Role of Gastrointestinal Hormones in the Proliferation of Normal and ...

Thomas et al. • Gastrointestinal Hormones and Proliferation Endocrine Reviews, October 2003, 24(5):571–599 579tissues. In addition, electron morphometric analysis indicatedthat the increase in pancreatic weight was due to hypertrophyof the acinar cells. Increases in pancreatic chymotrypsinand trypsinogen content were noted, with little effecton lipase or colipase and amylase levels. Similar to its effectson the pancreatic acini, BBS stimulates endocrine cells of thepancreas (129).Liehr et al. (130) assessed the role of CCK in BBS-inducedgrowth in rats. Sprague-Dawley rats received sc injections ofBBS every 8 h for 5 d, alone or in combination with the CCKreceptor antagonist, L-364,718. BBS produced a dose-dependentincrease in pancreatic weight, DNA and protein content,as well as amylase and chymotrypsinogen levels. L-364,718significantly inhibited pancreatic growth induced by a highconcentration (5 nmol/kg) of BBS but had minimal effects ongrowth induced by lower dosages of BBS. These results suggestthat low doses of BBS stimulate pancreatic growth in adirect manner, independent of CCK, whereas high doses ofBBS act in part through CCK release.More recently, Fiorucci et al. (131) found that chronic BBSadministration stimulated pancreatic regeneration after pancreatectomyin pigs. Furthermore, these studies examinedthe cellular processes that may be regulated by BBS. Threegroups of pigs underwent sham operation, subtotal distalpancreatectomy, or subtotal pancreatectomy combined withBBS for 4 wk. After treatment, the pancreas was removed,weighed, and assayed for p42 and p44 MAPK, p46 Shc ,p52 Shc , p66 Shc , and Grb2. BBS administration resulted in a100% increase in residual pancreatic tissue when comparedwith control animals and approximately a 3-fold increase inthe rate of pancreatic acinar cell proliferation. Also, BBSadministration significantly increased p46 Shc /p52 Shc andMAPK expression and/or activity in whole pancreas extracts.These results further demonstrate a proliferative effectof BBS in a large animal model and provide evidence that BBScan stimulate cell proliferation via the MAPK pathway.Upp et al. (128) demonstrated that BBS had both direct andindirect actions in the pancreas. Polyamine synthesis, anessential part of DNA synthesis, was assessed with BBS administrationover a time course. BBS produced significantpancreatic hyperplasia (increased pancreatic weight, protein,and DNA content) after 14 d of treatment. CR1409, the CCKreceptor antagonist, inhibited only BBS-mediated increasesin DNA content. BBS stimulated polyamine biosynthesis asearly as 2 h after administration; CR1409 did not inhibit thisincrease in polyamines. These results suggested that the trophicactions of BBS are both direct and indirect and that thedirect effects are mediated by polyamine synthesis.D. NTThe physiological functions of NT in the GI tract includestimulation of pancreatic and biliary secretions (37) and inhibitionof small bowel and gastric motility (38). In addition,NT stimulates growth of the gastric antrum, small bowel (33,34, 42), colon (132), and pancreas (40, 133).1. Stomach. Feurle et al. (40) demonstrated that sc administrationof high dosages of NT for 2 wk increased proteinconcentration and thickness of the gastric antrum in Wistarrats, whereas DNA content and weight were not affected. Incontrast, Hoang et al. (134) noted that NT alone had no effecton the oxyntic gland area or the antrum, but it inhibitedincreases in antral weight, DNA, and protein induced bysecretin. The effects of NT on antral growth are, therefore,minimal at best and may occur with prolonged, high dosagesof NT.2. Small bowel. In contrast to the stomach, the trophic effectsof NT in the small bowel are more pronounced. Wood et al.(42) first noted that NT stimulated the small bowel mucosaof rats fed a normal chow diet. We have shown that administrationof NT prevents gut mucosal atrophy induced byfeeding rats an ED (Fig. 4) (Ref. 34) and stimulates mucosalgrowth in defunctionalized self-emptying jejunoileal loopsor isolated TVFs, thus supporting a direct role for NT in thestimulation of gut mucosal growth. These findings demonstratethat NT is an important trophic hormone that canmaintain and even augment gut mucosal structure by anincrease in overall mucosal cellularity. Consistent with ourfindings, Vagianos et al. (135) reported that NT restores gutFIG. 4. NT prevents small bowel mucosal atrophy associatedwith ED. Histology of Sprague-Dawley ratsmall bowel after ED, ED and NT (injected sc 300 g/kgthree times a day), and chow (control) for 5 d.Downloaded from edrv.endojournals.org by on July 16, 2007