Effects of misoprostol on cell migration and transit in the dog stomach

Prostaglandins of the E series increase stomach mucosal mass by inducing hyperplasia, which could be the result either of increased cell production or of decreased cell loss. This report describes an investigation of the effect of the prostaglandin E1 analogue, misoprostol, on cell migration and transit. 3H-thymidine was used to label those cells synthesizing deoxyribonucleic acid in dogs that had been given an oral dose of 300 micrograms/kg per day misoprostol for 11 weeks. The animals were killed at timed intervals, and tissue from the gastric fundus was prepared for autoradiography. The distribution of labeled cells at various times after labeling was used to follow the movement of the wave of label and to calculate median cell migration rates and transit times. The migration rate of cells toward the gastric lumen was significantly increased from 1.4 +/- 0.3 to 3.6 +/- 0.6 cell positions per day in the misoprostol-treated group (p less than 0.001); however, the gland length (from the most basal mucous neck cell to the luminal surface) was also increased (from 52.1 +/- 1.1 to 74.0 +/- 1.6; p less than 0.001), thus there was no significant difference in the (transit) time taken for cells to reach the top of the gland (control, 17.5 +/- 9.8 days; test, 12.2 +/- 7.1 days).     

Effect of misoprostol and cimetidine on gastric cell labeling index

The effect of misoprostol and cimetidine on gastric cell turnover was studied. Endoscopic biopsy specimens of fundic and antral mucosa were obtained from duodenal ulcer patients before and after 4 wk of therapy with cimetidine 1.2 g/day or misoprostol 800 micrograms/day. Biopsy specimens were incubated with [3H]thymidine. Glandular column length and number of labeled cells were determined after autoradiography. There was no significant difference in column length of antral or fundic glands before or after therapy with cimetidine and misoprostol. The number of antral and fundic labeled cells was significantly decreased after misoprostol treatment (3.6 +/- 0.3 and 4.6 +/- 0.4, mean +/- SE), as opposed to their respective number before therapy (6.9 +/- 0.5 and 8.3 +/- 0.8) (p less than 0.01). On the other hand, after treatment with cimetidine, the number of antral and fundic labeled cells was significantly higher (11.8 +/- 0.9 and 7.5 +/- 1.0, respectively) as compared with their number before therapy (5.7 +/- 0.5 and 5.6 +/- 0.6, respectively). The decreased gastric cell turnover induced by misoprostol indicates that the trophic effect of prostanoids on gastric mucosa is not due to an increase in cellular kinetics. The increased gastric cell turnover induced by cimetidine may contribute to its therapeutic effect in peptic ulcer disease.     

Restoration of colorectal continuity reverses atrophy in human rectal mucosa

Cell kinetic activity and adaptive response of rectal mucosa from patients with Hartmann's procedure were studied before and after restoration of colorectal continuity. Patients without colostomy and with normal rectal mucosa were used as controls. Autoradiography ofin vitro labeled mucosal samples with [³H]thymidine was used. The proliferative activity in the rectal crypts was estimated by measuring labeling and mitotic indices, total DNA of isolated crypts, and total crypt cell numbers. One hundred forty days after creating a proximal end colostomy, labeling index (P<0.05), mitotic index (P<0.01), DNA content per crypt (P<0.05), and number of cells per crypt (P<0.05) decreased significantly compared to control values. Restoration of colorectal continuity resulted in a significant increase of the labeling index (P<0.05), the mitotic index (P<0.07), the DNA content per crypt (P<0.05), and the cell number per crypt (P<0.05). There were no significant differences between the postclosure values and the controls. These data indicated that excluding the human rectal mucosa from fecal stream determined a mucosal atrophy that could be reversed by restoration of colorectal continuity.     

