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Gut hyperplasia in artificially reared suckling rats — Role of EGF and TGF-alpha
Ahsrmcrs
28
GLYCINE-EXTENDED
GASTRIN
STIMULATES
- REGPEP
2000
PROLIFERATION
OF COLONIC
MUCOSA
Baldwin, Graham S; Aly, A; Shulkes, Arthur The University of Melbourne, Department of Surgery, Australia Recent interest has focussed on the potential trophic properties of non-amidated progastrin-derived peptides such as glycine extended gastrin (G-gly) in colonic mucosa, as well as their potential role as autocrine growth The aim of this project was to investigate the possible growth promoting factors in colorectal carcinoma.’ effect of G-gly on colonic mucosa in the rat. The effect on colonic mucosal proliferation was examined in animals with intact colons and in animals with a defunctioned rectum, in which the hypoplastic mucosa induced by defunctioning may provide increased sensitivity to potential growth factors by providing a low proliferative baseline. METHODS: Miniosmotic pumps were used to deliver G-gly systemically over a one or four week experimental period at 10 nmol/kg/hr or 2.5 nmol/kg/hr respectively. Mucosal proliferation was measured by two indices; (i) metaphases per crypt accumulated over 3 hours and (ii) crypt height. RESULTS: A slight stimulation of growth by G-gly, which did not reach statistical significance, was seen throughout the functional colon. The proliferative effect of G-gly was potentiated in the defunctioned rectum, in which significant increases in metaphase index (40%) and crypt height (11%) over controls were observed in the group treated for one week. Stimulation was greater in the 4 week treatment group, in which a 90% increase in metaphase index and a 20% increase in crypt height were observed in the defunctioned rectum. CONCLUSION: We conclude that the colonic mucosa of the rat proliferates in response to systemic exposure to G-gly and that this response is more pronounced with increased duration of exposure. These observations provide the first evidence that short term administration of G-gly has trophic effects in the colon. Baldwin GS, Shulkes A. Gastrin, gastrin receptors and colorectal carcinoma. Gut42(4): 581-584 (1998).
GUT HYPERPLASIA
IN ARTIFICIALLY
Dvorak, Bohuslav; Williams, University of Arizona, USA
Catherine
REARED SUCKLING S; McWilliam,
RATS - ROLE OF EGF AND TGF-alpha
Debra L
The artificially reared rat is an excellent model to study the effects of nutrition on neonatal gastrointestinal growth and development. Previously, we have shown that hyperplasia of the small intestine results from feeding artificial diets. However, dietary components causing these changes are not known. Epidermal growth factor (EGF) and transforming growth factor-alpha (TGFa) are potent mitogens found in the neonatal gut which could contribute to hyperplastic growth. In this study, we tested the hypothesis that EGF and TGFa play role in the accelerated growth of the small intestine of artificially-fed neonatal rats. METHODS: Animals: 8-day old Sprague Dawley rat pups were gastrostomized and artificially fed for 4 days. Diets: manually-expressed rat milk (RM) or growth factor-free rat milk substitute (RMS) were used in this study. Dam-fed (DF) littermates served as controls. Measurements: Body weight gain, tail length, and the small intestine weights were assessed. Intestinal EGF and TGFa peptide levels were measured using RIA. RESULTS: After four days of feeding, small intestines of rats receiving the artificial diet increased 60% in weight over rats receiving rat milk. Body weight gain was similar among RM, RMS and DF. Levels of EGF peptide in RMS small intestinal tissue were reduced by 85% compared to RM or DF (pcO.01). In contrast, TGFa peptide levels in the RMS small intestine increased approximately 33% over RM or DF. CONCLUSION: Since growth factor-free diet caused significant intestinal overgrowth we conclude that milkborne EGF is not responsible for intestinal hyperplasia. However, the enhanced growth of the small intestine observed in the artificially-fed neonatal rat may in part be due to an increase in endogenous production of TGFa. Supported by the NIH Grant HD-26013.
