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

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580 Endocrine Reviews, October 2003, 24(5):571–599 Thomas et al. • Gastrointestinal Hormones and Proliferationmucosal integrity in rats and prevents the translocation ofindigenous bacteria after radiation-induced mucosal injury.We have extended the observation that NT increases proliferationof small bowel mucosa by evaluating the effects of NTin rats of different age groups and found that increases ofgrowth measurements (DNA, RNA, and protein) were thegreatest in the small bowel mucosa of aged rats. These findingsdemonstrate that, with aging, the ability of the smallbowel mucosa to respond to the trophic stimulus of NT isretained and may, in fact, be greater when compared with theproliferative response in young rats given NT.Izukura et al. (136) demonstrated that administration of NTaugments the normal adaptive hyperplasia of gut mucosathat is associated with massive (i.e., 70%) small bowel resection.Consistent with our results, de Miguel et al. (137) usedan 80% bowel resection model and demonstrated that exogenousNT significantly increased villus length in both thejejunum and ileum compared with the resected group notreceiving NT, suggesting that administration of exogenousNT potentiated the growth of the intestinal villi and acceleratedthe trophic response after massive small bowel resection.These investigators also noted increased circulatinglevels of enteroglucagon after NT administration and postulatedthat this may have contributed to the proliferativeeffect noted with NT. Ryan et al. (138) demonstrated in arabbit model of midgut bowel resection that either epidermalgrowth factor (EGF) or NT resulted in significantly increasedmicrovillus height and brush-border surface areas after administration.After bowel resection, both EGF and NT inducedenterocyte microvillus hypertrophy and increased absorptivesurface area in the remnant bowel. It was suggestedthat these peptides might be useful in accelerating smallbowel adaptation and preventing the development of shortbowel syndrome. The effects of NT on intestinal adaptationhave also been studied in a colectomy model (139). After acolon resection, jejunal proliferation increased significantlyin rats treated with NT, with less pronounced effects notedin the remaining colon and ileum. This study provides additionalsupport that NT augments the adaptive response ofeither the small bowel or colon after bowel resection.3. Colon. We have shown that NT (300 g/kg three timesdaily) stimulates proliferation of colonic mucosa in youngand aged rats in a differential fashion (41). Colonic proliferationin young (2-month-old) rats was characterized byincreases in cell number, whereas in aged (2-yr-old) rats,indices of hypertrophy were elevated significantly without aconcomitant increase in cell number. This study shows thatNT is not only important for small bowel growth and mucosalintegrity, but also functions as an important hormoneregulating colonic mucosal proliferation. Furthermore,Hoang et al. (134) demonstrated that NT (100 g/kg) significantlyincreased protein content in the colon but did notaffect weight or DNA content in F344 rats. The decreasedeffect noted in their study relates to the decreased dosage ofNT compared with our previous study. It is clear that, althoughnot as pronounced as the small bowel, NT can stimulateproliferation of colonic mucosa.4. Pancreas. Feurle et al. (40) demonstrated that administrationof NT increased pancreatic weight, DNA, RNA, andprotein contents as well as lipase and amylase concentrations.A proliferative effect for NT on the pancreas was likewisedemonstrated by Wood et al. (133) by chronic administrationof NT, which produced small but statisticallysignificant trophic effects in the pancreas, with the highestdose of NT (300 g/kg) increasing pancreatic weight by 16%,DNA content by 12%, and protein content by 17%. When NTwas given in combination with either cerulein or secretin, ithad minimal additive effects on the responses of these twopeptides (134). Therefore, from these studies it can be concludedthat NT stimulates pancreatic growth but not to thesame extent as CCK or BBS/GRP.E. PYYPYY inhibits blood flow to the GI tract (140, 141), inhibitssmall bowel fluid and electrolyte secretion (142–144), andregulates GI motility. In addition, administration of PYY canstimulate