Cell kinetic analysis of intact rat colonic crypts by confocal microscopy and immunofluorescence

BACKGROUND & AIMS: Precise quantitative and spatial analysis of cell cycle-related biomarkers in colonic crypts is often vital for studies of colon carcinogenesis and cancer prevention. To overcome the limitations of histology, confocal laser microscopy of microdissected whole crypts was used to quantitate S phase and mitotic cells. METHODS: Microdissected distal colonic crypts were studied in a modified rat starvation refeeding model. S phase cells were labeled in vivo with 5- bromodeoxyuridine. Mitotic cells were labeled with MPM2 (antibody to mitosis-specific epitope) and also assessed for chromatin morphology with propidium iodide. Sequential optical crypt sections, produced by confocal microscopy, were digitally imaged. S phase labeling indices per whole crypt were also compared with those derived by conventional immunohistochemistry. RESULTS: S phase and mitotic cells were clearly discriminated without background staining. The labeled S phase cell number and fraction per whole crypt were significantly decreased with starvation and increased with refeeding. Variability in the labeling index between whole crypts analyzed by confocal microscopy was significantly smaller than between histological crypt sections. Consequently, the intervention contributed to 92.2% of the total variability of the labeling index in whole crypts but only to 59% of the variability in histological sections. CONCLUSIONS: Major limitations of histology are overcome by crypt microdissection and confocal microscopic analysis. The total crypt cell population as well as labeled M phase and S phase cells can be imaged, localized, and quantitated with improved precision. (Gastroenterology 1996 Dec;111(6):1493-500)     

HIV enteropathy: crypt stem and transit cell hyperproliferation induces villous atrophy in HIV/Microsporidia-infected jejunal mucosa

OBJECTIVES: The study aim was to analyse the kinetics of stem and transit cells in the crypts of jejunal mucosa infected with HIV and Microsporidia. DESIGN: The size of villi, depth of crypts and proliferative activity of transit and stem cells in jejunal mucosa were measured using morphometric techniques. METHODS: The surface area/volume ratio (S/V) of jejunal biopsies was estimated under light microscopy using a Weibel graticule. Crypt length was measured by counting enterocytes along the crypt side from the base to the villus junction, and the mean crypt length was calculated. The S/V and crypt lengths of the jejunal mucosa of 21 HIV and Microsporidia-infected test cases were compared with 14 control cases. The labelling index in relation to the crypt cell position of 10 of the test cases was analysed compared with 13 control cases. RESULTS: Differences were found in the S/V and crypt length, and there was a negative correlation between S/V and crypt length in test and control cases combined. Cell labelling indices fell into low and high proliferation groups. There were significant differences in labelling indices between low proliferation test cases and controls, between high proliferation test cases and controls, and between high and low proliferation test cases. CONCLUSION: Villous atrophy induced by HIV and Microsporidia is attributed to crypt cell hyperplasia and the encroachment of crypt cells onto villi. These infections induce crypt hypertrophy by stimulating cell mitosis predominantly in transit cells but also in stem cells. Increased stem cell proliferation occurs only in high proliferation cases.     

Variability of cell proliferation in the proximal and distal colon of normal rats and rats with dimethylhydrazine induced carcinogenesis

AIM：To investigate the patterns of cell proliferation in proximal and distal colons in normal rats and rats with1,2-dimethylhydrazine(DMH)induced carcinogenesis using the thymidine analogue bromodeoxyuridine.METHODS:Colonic crypt cell proliferation was immunohistochemically detected using the anti-bromodeoxyuridine Bu20a monoclonal antibody.RESULTS:Marked regional differences were found in both groups.Total labelling index(LI)and proliferative zone size in both normal(8.65&#177;0.34vs7.2&#177;0.45,27.74&#177;1.07vs16.75&#177;1.45)andDMH groups(13.13&#177;0.46vs11.55&#177;0.45,39.60&#177;1.32vs35.52&#177;1.58)were significantly higher in distal than in proximal colon(P&lt;0.05).although the number of cells per proxmal crypt was greater(31.45&#177;0.20vs34.45&#177;0.39,42.68&#177;0.53vs49.09&#177;0.65,P&lt;0.001).Crypt length,total LT and proliferative zone size all increased in both proximal and distal regions of DMH rats compared to normal controls(P&lt;0.0001).In DMH-treated rat colon a shift of labelled cells to higher crypt cell positions was demonstrated distally whist a bi-directional shift was evident proximally(P&lt;0.05).CONCLUSION:Our results show that changes in cell proliferation patterns,as assessed by bromodeoxyuridine uptake,can act as a reliable intermediate marker of colonic cancer formation.Observed differences between proliferation patterns in distal and proximal colon may be associated with the higher incidence of tumors in t he distal colon.     

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).     

