Growth control factors in the gastrointestinal tract.
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Adaptation, Physiological↗
Biomedical subjects
R A Goodlad
Publications and source records attributed to R A Goodlad.
Prostaglandins and the dog stomach: effects of misoprostol on the proportion of mucosa to muscle and on the proportion of different epithelial cell types.
Dogs were given an oral dose of 300 micrograms/kg/day of the prostaglandin E1 analogue, misoprostol for 11 weeks. The relative areas of the main components of the fundus and antrum per unit area of serosa were quantified. While the volume occupied by the muscle layers did not change, there was an increase in mucosal volume in both sites. The relative volume fraction of the main mucosal cell types was then determined by a point counting technique. Misoprostol very highly significantly increased the fraction of mucosal volume occupied by surface mucus cells, and also significantly decreased the volume fraction of the parietal cells.
Alprostadil↗
Is peptide YY trophic to the intestinal epithelium of parenterally fed rats?
Four groups of intravenously maintained rats were infused with 0, 5, 20 or 80 micrograms/rat/day of peptide tyrosine tyrosine (PYY) for 3 days. After 3 days the rats were injected with 1 mg/kg of vincristine in order to arrest cells entering metaphase and were killed 2 h later. The gastrointestinal tract was removed, weighed and fixed. Samples of small intestine and colon were stained, microdissected and the mean number of metaphases per crypt determined. No significant effect on intestinal tissue mass or the 2-hour collection of metaphases was observed. It is concluded that PYY is not trophic to the gastrointestinal tract.
Animals↗
The effects of the prostaglandin analogue, misoprostol, on cell proliferation and cell migration in the canine stomach.
Increased mucosal mass is associated with prostaglandin administration, raising the question as to whether this is the consequence of increased cell production or decreased cell loss. 3H-thymidine was injected into 30 test dogs given 300 micrograms/kg/day of the prostaglandin E1 analogue, misoprostol, orally for 11 weeks, and into 30 dogs which had been given the vehicle alone. Six test and 6 control dogs were killed 1 h after thymidine labelling, and the remainder were killed subsequently at timed intervals to determine cell migration rates and transit times. Misoprostol significantly increased the stomach weight, but nonetheless did not significantly increase the labelling index, nevertheless, the number of labelled cells per gland was significantly increased, which was a consequence of the increased gland length. When the data was expressed as a gland cell production rate significant increases were thus observed. The migration rate of cells toward the gastric lumen increased one and a half times in the misoprostol-treated group; however, as the gland length also significantly increased, there was no significant difference in the transit time. It must be concluded that the hyperplasia associated with exogenous prostaglandins is the consequence of increased cell production, not decreased cell loss, and that previous reports to the contrary are the result of failure to allow for concomitant changes in the denominator of proliferative indices.
Alprostadil↗
Changes in intestinal cell proliferation, absorptive capacity and structure in young, adult and old rats.
Intestinal epithelial morphology, crypt cell production and absorptive function were investigated in 9 groups of rats, aged from 3 to 121 weeks. Absorption per unit length of intestine peaked in the first weeks of life and this was associated with increased villus size, crypt length and absorption per mg tissue weight. Absorption per gut continued to increase throughout life, which could be attributed to a similar increase in intestinal length and weight per cm, despite a decreased absorption per mg in the adult animals. Crypt-villus ratio increased rapidly between 6 and 8 weeks, but then appeared to reach a plateau. Crypt cell production started off at high rate in all sites and then decreased in the young adult. While there was some evidence for a small, non-significant, increase in proliferation in the very old rats, there was no evidence of the marked elevation reported by some workers.
Aging↗
Plasma enteroglucagon, peptide YY and gastrin in rats deprived of luminal nutrition, and after urogastrone-EGF administration. A proliferative role for PYY in the intestinal epithelium?
