2000 Fiscal Year Final Research Report Summary
抗炎症薬による胃損傷誘発・潰瘍治癒遅延作用とそれらの機序の分子レベルでの解明
| Project/Area Number |
11470490
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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 |
Biological pharmacy
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| Research Institution | Kyoto Pharmaceutical University |
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Principal Investigator |
OKABE Susumu Kyoto Pharmaceutical University, Department of Applied Pharmacology, Professor, 薬学部, 教授 (90012624)
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| Co-Investigator(Kenkyū-buntansha) |
AMAGASE Kikuko Kyoto Pharmaceutical University, Department of Applied Pharmacology, Research Associate, 薬学部, 助手 (60278447)
TAKAHASHI Satoru Kyoto Pharmaceutical University, Department of Applied Pharmacology, Associate Professor, 薬学部, 助教授 (20268098)
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| Project Period (FY) |
1999 – 2000
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| Keywords | NSAID / Mongolian gerbil / Cytokines / Aceti acid ulcer / Helicobacter pylori / Angiogenesis / Prostaglandin / Delayed ulcer healing |
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| Research Abstract |
It is known that Helicobacter pylori (H.pylori) infection or repeated administration of indomethacin delays the healing of experimental gastric ulcers (including acetic acid ulcers). Treatment with indomethacin or H.pylori (cag A and vac A positive) for 2 weeks to gerbils with ulcers tended to delay the ulcer healing. On the other hand, treatment with indomethacin to H.pylori-infected gerbils significantly delayed the ulcer healing. After 4-wk treatment, the healing of gastric ulcers was significantly delayed by H.pylori alone and H.pylori+indomethacin. However, there was no significant difference between H.pylori-infected gerbils with or without indomethacin treatment. This finding strongly suggests that prostaglandin (PG) plays an important role for the initial healing, but with 4 week. experiments, H.pylori might be related to the development of an inflammatory response, ultimately leading to delayed healing of the ulcers. It is also well known that indomethacin significantly delays
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healing of acetic acid ulcers-induced in rats due to the reduced PGE_2 synthesis. In addition, our results suggest that the inhibited angiogenesis and abnormal formation of granulation tissue with indomethacin treatment involve in the mechanism underlying the delayed healing. We found that vascular endothelial growth factor (VEGF) was not involved in the inhibited angiogenesis responsible to delayed ulcer healing. Indeed, bFGF expression was decreased according to the development of acetic acid ulcers, and the expression signal was weaker than indomethacin-treated group. While HSP47 were markedly expressed in the ulcer base after ulceration, but decreased with ulcer healing. Indomethacin treatment markedly enhanced HSP47 expression in the ulcer base and the expression of Collagen I (α) mRNA, resulting in the increased content of collagen.
In conclusion, the mechanism by which indomethacin delays ulcer healing appears to be due to 1) the inhibition of angiogenesis following the reduction of PGE_2 synthesis and bFGF expression, 2) over expression of HSP47 leading to the accumulation of collagen content in the ulcer base. Less
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