proliferation of small bowel and colonic mucosa.The effects of PYY on the stomach and pancreas are notknown.1. Small bowel and colon. Gomez et al. (51) first demonstrateda trophic effect for PYY (150–200 nmol/kg, three times daily)on the small bowel and colonic mucosa of both rat andmouse. Consistent with these findings, Chance et al. (145)found that PYY treatment (1 nmol/kgh) in Sprague-Dawleyrats given TPN produced significant increases in jejunal,ileal, and colonic protein contents.The trophic effects noted for PYY were in contrast to workby Guan et al. (146) demonstrating that PYY, administered at400 pmol/kgh (continuous infusion) for 4 d, failed to affectduodenal weight, protein, or DNA/RNA contents in maleWistar rats. In addition, using either a small bowel resectionmodel (147) or a gut atrophy model induced by TPN (148),administration of PYY failed to elicit a trophic effect on smallbowel mucosa. These negative results were attributable tothe smaller doses and different experimental designs.F. GLP-2A trophic effect for proglucagon-derived peptides(PGDPs) on the intestinal mucosa has been postulated sincethe description of a glucagon-secreting tumor of the kidneyassociated with small bowel mucosal hypertrophy. Druckeret al. (149) were the first to demonstrate that the intestinotrophicfactor was GLP-2.1. Small intestine. To assess the potential consequences ofincreased proglucagon gene expression on intestinal growth,Brubaker et al. (150) created glucagon-SV40 T-antigen transgenicmice that developed proglucagon-producing tumorsand elevated levels of the PGDPs. Small bowel mucosal hypertrophywas noted in the transgenic mice; however, it wasnot possible to ascertain which of the PGDPs was responsiblefor small bowel growth. To better ascertain which of thePGDPs stimulated gut growth, nude mice with three differentsc proglucagon-producing tumor xenografts (InR1-G9,RIN1056A, and STC-1 cells) were analyzed (149). Furthermore,CD1 mice were treated with GLP-1, GLP-2, glicentin,and intervening peptide (IP)-1 (all are produced from theDownloaded from edrv.endojournals.org by on July 16, 2007
Thomas et al. • Gastrointestinal Hormones and Proliferation Endocrine Reviews, October 2003, 24(5):571–599 581proglucagon gene). Mice with all three xenograft types demonstratedan increase in small bowel weight, crypt-villusheight, and percentage of BrdU-positive cells; glicentin (43.75g) administered twice daily for 10 d produced modest increasesin total small bowel weight. Neither GLP-1 nor IP-1had an effect on the gut mucosa, whereas GLP-2 produceda 50% increase in small bowel weight. Furthermore, onlyGLP-2 produced a significant increase in mucosal thickness,with the increase attributable to increased villus height (149).Similarly, Ghatei et al. (151) demonstrated prominent trophiceffects of GLP-2 in Wistar rats. Using varying doses of enteroglucagon,GLP-1, oxyntomodulin, and GLP-2, onlyGLP-2 produced a dose-dependent increase in the weight ofstomach, small intestine, and colon of parenterally fed rats.Therefore, these studies confirmed that, of the PGDPs, GLP-2was the major mediator of intestinal epithelial proliferation.Litvak et al. (152, 153) demonstrated that GLP-2 (1.75g/kg twice a day) significantly increased the weight ofjejunum, ileum, and colon of athymic nude mice comparedwith both control mice and mice treated with NT (600 g/kgthree times a day). These studies confirmed the previousfindings of a trophic effect for GLP-2 and demonstrated thatthe proliferative effects were equal to or greater than thoseof NT. In another study, GLP-2-producing tumor cells (STC-1cells) were implanted in athymic mice and then randomizedto receive either NT or saline (152, 153). The mice treated withNT and GLP-2 (from STC-1) displayed significant increasesin jejunal and ileal weight and protein content over either NTor GLP-2 alone. The administration of NT appeared to enhancethe enterotrophic effects of GLP-2, suggesting that thecombination may be useful to enhance intestinal growth inpatients with short bowel syndrome.In addition to the effects of GLP-2 on normal mucosa, theeffects of this agent during periods of gut injury or atrophyhave also been assessed. Mice treated with the nonsteroidalagent indomethacin develop small bowel enteritis associatedwith significant mortality at 48–72 h after administration;treatment with human [Gly 2 ]GLP-2 before, during, or