1994 Fiscal Year Final Research Report Summary
MOLECULAR APROACH FOR INVESTIGATION OF ONSET MECHANISM IN ACUTE PANCREATITIS
| Project/Area Number |
04404052
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| Research Category |
Grant-in-Aid for General Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Research Field |
Digestive surgery
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| Research Institution | KOBE UNIVERSITY SCHOOL OF MEDICINE |
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Principal Investigator |
SAITOH Yoichi KOBE UNIVERSITY SCHOOL OF MEDICINE,SURGERY,PROFESSOR, 医学部, 教授 (90004803)
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| Co-Investigator(Kenkyū-buntansha) |
TAKEYAMA Yoshifumi KOBE UNIVERSITY SCHOOL OF MEDICINE,SURGERY,ASSISTANT PROFESSOR, 医学部, 助手 (70263374)
YAMAMOTO Masahiro KOBE UNIVERSITY SCHOOL OF MEDICINE,SURGERY,ASSOCIATE PROFESSOR, 医学部, 助教授 (40166822)
OHYANAGI Harumasa KINKI UNIVERSITY SCHOOL OF MEDICINE,SURGERY,PROFRSSOR, 医学部, 教授 (00030958)
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| Project Period (FY) |
1992 – 1994
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| Keywords | Acute pancreatitis / Cytoskeleton / Microtubules / Small molecular GTP-pinding protein / Caerulein-induced pancreatitis |
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| Research Abstract |
The aim of the project was to clarify the molecular mechanism in the onset of acute pancreatitis, forcusing on the molecular events in vesicular transport in pancreatic acinar cells.
For the first step, we examined the effects of colchicine, a microtubule disrupting agent, on rat exocrine pancreas in comparison with a microtubule stabilizer taxol for the purpose of analyzing the pathogenesis of caerulein-induced acute pancreatitis. Taxol ameliorated inhibition of pancreatic secretion, elevation of serum amylase level, pancreatic edema, and histological alterations induced by supramaximal caerulein stimulation. In contrast, colchicine by itself and colchicine followed by caerulein stimulation (maximal and supramaximal) inhibited pancreatic secretion, but did not induce hyperamylasemia, pancreatic edema, or formation of large vacuoles, which characterized caerulein-induced pancreatitis. Electron microscopic studies in the colchicine-treated rats revealed that transport vesicles were accum
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ulated in the supranuclear region and that no large vacuoles were observed in the apical lesion. Immunofluorescence studies confirmed that colchicine inhibited pancreatic secretion and disrupted the arrangement of microtubules. Posttreatment of colchicine did not prevent the development of caerulein-induced pancreatitis.
Next, we investigated the mode of existence of small molecular GTP-binding protein, rab11p24 in physiological exocrine stimulation on the acinar cell. The protein was translocated from the cytosol fraction to the zymogen fraction upon the physiological exocrine stimulation of caerulein or cholecystokinin. On the other hand, the spuramaximal stimulation of cholecystkinin did not induce the translocation.
The results obtained in this study suggest that microtubule disorganizaition at certain specific step in the process of intracellular vesicular transport causes caerulein-induced pancreatitis, that this step is more apical than that where colchicine inhibits secretion in the pancreatic acinar cells, and that the distubance in translacation of rab11p24 in the specific step is involved in the onset machanism of this type of acute pancreatitis. Less
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