Abnormal pattern of cell proliferation in the entire colonic mucosa of patients with colon adenoma or cancer

Using autoradiography after 1 h of pulsed labeling with tritiated thymidine in endoscopic biopsy specimens from normal-appearing mucosa, cell proliferation was determined at six predetermined sites of the whole colon in patients with neoplastic disease of the large bowel and was compared with that of subjects without macroscopic colonic pathology. The labeling index (the percentage of cells incorporating [3H]thymidine) was 8.6 +/- 0.5 (mean +/- SEM) in 13 patients with colon carcinoma (p less than 0.001 vs. 16 control patients whose labeling index was 4.9 +/- 0.2) and 9.1 +/- 0.4 in 11 patients with a large adenoma in the colon (p less than 0.001 vs. controls). Twenty-one patients with one or more small adenomas (diameter less than 1 cm) had a moderately increased cell proliferation compared with controls (labeling index 6.2 +/- 0.3, p less than 0.02 vs. controls). In patients with neoplastic disease an enlargement of the proliferative compartment was found, whereas 6 patients with Crohn's colitis had values for labeling index and a distribution of labeled cells along the crypt comparable to that of control subjects. An increased cell proliferation was found along the entire colon under each of the neoplastic conditions studied. These findings indicate that although neoplastic lesions develop in a limited area of the colon, the entire large bowel may be at risk for tumor growth.     

Ileal epithelial cell migration after 40% small-bowel resection

Adaptation in the small bowel after resection is associated with increases in crypt cell proliferation and villus height. This paper gives the results of an autoradiographic investigation with [³H]thymidine of epithelial cell migration 60 days after 40% small-bowel resection in the rat. The mean number of cell positions between the crypt-villus junction and the leading labeled cell 30 hr after injection was increased by 19.4% in the resected group (P<0.02). The mean total number of cells per villus column was increased by 27.8% (P<0.002). Migration rate estimated in cell positions per hour was accelerated by 18.9% (P<0.001) after resection. The 8.1% lengthened life span of villus cells was not statistically significant. The increased number of cells per villus column and unaltered life span of villus cells would facilitate functional adaptation. The causal relationship between the larger villus cell population and accelerated migration after resection and increased crypt cell proliferation is unknown.This investigation was supported by the National Health and Medical Research Council.     

Methods for the determination of epithelial cell kinetic parameters of human colonic epithelium isolated from surgical and biopsy specimens

The purpose of this study is to introduce the application of new approaches to the determination of human colonic epithelial cell kinetic parameters. The isolation of pure and intact colonic epithelium from both surgical and biopsy specimens forms the basis of these approaches. The isolated epithelium is used in the determination of cell kinetic parameters by (a) flow cytometry, (b) Coulter counting, (c) dried cell preparations, and (d) crypt squashes. Using these methods, the following results were derived. The proportion of cells in the various phases of the cell cycle in the sigmoid epithelium was determined to be 81.6% +/- 2.15% (means +/- SE) in G1/G0 phase, 15.2% +/- 1.86% in S phase, and 3.2% +/- 0.62% in G2 + M phases. In the rectal epithelium, there were 79.6% +/- 3.35% in G1/G0 phase, 16.4% +/- 4.86% in S phase, and 4.08% +/- 1.90% in G2 + M phases. The total cell population in sigmoid epithelium was approximately 4.2 X 10(6) +/- 5.46 X 10(5) cells per cm2, and there were approximately 2.5 X 10(3) +/- 1.57 X 10(2) cells in each colonic crypt. Therefore, the number of crypts per square centimeter of human sigmoid mucosa could be estimated to be approximately 1.68 X 10(3). Lastly, in sigmoid epithelium, columnar cells of human sigmoid mucosa could be estimated to be approximately 1.68 X 10(3). Lastly, in sigmoid epithelium, columnar cells accounted for 76.3% +/- 6.18% of the epithelial cells, whereas the remaining epithelial cells, 23.7% +/- 4.08%, consisted of mucous cells.     

