal luminescence microscopy was used to measure changes in the diameter of arterioles, venules, and capillaries in response to stimulation with hypercapnic and isocapnic acidosis in isolated rat lungs injured by 90% OィイD22ィエD2 exposure for 48 hours. Observations were made with and without inhibition of constitutive isoforms of endothelial nitric oxide (NO) synthase (ecNOS) and cyclooxygenase (COX-1), and of inducible isoforms of NOS (iNOS) and COX (COX-2). The effect of excessive NO generated by nitroprusside on acidosis-elicited microvessel diameter changes was also investigated. Upregulation of NOS was estimated by measuring the enzyme protein content of lung homogenates by Western blot analysis, and enhancement of COX-related pathway was judged from perfusate concentrations of 6-keto-prostaglandin FィイD21ィエD2α. We found that ecNOS and COX-1, but not iNOS and COX-2, are upregulated in hyperoxia-injured lungs. The NO produced by ecNOS negatively modulates COX-1 activity in injured arterioles and venules, but COィイD22ィエD2 positively modulates it, leading to paradoxical dilatation of these microvessels under hypercapnic conditions with ecNOS inhibition. The NO-dependent COX-1 inhibition is confined to acinar microvessels, while NO excites COX-1 in other lung regions. High concentrations of COィイD22ィエD2, but not HィイD1+ィエD1, appear to be indispensable for excitation of COX-1. COX-1 inhibition enhances venule constriction in response to HィイD1+ィエD1. In conclusion, NOS inhibition may be useful in the clinical management of patients with permissive hypercapnic, but COX inhibition may not.
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