28
GLYCINE-EXTENDED
GASTRIN
STIMULATES
- REGPEP
2000
PROLIFERATION
OF COLONIC
MUCOSA
Baldwin, Graham S; Aly, A; Shulkes, Arthur The University of Melbourne, Department of Surgery, Australia Recent interest has focussed on the potential trophic properties of non-amidated progastrin-derived peptides such as glycine extended gastrin (G-gly) in colonic mucosa, as well as their potential role as autocrine growth The aim of this project was to investigate the possible growth promoting factors in colorectal carcinoma.’ effect of G-gly on colonic mucosa in the rat. The effect on colonic mucosal proliferation was examined in animals with intact colons and in animals with a defunctioned rectum, in which the hypoplastic mucosa induced by defunctioning may provide increased sensitivity to potential growth factors by providing a low proliferative baseline. METHODS: Miniosmotic pumps were used to deliver G-gly systemically over a one or four week experimental period at 10 nmol/kg/hr or 2.5 nmol/kg/hr respectively. Mucosal proliferation was measured by two indices; (i) metaphases per crypt accumulated over 3 hours and (ii) crypt height. RESULTS: A slight stimulation of growth by G-gly, which did not reach statistical significance, was seen throughout the functional colon. The proliferative effect of G-gly was potentiated in the defunctioned rectum, in which significant increases in metaphase index (40%) and crypt height (11%) over controls were observed in the group treated for one week. Stimulation was greater in the 4 week treatment group, in which a 90% increase in metaphase index and a 20% increase in crypt height were observed in the defunctioned rectum. CONCLUSION: We conclude that the colonic mucosa of the rat proliferates in response to systemic exposure to G-gly and that this response is more pronounced with increased duration of exposure. These observations provide the first evidence that short term administration of G-gly has trophic effects in the colon. Baldwin GS, Shulkes A. Gastrin, gastrin receptors and colorectal carcinoma. Gut42(4): 581-584 (1998).
GUT HYPERPLASIA
IN ARTIFICIALLY
Dvorak, Bohuslav; Williams, University of Arizona, USA
Catherine
REARED SUCKLING S; McWilliam,
RATS - ROLE OF EGF AND TGF-alpha
Debra L
The artificially reared rat is an excellent model to study the effects of nutrition on neonatal gastrointestinal growth and development. Previously, we have shown that hyperplasia of the small intestine results from feeding artificial diets. However, dietary components causing these changes are not known. Epidermal growth factor (EGF) and transforming growth factor-alpha (TGFa) are potent mitogens found in the neonatal gut which could contribute to hyperplastic growth. In this study, we tested the hypothesis that EGF and TGFa play role in the accelerated growth of the small intestine of artificially-fed neonatal rats. METHODS: Animals: 8-day old Sprague Dawley rat pups were gastrostomized and artificially fed for 4 days. Diets: manually-expressed rat milk (RM) or growth factor-free rat milk substitute (RMS) were used in this study. Dam-fed (DF) littermates served as controls. Measurements: Body weight gain, tail length, and the small intestine weights were assessed. Intestinal EGF and TGFa peptide levels were measured using RIA. RESULTS: After four days of feeding, small intestines of rats receiving the artificial diet increased 60% in weight over rats receiving rat milk. Body weight gain was similar among RM, RMS and DF. Levels of EGF peptide in RMS small intestinal tissue were reduced by 85% compared to RM or DF (pcO.01). In contrast, TGFa peptide levels in the RMS small intestine increased approximately 33% over RM or DF. CONCLUSION: Since growth factor-free diet caused significant intestinal overgrowth we conclude that milkborne EGF is not responsible for intestinal hyperplasia. However, the enhanced growth of the small intestine observed in the artificially-fed neonatal rat may in part be due to an increase in endogenous production of TGFa. Supported by the NIH Grant HD-26013.