Degraded carrageenan-induced colitis in CF1 mice. A clinical, histopathological and kinetic analysis

Delivery of 10% carrageen (degraded carrageenan, Glaxo, France) for 10 days in the drinking water to CF1 mice induced bloody diarrhea, pericryptal inflammation, and marked dilatation of the cecum and ascending colon. Histologically, the mucosa was characterized by distorted crypt architecture, inflammatory infiltration of the lamina propria, and ulceration, conditions which were more pronounced in the proximal colon but were also present in the distal colon. Treatment with hydrocortisone and levamisole reduced the severity of all phases of the reaction. Alterations in colonic epithelial cell proliferation corresponded with the clinical and histopathological findings. Labeling indices (LI) significantly increased over control values in both proximal (12.9 +/- 4.9 vs. 7.6 +/- 2.9) and distal colon (13.9 +/- 5.2 vs. 7.2 +/- 2.4), effectively doubling the number of proliferating cells per crypt column in both areas. However, DNA-synthesizing cells extended further upward along the cryptal wall of the proximal colon reflecting greater mucosal damage. Only in the proximal colon did the proliferative compartment (PC) extend to the upper third of the glands, normally not a proliferative zone. Hydrocortisone and levamisole administered concurrently with 10% carrageen were less effective in protecting the proximal colon since LI and numbers of labeled cells per crypt column were consistently lower in the distal colon. Moreover, hydrocortisone alone significantly depressed DNA synthesis only in the distal colon. All distal colonic crypts were not equally protected by administration of hydrocortisone since some continued to express large numbers of proliferating cells and an extended PC, well characterized preneoplastic defects in regulatory control of colonic epithelial cell proliferation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Selective irradiation of the vascular endothelium has no effect on the survival of murine intestinal crypt stem cells

The possible role of vascular endothelial cell damage in the loss of intestinal crypt stem cells and the subsequent development of the gastrointestinal (GI) syndrome is addressed. Mice received whole-body epithermal neutron irradiation at a dose rate of 0.57 +/- 0.04 Gy x min(-1). An additional dose was selectively targeted to endothelial cells from the short-ranged (5-9 microm) particles released from neutron capture reactions in 10B confined to the blood by incorporation into liposomes 70-90 nm in diameter. Different liposome formulations produced 45 +/- 7 or 118 +/- 12 microg/g 10B in the blood at the time of neutron irradiation, which resulted in total absorbed dose rates in the endothelial cells of 1.08 +/- 0.09 or 1.90 +/- 0.16 Gy x min(-1), respectively. At 3.5 d after irradiation, the intestinal crypt microcolony assay showed that the 2- to 3-fold increased doses to the microvasculature, relative to the nonspecific whole-body neutron beam doses, caused no additional crypt stem cell loss beyond that produced by the neutron beam alone. The threshold dose for death from the GI syndrome after neutron-beam-only irradiation was 9.0 +/- 0.6 Gy. There were no deaths from the GI syndrome, despite calculated absorbed doses to endothelial cells as high as 27.7 Gy, in the groups that received neutron beam doses of <9.0 Gy with boronated liposomes in the blood. These data indicate that endothelial cell damage is not causative in the loss of intestinal crypt stem cells and the eventual development of the GI syndrome.     

Divergent effects of epidermal growth factor and calcipotriol on human rectal cell proliferation.

Vitamin D may protect against colorectal cancer by reducing cell proliferation and inducing differentiation. By contrast, epidermal growth factor (EGF) stimulates cell proliferation and may encourage gastrointestinal mucosal healing. This study investigated the effect of a synthetic vitamin D analogue, calcipotriol, and EGF on human rectal epithelial cell proliferation in patients with familial adenomatous polyposis (FAP). In addition, a new technique to measure the cell cycle time is described. Sigmoidoscopic biopsy specimens were obtained from 14 patients with FAP. Tissue was established in organ culture, with or without the addition of EGF (n = 8), or calcipotriol (n = 6). Proliferation was determined using (a) metaphase arrest to measure the crypt cell production rate, (b) native mitotic index, and (c) the growth fraction using PC10 antibody. EGF receptor expression was shown using a polyclonal antibody AP12E. Calcipotriol reduced crypt cell production rate by 52% from mean (SEM) 5.29 (1.18) to 2.56 (0.80) cells/crypt/hour (p < 0.01) and EGF increased crypt cell production rate by 102% from 3.62 (0.59) to 7.33 (0.90) cells/crypt/hour (p < 0.05), and this tissue expressed the EGF receptor. The growth fraction was 48.40 (4.0)%, and the native mitotic index 1.08 (0.14)%. The cell cycle time was estimated as 94.5 hours and the time for mitosis as one hour. Thus, calcipotriol and EGF have divergent effects on human rectal mucosal proliferation.     

