| Project/Area Number |
05454254
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| Research Category |
Grant-in-Aid for General Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Respiratory organ internal medicine
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| Research Institution | JICHI MEDICAL SCHOOL |
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Principal Investigator |
KITAMURA Satoshi JICHI MEDICAL SCHOOL,DEPT.OF PULMONARY MEDICINE,PROFESSOR, 医学部, 教授 (60010427)
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| Co-Investigator(Kenkyū-buntansha) |
KOBAYASHI Jun JICHI MEDICAL SCHOOL,DEPT.OF PULMONARY MEDICINE,ASSISTANT PROFESSOR, 医学部, 講師 (90195785)
SUGAMA Yasuo JICHI MEDICAL SCHOOL,DEPT.OF PULMONARY MEDICINE,ASSISTANT PROFESSOR, 医学部, 講師 (20187636)
ISHII Yoshiki JICHI MEDICAL SCHOOL,DEPT.OF PULMONARY MEDICINE,ASSISTANT PROFESSOR, 医学部, 講師 (20254914)
大野 彰二 自治医科大学, 医学部, 講師 (40203880)
杉山 幸比古 自治医科大学, 医学部, 助教授 (70183415)
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| Project Period (FY) |
1993 – 1995
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| Project Status |
Completed (Fiscal Year 1995)
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| Budget Amount *help |
¥6,500,000 (Direct Cost: ¥6,500,000)
Fiscal Year 1995: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1994: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1993: ¥4,500,000 (Direct Cost: ¥4,500,000)
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| Keywords | ADHESION MOLECULES / ACUTE LUNG INJURY / CD18 / ICAM-1 / VASCULAR ENDOTHELIAL CELL / LEUKOCYTE / CYTOKINES / 接着分子 / ICAM-1 / CD18 / エンドトキシン / 接着阻害療法 / 好中球 / ARDS / 急性肺損傷 / びまん性肺疾患 / サルコイドーシス / 放射線肺臓炎 |
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| Research Abstract |
Neutrophils (PMN) are important effector cells in the pathophysiology of acute lung injury. By various stimuli, circulating neutrophils adhere to vascular endothelial cells and transmigrate to the interstitium. In these steps, PMN are activated and release reactive oxygen species (ROI) and proteases, which cause increase in endothelial permeability and tissue injury. Adhesion molecules play a central role in these neutrophil-mediated mechanisms of lung injury. Using an endothelial monolayr system for in vitro permeability assay, we examined whether the increase in vascular endothelial permeability is dependent on adhesion of PMN to endothelial cells via ahdesion molecules (through the CD18 integrin on PMN and ICAM-1 on the endothelium) and it is mediated by the toxic mediators, such as hydrogen peroxide and neutrophil elastase, released from PMN.Lechitinized-SOD and elastase inhibitors (ONO-5046 and urinastatin) decreased PMA-stimulated PMN-mediated increase in endothelial permeability
… More
. The inhibition of PMN adhesion to endothelial cells using an anti-CD18 mAb or an anti-adhesion agent, leumedin, also blocked the PMN-mediated increase in endothelial permeability. Theses findings indicated that the adhesion event is critical in mediating the PMN-dependent increase in vascular endothelial permeability. We also examined the effect of transmigration of PMN on endothelial barrier function. PMN-migration through endothelial monolayrs induced by the concentration gradient of IL-8 did not increase the endothelial permeability by itself, but it did increase the permeability when endothelial monolayr was pretreated with low concentration of TNFa. This effect of TNFa was inhibited by an anti-CD18 mAb.
Recently, it has been reported that reactive oxygen intermediates (ROI), such as hydrogen peroxide, play an important role in the pathophysiology of acute lung injury not only as a terminal effector, but also as a second messenger of signal transduction pathway. We investigated the role of ROI in the mechanism of adhesion molecule expression. N-acetylcysteine (NAC), an antioxidant, decreased the TNFa-induced expression of intercellular adhesion molecule-1 (ICAM-1) on the cultured human bronchial epithelial cells (BEAS-2B). NAC also attenuated the intratracheal LPS-induced PMN sequestration and ICAM-1 expression in rat lungs. These findings suggest that adhesion molecule expression in lung is mediated by the production of ROI.NF-kB activation may be involved in this pathway.
Since adhesion molecules play a crucial role in the pathophysiology of neutrophil-mediated acute lung injury, the inhibition of adhesion using anti-oxidants like NAC as well as monoclonal antibodies against adhesion molecules may be useful therapeutic agents. Less
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