Intestinal tissue mass was significantly reduced throughout the gastrointestinal tract (p less than 0.001) of intravenously fed (TPN) rats. Urogastrone-epidermal growth factor, (URO-EGF), reversed these changes. Although plasma enteroglucagon and gastrin levels showed a small increase with URO-EGF, this was far less than the gut tissue weight change, suggesting that it was unlikely that they were involved in modulating the proliferative response of the intestine to URO-EGF. Peptide tyrosine tyrosine (PYY) levels were however significantly increased by URO-EGF, indicating that PYY may possibly have a role in the modulation of intestinal cell proliferation.
Animals↗
Is polyamine synthesis involved in the proliferative response of the intestinal epithelium to urogastrone-epidermal growth factor?
1. Intestinal epithelial cell proliferation was measured in rats maintained on total parenteral nutrition (TPN), in TPN rats given 300 micrograms of recombinant human epidermal growth factor (urogastrone-epidermal growth factor, URO-EGF) day-1 kg-1, and in further groups given URO-EGF and difluoromethylornithine (DFMO), an inhibitor of the enzyme ornithine decarboxylase (ODC). 2. URO-EGF significantly increased intestinal cell proliferation throughout the gastrointestinal tract. The proliferative response of the colon was particularly pronounced. 3. DFMO reduced the proliferative effect of urogastrone in the stomach and small intestine. DFMO also reduced URO-EGF-stimulated intestinal cell proliferation in the colon, but to a lesser extent. 4. It is concluded that ODC is essential for effecting the proliferative response of the stomach and small intestine to URO-EGF, but this role may be less important in the colon.
Animals↗
Plasma enteroglucagon, gastrin and peptide YY in conventional and germ-free rats refed with a fibre-free or fibre-supplemented diet.
Germ-free rats and conventional rats were starved and then refed with either an elemental diet (Flexical), or Flexical plus 30% kaolin, or Flexical plus 30% of a fibre mixture. Plasma levels of enteroglucagon, gastrin and peptide YY (PYY) were all significantly affected by diet. Enteroglucagon and especially PYY were significantly increased by the addition of fermentable fibre to the diet, but only in the conventional, not in the germ-free rats. Gastrin was not affected by the addition of fermentable fibre, but was increased by kaolin. Enteroglucagon and PYY were, however, both very much elevated in the germ-free animals, in which there is no proliferative response to fibre. Enteroglucagon and PYY levels were similar to those usually associated with extreme hyperproliferative states, indicating that it is unlikely that these hormones are involved in the proliferative response of the gastrointestinal tract to dietary fibre, and casting doubt on their role in other responses.
Animals↗
Prostaglandins and the gastric epithelium: effects of misoprostol on gastric epithelial cell proliferation in the dog.
The effects of the methyl ester analogue of prostaglandin E1, misoprostol, on gastric epithelial cell proliferation were investigated in six dogs given 300 micrograms/kg/day of misoprostol orally for 11 weeks and in six control dogs given placebo for 11 weeks. Misoprostol treatment resulted in a 36% increase in stomach weight (p less than 0.01) and a 30% increase in the length (measured as the cell column count from the base/neck junction to the surface) of the fundic gastric glands (p less than 0.01). This mucosal hyperplasia was predominantly caused by enlargement of the foveolar region of the gland, with little change occurring in the neck or in the isthmus. The hyperplasia was the result of an increased number of mitotic (p less than 0.01) and DNA synthesising cells (p less than 0.05) in each gastric gland, which resulted in a significant increase in the gland cell production rate, from 22.5 to 42.6 cells per gland per day (p less than 0.05).
Alprostadil↗
Does dietary fibre stimulate intestinal epithelial cell proliferation in germ free rats?
The aim of the present experiment was to investigate the role of hind gut fermentation in the proliferative response of the intestinal epithelium to dietary fibre. We have previously shown that refeeding starved rats with an elemental diet supplemented with fermentable dietary fibre (but not inert bulk) is capable of stimulating intestinal epithelial cell proliferation throughout the gastrointestinal tract. Three groups of 10 germ free (GF) rats and three groups of 10 conventional (CV) rats, were used. All groups were starved for three days and then refed for two days with either an elemental diet (Flexical); Flexical plus 30% kaolin; or Flexical plus 30% of a fibre mixture. Cell production was determined by the accumulation of vincristine arrested metaphases in microdissected crypts. There was no significant difference between refeeding the rats with an elemental diet alone or with kaolin supplementation, however, the addition of fibre in CV rats was associated with a significant increase in intestinal crypt cell production rate in both the small intestine (p less than 0.01) and the colon (p less than 0.001). This marked proliferative effects of fibre was abolished in the GF rats. It can be concluded that it is the products of hind gut fermentation, not fibre per se that stimulate intestinal epithelial cell proliferation in the colon and small intestine.