Changes in the structure and regeneration mode of the rat small intestinal mucosa following benzalkonium chloride treatment

Tritiated thymidine was administered IP to rats that had been exposed to benzalkonium chloride in the duodenum, jejunum, and ileum, resulting in neuronal ablation. Epithelial cell proliferation and migration were studied 21 and 7 days after treatment. Significant hyperplasia and hypertrophy of the villi and crypts was seen from day 7 on. This was half as pronounced as that of the muscle layer, whose maximal percent increase was not seen until day 21. In the crypt, the proliferation had increased significantly (65% 3H index corrected) and its zone had expanded proportionally to the total crypt depth. After an average of 36 hours in the ileum (48 hours in normal rats), labeled cells reached the tip of the lengthened villi, reflecting significantly accelerated migration. Concerning the distributional pattern of the labeled cells in the crypt, a nonsignificant shift to the lower two thirds of the crypt could be distinguished. From this the author concludes that treatment with benzalkonium chloride influences the proliferation and migration of the epithelial cells in the treated area. These alterations may result from loss of the myenteric plexus, but other factors cannot be excluded.     

Immunohistochemical study of epithelial cell proliferation in hyperplastic polyps, adenomas, and adenocarcinomas of the large bowel

A monoclonal antibody to bromodeoxyuridine was used in tissue specimens previously incubated with bromodeoxyuridine to show S-phase cells by immunohistochemical technique. Biopsy specimens of normal mucosa (n = 10), hyperplastic polyps (n = 10), adenomas with low-grade dysplasia (n = 20), adenomas with high-grade dysplasia (n = 10), and invasive adenocarcinomas (n = 10) of the large bowel were studied. Labeling index and cell proliferative patterns were analyzed. No statistically significant difference was found in labeling index between normal mucosa and hyperplastic polyps or between adenomas with high-grade dysplasia and adenocarcinomas. The labeling index was significantly lower in normal mucosa and in hyperplastic polyps than in adenomas and adenocarcinomas (p less than 0.001). The difference in labeling index between adenomas with high-grade dysplasia and low-grade dysplasia was also statistically significant (0.01 less than p less than 0.05). In normal mucosa and in hyperplastic polyps the proliferative zone was confined to the lower two-thirds of the crypt; no kinetic activity was found in the upper portions of the crypt or in surface epithelium. In adenomas the labeled cells were either present in the upper third or scattered along the whole axis of the crypt and in the surface epithelium. Labeling patterns in invasive carcinomas were similar to those observed in adenomas with high-grade dysplasia. The difference in proliferative patterns between hyperplastic polyps and adenomas supports a different significance of the two polypoid lesions in the histogenesis of large bowel cancer; our results confirm the subsequent steps of the adenoma-carcinoma sequence. Immunohistochemical labeling patterns observed with monoclonal antibody to bromodeoxyuridine in polypoid and cancer lesions of the large bowel are similar to those described by autoradiographic studies.     

Ileal epithelial cell migration in acute renal failure

Previous investigations have shown an inhibition of gastrointestinal epithelial cell proliferation in acutely uremic mice. This paper gives the results of an autoradiographic investigation with³H-thymidine of the effect of acute renal failure on ileal epithelial cell migration. Acute renal failure was produced by urinary outflow obstruction and control mice subjected to sham operation. The mean number of cell positions between the cryptvillus junction and the leading labeled cell 30 hours after operation was decreased in the uremic group (P<0.01). No significant difference was found in the number of cells per villus column. Estimates showed a decrease in mean migration rate from 0.69 to 0.55 positions per hour and an increase in the life span of villus cells from 54.2 to 73.8 hours. Decreased crypt and villus cell renewal may contribute to the development of uremic gastrointestinal lesions.This investigation was supported by the National Health and Medical Research Council.     

Granulosa cell proliferation is impaired in the Igf1 null ovary.

