| Project/Area Number |
16591919
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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 |
Conservative dentistry
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| Research Institution | Kagoshima University |
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Principal Investigator |
SUWA Motoko Kagoshima University, University Hospital, Faculty of Medicine and Dentistry, Research Associate, 医学部・歯学部附属病院, 助手 (80206599)
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| Co-Investigator(Kenkyū-buntansha) |
TOKUDA Masayuki Kagoshima University, University Hospital, Faculty of Medicine and Dentistry, Assistant Professor, 医学部・歯学部附属病院, 講師 (20253891)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2004: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | dental pulp cell / protease-activated receptor / PAR / neuropeptide / mitogen-activated protein kinase / activator protein-1 / pain / pulpitis / MARK |
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| Research Abstract |
Gingipains, cysteine proteinases which are produced by Porphyromonas gingivalis, a causative bacterium of periodontitis. We hypothesized gingipains affect human pulpal cell(HPC)and trigger release of proinflammatory substances. HPC expressed only protease-activated receptor(PAR-2) and an antisense nucleotide directed against PAR-2 caused a complete loss of the gingipains-induced PAR-2 mRNA as determined by RT PCR. Gingipains, Kgp and RgpB, dose- and time-dependently induced calcitonin gene related peptide(CGRP) and Substance P(SP) production as determined by ELISA. The RgpB effect was clearly reduced by leupeptin, a potent gingipains inhibitor. Gingipains-induced release of CGRP and SP was inhibited by PAR-2 antisense oligonucleotides but not by a sense control as judged by ELISA. CGRP and SP were produced by PAR-2 agonist peptide SLIGKV, suggesting that gingipains-induced CGRP and SP production is mediated by PAR-2 activation. The western blot analysis showed that gingipains triggered
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the activation of extracellular protein, kinase 1/2 and p38 MAPK but not Jun N-terminal kinase (JNK). U0126, a specific inhibitor of MEK 1/2, abolished gingipains-induced CGRP and SP production. SB 203580, a specific inhibitor of p38 MAPK attenuated gingipains induced-CGRP and SP production. Our, data demonstrate, for the first time, that gingipains activate PAR-2 and induce production of CGRP and SP in HPC via ERK 1/2 and p38 activation, leading to an important role in the development of acute pulpitis.
We also examined the effect of nafamostat mesilate(Fut-175) as PAR-2 antagonist. We got following results. 1.Fut-175 inhibited protease activity of RgpB in dose-dependency. 2.Fut-175 inhibited RgpB-induced SP detected by enzyme-linked immunosorbent assay. 3.Fut-175 inhibited the immunoresponsibility to SP in HPC. These results indicate Fut-175 is possible to be anti-pain drug to dental pulpitis-derived inflammatory pain. We could not determined the relationship of PAR to the tissue regeneration. Less
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