Animals↗
Gastrointestinal epithelial cell proliferation.
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Animals↗
Epithelial cell proliferation and intestinal absorptive function during starvation and refeeding in the rat.
1. Intestinal epithelial cell production and intestinal absorption were measured in fed, starved and refed rats. 2. Four days' starvation significantly decreased the crypt cell production rate (CCPR), absorption, small intestinal length and crypt cell population. 3. There was an immediate increase in absorption 1 day after refeeding, which preceded a slower increase in CCPR. The absorption rate then decreased progressively after refeeding, and was significantly lower than control levels 1 week after refeeding. The CCPR, however, increased more gradually, reaching control levels after 2 days and then 'overshooting' control values. 4. There was no significant change in the crypt cell population immediately after refeeding; thus we propose that the initial increase in absorption on refeeding is either due to an accelerated maturation rate of the enterocytes or to the migration of enterocytes from the base of the villus to the functional zone. 5. The rapid recruitment of absorptive function appeared to be a 'one-off' event, the villus compartment then having to wait for increased cell production in the crypts to repopulate the villi.
Animals↗
Does resection enhance the response of the intestine to urogastrone-epidermal growth factor in the rat?
1. The objective of this study was to see whether another proliferative stimulus could modify the marked proliferative effect of human epidermal growth factor (urogastrone-epidermal growth factor, URO-EGF) on the gastrointestinal epithelium. 2. The response of the gastrointestinal tract to URO-EGF was investigated in rats maintained on total parenteral nutrition (TPN) with or without 75% small bowel resection. 3. Continuous infusion of 60 micrograms of recombinant beta-urogastrone/day per rat increased proliferation in the stomach by over four times (P less than 0.01), doubled proliferation in the small intestine (P less than 0.001) and increased it by four and a half times in the colon (P less than 0.001) in the control group. No significant effect of urogastrone was observed in the stomach of the resected groups, but proliferation was also increased in the small intestine by one and a half times (P less than 0.001) and by nearly four times in the colon (P less than 0.001). 4. Two-way analysis of variance showed that resection had a significant effect (P less than 0.01) on proliferation below the anastomosis and in the ileum. However, the response of the ileum was only half that observed in orally fed rats, which confirms the importance of 'luminal nutrition' in the response to resection. 5. Intestinal resection in the TPN rat was associated with a small rise in plasma enteroglucagon levels, suggesting that this hormone may be implicated in the adaptive response of the small intestine to resection.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Effects of urogastrone (epidermal growth factor) on the intestinal epithelium.
Recombinant urogastrone (human epidermal growth factor) was infused into rats in which intestinal cell proliferation was reduced to a steady state basal level by feeding them intravenously. Urogastrone elevated the augmented metaphase index and weight of all sections of the gastrointestinal tract in a dose-related manner. Infusion of urogastrone at a dose which has a minimal effect on gastric acid secretion significantly increased crypt cell production and tissue weights throughout the gastrointestinal tract. Intravenous urogastrone was also effective in restoring cell proliferation after the intestine had become hypoproliferative. Urogastrone administered luminally had no significant effect on either intestinal weight, crypt cell production rate, or metaphase collection.
Animals↗
Peptides and epithelial growth regulation.