Insulin-like growth factor-I (IGF-I) expression is highly correlated with ovarian follicular growth and granulosa cell proliferation in both pre-pubertal and mature murine ovaries. Igf1 gene deleted mice are infertile, with ovarian follicles arrested at an early stage of development. To elucidate the cause of follicular dysfunction in Igf1 null mice, this study compared granulosa cell proliferation at baseline and in response to exogenous oestradiol (E2) in prepubertal Igf1 null and wild-type (WT) littermate mice. The basal granulosa cell mitotic index was 3.8+/-0.48 in WT and 1.3+/-0.7 in Igf1 null mice (P=0.03). After E2 treatment, WT granulosa mitotic index was 12.7+/-0.0 vs 5.5+/-0.8 for Igf1 null mice (P<0.001). Granulosal BRDU incorporation was also significantly reduced as were cyclin D2 and B1 immunoreactivities in Igf1 null compared with WT mice. The incidence of apoptosis was not increased in Igf1 null follicles, although BAX immunostaining was increased. These data suggest that IGF1 is essential for normal basal and oestrogen-induced granulosa cell proliferation and follicular growth.     

Flow cytometric analysis of deoxyribonucleic acid in human granulosa cells from in vitro fertilization cycles: relationships to oocyte maturity and fertilizability and to follicular fluid steroids

We measured the mitotic activity of granulosa cells, sex steroid concentrations in follicular fluids, and the maturity and fertilizability of oocytes from 49 follicles. Flow cytometric measurements of DNA were used to determine the percentage of cells in G0/G1, S, and G2/M phases of the cell cycle. Mitotic index was designated as the percentage of granulosa cells in S + G2/M. The progesterone concentration and the progesterone to estradiol ratio in follicular fluids were inversely correlated to mitotic index (r = -0.506; P less than 0.001, and r = -0.320; P less than 0.02, respectively). Estradiol and androstenedione levels did not correlate with the mitotic index. The mitotic index was higher in follicles with immature oocytes [25.6 +/- 2.0% (+/- SE); n = 7] than in follicles with mature oocytes (15.6 +/- 1.2%; n = 41; P less than 0.001). The mitotic index of granulosa cells was lowest in follicles with oocytes that fertilized (15.5 +/- 1.8%), higher in follicles with oocytes that remained unfertilized (18.5 +/- 1.3%; P less than 0.03), and highest in follicles with oocytes that fertilized abnormally (24.0 +/- 2.1%; P less than 0.02). Differences in maturity or fertilizability of oocytes were not associated with variations in follicular fluid progesterone concentrations. The study supports the concept that mitotic activity is decreased when granulosa cells become luteinized. During early follicular growth it is assumed that estradiol and perhaps androstenedione may be important regulators of cell division. Our findings suggest that progesterone, perhaps acting as an antiestradiol, is more important in controlling granulosa cell division of preovulatory follicles during the late follicular phase.     

Intestinal morphology and cytokinetics in pancreatic insufficiency

Intraluminal pancreatic enzymes influence intestinal function, adaptation, and susceptibility to injury. These effects may be mediated partly through changes in the rate of epithelial cell turnover. We assessed intestinal morphology and cytokinetics in a rat model of exocrine pancreatic insufficiency that does not alter anatomic relationships or animal growth. Pancreatic duct occlusion was performed by applying metal clips on both sides along the common bile duct. Control animals underwent sham-operation with exposure and manipulation of the pancreas without duct occlusion. Twelve days later, pulse labeling with tritiated thymidine was performed, and mitotic arrest was induced with colcemid. Groups of animals were sacrificed at 0 and 2 hr after colcemid injection. Specimens for histopathology, morphometry, and autoradiography were obtained from duodenum, proximal jejunum, distal jejunum, and ileum. Labeling index, grain counts, mitoses per crypt, cells per crypt, cells per villus, crypt depth, villus height, and number of goblet cells per villus were used as end points. Pancreatic duct occlusion resulted in increased labeling index across intestinal segments relative to sham-operated controls (P<0.01) and increased labeling index and mitotic rate in distal compared to proximal intestine (P<0.05). Grain-count histograms were similar in the two experimental groups. There were no significant morphologic differences between pancreatic duct-occluded animals and controls. Exocrine pancreatic insufficiency increases crypt cell proliferation in distal small intestine but does not alter the duration of S phase. These changes are most likely due to an increase in the size of the proliferative compartment and may be partly responsible for changes in small bowel function and response to injury.Supported by grant 88.616 from The Norwegian Cancer Society.