afterindomethacin administration resulted in reduced mortalityand decreased mucosal injury (154). The protective effectswere attributed to significantly increased crypt cell proliferationand decreased crypt compartment apoptosis. Theeffect of GLP-2 on chemotherapy-induced intestinal mucositishas also been assessed. Pretreatment of mice with human[Gly 2 ]GLP-2 before administration of the topoisomerase inhibitoririnotecan resulted in reduced bacterial infection, intestinaldamage, and mortality (155). Histological and biochemicalanalyses revealed significant reductions in cryptcompartment apoptosis and reduced caspase-8 activation.Consistent with these reports, Tavakkolizadeh et al. (156)noted decreased intestinal damage in rats given GLP-2 incombination with the chemotherapeutic agent 5-fluorouracil.Finally, repeated cyclical administration of both human[Gly 2 ]GLP-2 and irinotecan resulted in decreased mortalityin groups of BALB/C mice implanted with sc CT-26 coloncarcinomas. These data suggest that GLP-2 may have therapeuticadvantages for cancer patients by supporting bowelintegrity without diminishing the effectiveness of thechemotherapy.2. Colon. Although the small bowel is significantly moresensitive to the effects of GLP-2, studies have shown thatGLP-2 and GLP-2 analogs can stimulate the growth of colonicmucosa. As previously noted, Litvak et al. (152) demonstrateda trophic effect of GLP-2 on the colonic mucosa ofathymic nude mice. Drucker et al. (157) demonstrated anincrease in colonic growth using dipeptidyl peptidase IVresistantGLP-2 analog, human [Gly 2 ]GLP-2 in CD1 mice.Furthermore, the combination of this agent with IGF-I, GH,or long [Arg3]IGF-I produced a greater increase in largebowel mass than mice treated with [Gly 2 ]GLP-2 alone.Treatment with GLP-2 has also been shown to reducecolonic mucosal injury, similar to the findings in the smallbowel (51). In a dextran sulfate-induced colitis model, concomitantadministration of sc human [Gly 2 ]GLP-2 and oraldextran sulfate for 10 d resulted in markedly reduced colonicdamage and decreased weight loss in CD1 and BALB/Cmice. Treatment with [Gly 2 ]GLP-2 preserved colonic length,decreased intestinal histological damage, reduced IL-1 expression,and increased crypt cell proliferation.G. SomatostatinSomatostatin has predominantly inhibitory effects, whichhave been used to advantage in certain clinical scenarios.Somatostatin inhibits pancreatic and GI secretion and GImotility and inhibits the release of GH and all known GIhormones (3). The active peptide analog of somatostatin(octreotide) has been effectively used as an agent to amelioratesymptoms associated with endocrine-overproducingtumors, pancreatic fistulas, and enterocutaneous fistulas(158, 159). In experimental studies, somatostatin has alsobeen shown to inhibit the growth of the GI mucosa andnormal pancreas (158, 159). These effects may be througheither an indirect mechanism such as inhibition of othertrophic hormones or a direct effect through interaction withthe somatostatin receptor subtype 2 (160, 161). This somatostatinreceptor subtype associates and stimulates tyrosinephosphatase src homology 2-containing tryosine phosphatase1 activity, which in turn arrests cells in the G o /G 1 phaseof the cell cycle associated with up-regulation of thecyclin-dependent kinase inhibitor p27 kip1 and an increase inhypophosphorylated retinoblastoma protein levels (160,161). Although the major portion of this review has focusedon the stimulatory effects of various GI hormones, it is importantto discuss the inhibition of growth using somatostatinand its analogs.1. Stomach. The effects of somatostatin on gastric mucosalgrowth have been assessed. Treatment of Wistar rats withsomatostatin (50 g/kgh) reduced nuclear uptake of[ 3 H]thymidine and cell division in both fundic and antralprogenitor cells (162). Furthermore, the combination of somatostatinand gastrin reduced gastrin-stimulated DNA synthesisin the gastric mucosa. In contrast, in the duodenumand jejunum, the effects of somatostatin were less consistent,with nocturnal somatostatin producing slight decreases inDNA synthesis. These findings suggested that somatostatincould inhibit cell proliferation in the mucosa of the normalGI tract and, furthermore, could antagonize the trophic ac-Downloaded from edrv.endojournals.org by on July 16, 2007
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