Gastrin increases murine intestinal crypt regeneration following injury.
OBJECTIVE
A number of growth factors affect the regeneration of intestinal epithelia following injury, but the effects of amidated gastrin have not previously been assessed. We therefore investigated the effects of gastrin on intestinal regeneration following a range of stimuli.


METHODS
Intestinal crypt regeneration was assessed in transgenic mice overexpressing amidated gastrin (INS-GAS) and mice in which hypergastrinemia was induced using omeprazole, following gamma-radiation, 5-fluorouracil, and dextran sulphate sodium (DSS). Abundance of the CCK-2 receptor was assessed in intestinal epithelia and IEC-6 intestinal epithelial cells following gamma-radiation.


RESULTS
Four days following 14 Gy gamma-radiation, or 2 injections of 400 mg/kg 5-fluorouracil, INS-GAS mice exhibited significantly increased small intestinal and colonic crypt survival compared with their wild-type counterparts (FVB/N). INS-GAS mice treated with 3% DSS for 5 days showed less weight loss and increased colonic crypt regeneration at 8 days compared with FVB/N. Increased small intestinal and colonic crypt survival was also demonstrated following gamma-radiation in FVB/N mice rendered hypergastrinemic using omeprazole. The increased crypt survival in INS-GAS mice following 14 Gy gamma-radiation was inhibited by administration of a CCK-2 receptor antagonist (YF476). Increased abundance of the CCK-2 receptor was demonstrated in intestinal epithelia following 14 Gy gamma-radiation by Western blotting and immunohistochemistry. Similarly, increased CCK-2 receptor mRNA abundance and increased 125I-gastrin binding was demonstrated in IEC-6 cells following 4 Gy gamma-radiation.


CONCLUSIONS
Hypergastrinemia increases regeneration of intestinal epithelia following diverse forms of injury. Induction of the CCK-2 receptor in damaged epithelium confers potential for protection against injury by administration of gastrin.
Ottewell
Penelope D
PD
Division of Gastroenterology, University of Liverpool, Liverpool, UK.
Duckworth
Carrie A
CA
Varro
Andrea
A
Dimaline
Rod
R
Wang
Timothy C
TC
Watson
Alastair J M
AJ
Dockray
Graham J
GJ
Pritchard
D Mark
DM
D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003092:Colitis / Q000139:chemically induced / Q000473:pathology; D016264:Dextran Sulfate / Q000494:pharmacology; D004751:Enteritis / Q000139:chemically induced / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology; D005720:Gamma Rays; D005755:Gastrins / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D006133:Growth Substances / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000293:injuries* / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009853:Omeprazole / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D054328:Proton Pump Inhibitors; D043887:Receptor, Cholecystokinin B / Q000037:antagonists & inhibitors / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects; D014947:Wounds and Injuries / Q000503:physiopathology
D001570:Benzodiazepinones; D004791:Enzyme Inhibitors; D005755:Gastrins; D006133:Growth Substances; D010671:Phenylurea Compounds; D054328:Proton Pump Inhibitors; D043887:Receptor, Cholecystokinin B; C013550:gastrin 17; D016264:Dextran Sulfate; C104428:YF 476; D009853:Omeprazole; D005472:Fluorouracil