There is now considerable evidence implicating several peptides in the control of gastrointestinal epithelial cell proliferation and cell renewal. While some of these may act directly, many may be involved in regulating the powerful trophic effects of the intake and digestion of food on the gut epithelium. Several peptides have been associated with the regulation of intestinal cell proliferation. There is little doubt that gastrin is trophic to the stomach, but, its role in the rest of the gastrointestinal tract is debatable. Enteroglucagon has often been associated with increased intestinal epithelial proliferation, but at the moment all the evidence for this is circumstantial. The effects of peptide YY and bombesin warrant further study. The availability of recombinant epidermal growth factor (EGF) has recently enabled us to demonstrate a powerful trophic response to infused EGF throughout the gastrointestinal tract. The increasing availability of peptides will eventually allow the rigorous in vivo evaluation of the trophic role of these potentially very important peptides.
Animals↗
The relationship between intestinal crypt cell production and intestinal water absorption measured in vitro in the rat.
In studies on intestinal adaptation it is often important to obtain contemporaneous data on the rate of cell production and the functional status of the intestine. The measure of the rate of accumulation of vincristine arrested metaphases in microdissected intestinal crypts to determine the crypt cell production rate (CCPR), is one of the most effective methods of estimating intestinal epithelial cell proliferation which is robust enough to withstand scrutiny. However, studies in the field of intestinal adaptation could be much more informative if a valid measure of intestinal function could also be included. One such method is the water absorption capacity in vitro. The intraperitoneal injection of vincristine sulphate (1 mg/kg) had no significant effect on the water absorption capacity of the small intestine, as measured by the segmented flow single pass perfusion method; thus the CCPR of the jejunum and intestinal water absorption were both measured in 19 groups of hypo- and hyper-proliferative rats which should have been in a relatively 'steady state' of cell production and turnover. The minimum values were obtained after hypophysectomy and the maximum values were observed in lactation. CCPR and absorption were significantly correlated (P less than 0.001) with each other. There was a significant (P less than 0.001) correlation between both CCPR and absorption and dry weight of the intestinal segment studies with food intake. Body weight was a poor predictor of either CCPR or absorption.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Effects of an elemental diet, inert bulk and different types of dietary fibre on the response of the intestinal epithelium to refeeding in the rat and relationship to plasma gastrin, enteroglucagon, and PYY concentrations.
Refeeding starved rats with an elemental diet resulted in a marked increase in crypt cell production rate (CCPR) in the proximal small intestine but not in the distal regions of the gut. Little effect on CCPR was noted when inert bulk (kaolin) was added to the elemental diet. Addition of a poorly fermentable dietary fibre (purified wood cellulose) had little effect on intestinal epithelial cell proliferation except in the distal colon where it significantly increased CCPR. A more readily fermentable fibre (purified wheat bran) caused a large proliferative response in the proximal, mid, and distal colon and in the distal small intestine. A gel forming fibre only significantly stimulated proliferation in the distal colon; the rats in this group, however, did not eat all the food given. There was no significant correlation between CCPR and plasma gastrin concentrations, but plasma enteroglucagon concentrations were significantly correlated with CCPR in almost all the sites studied. Plasma PYY concentrations also showed some correlation with CCPR, especially in the colon. Thus while inert bulk cannot stimulate colonic epithelial cell proliferation fermentable fibre is capable of stimulating proliferation in the colon, and especially in the distal colon: it can also stimulate proliferation in the distal small intestine and it is likely that plasma enteroglucagon may have a role to play in this process.
Animals↗
Intravenous but not intragastric urogastrone-EGF is trophic to the intestine of parenterally fed rats.
The effects of beta-urogastrone/human epidermal growth factor (URO-EGF) on intestinal epithelial cell proliferation were studied in rats in which intestinal cell proliferation had been reduced to a steady state basal level, by maintaining the rats on total parenteral nutrition. The accumulation of arrested metaphases over a two hour time period was determined in a dose response study. Increasing doses of URO-EGF progressively raised the two hour collection of metaphases and intestinal weights. Intravenous infusion of URO-EGF was also effective in restoring cell proliferation when it was infused after the intestine had become hypoproliferative. beta-urogastrone/human epidermal growth factor administered through an intragastric cannulae thrice daily had no significant effect on intestinal weight or crypt cell production rate or metaphase collection. It is proposed that one of the in vivo actions of urogastrone-epidermal growth factor is the maintenance of gastrointestinal growth and that this occurs through a systemic rather than a luminal mechanism.
Animals↗