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Background/aims: Leptin, the ob/ob gene product, is a recently discovered peptide hormone, secreted by adipocytes, which can act as a satiety factor to regulate food intake. Its levels thus will be related to the presence of food in the lumen of the gut, and food intake is one of the most potent stimuli for intestinal epithelial cell proliferation. Leptin has a variety of other actions and the aim of this study was to see if one of these was to stimulate mucosal growth., Methods: Three groups of mice were fed ad libitum, starved for 48 h or starved for 48 h and given twice-daily intraperitoneal injections of recombinant leptin (1 microg/g)., Results: Starvation led to a 20% decrease in body weight and a similar decrease in the weights of the intestines. Starvation also markedly inhibited intestinal epithelial cell proliferation. Leptin had little effect on the small intestine and did not stimulate proliferation. However, in the hind gut it was associated with small but significant decreases in caecal weight, distal colon mitotic counts (p = 0.036) and in colonic crypt area (approximately 20%, p<0.001)., Conclusion: Leptin did not stimulate intestinal cell proliferation, however it did have a paradoxical inhibitory action on the caecum and colon., (Copyright 2000 S. Karger AG, Basel.)

Epidermal growth factor (EGF) and transforming growth factor alpha (TGF alpha) bind to a common receptor and are both present in the normal gastrointestinal tract. Although many studies have examined their function in isolation, there is little information directly comparing their actions. We examined the relative potency of TGF alpha and EGF in stimulating 3H-thymidine uptake into primary rat hepatocytes at various doses in vitro and on the crypt cell production rate (CCPR) within the gastrointestinal tract when infused intravenously at 49 nmol/kg/day into rats receiving total parenteral nutrition. In vitro, maximal stimulatory activity was similar in EGF- and TGF alpha-treated cells, however, the dose of EGF required to stimulate 3H-thymidine uptake to 50% of maximal levels was only one third of that required using TGF alpha. In vivo, EGF and TGF alpha significantly increased the weight and proliferative indices throughout the gastrointestinal tract. The response (as determined by CCPR) was about 80% higher in animals which had received EGF when compared to animals receiving TGF alpha. Treatment with EGF also caused significant rises in plasma PYY, enteroglucagon and gastrin levels, whereas the equivalent dose of TGF alpha only caused a significant rise in plasma gastrin levels. We conclude that TGF-alpha, like EGF, is trophic to the entire gastrointestinal tract of the rat, however, it is a less effective mitogen, and has differential hormonal effects.

Dogs were given a prostaglandin analogue, misoprostol, at a dose that significantly increases gastrointestinal epithelial cell proliferation. Both basal and postprandial concentrations of gastrin were significantly higher in the misoprostol-treated dogs and more than doubled after the meal in both the controls and in the test group. Plasma enteroglucagon, cholecystokinin, insulin and glucose-dependent insulinotrophic peptide all increased postprandially, with no effect of misoprostol. Tissue concentrations of bombesin, gastrin and somatostatin were unaffected by misoprostol, but the fundic glucagon-like immunoreactivity was significantly increased. Thus high doses of misoprostol have only minor effects on gastrointestinal regulatory peptides, suggesting that the trophic effect of prostaglandins on the intestinal tract may be direct.

We demonstrate that, in patients taking non-steroidal anti-inflammatory drugs (NSAIDs), there is inhibition of the proliferation of mucosal cells that normally leads to healing of duodenal ulcers. A microdissection technique was used to quantitate mitosis in duodenal crypts at the ulcer edge, giving a regeneration index of mitotic rate at that site, as compared to nearby mucosa. In patients with duodenal ulcers occurring in the absence of NSAID therapy, there was a brisk regenerative response (median index 2.48, range 1.55-9.81, n = 8), significantly greater than in patients taking NSAIDs (median index 1.10, range 0.73-2.16, n = 10, p = 0.014). Inhibition of the process of epithelial cell division normally involved in duodenal ulcer healing could contribute to the delay in ulcer healing which may explain the higher complication rate for duodenal ulcer during NSAID therapy.

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.

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.

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.

The quantification of mucosal DNA as a measure of epithelial cellularity has been criticized because it would include the non-epithelial cell populations present in the mucosa. The weight, DNA content and tritiated thymidine uptake of Peyer's patches and the remaining mucosa were measured and compared. Although the Peyer's patches only contribute 2.5% to the weight of the small intestine, they contained 12% of the DNA and 7% of the tritiated thymidine which would be found in a mucosal scrape.