To the extent possible under law, AOP-Wiki has waived all copyright and related or neighboring rights to KER:2031
Increased acinar cell exocrine secretion leads to Acinar cell proliferation
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Trypsin inhibition leading to pancreatic acinar cell tumors||adjacent||High||Moderate||Arthur Author (send email)||Under development: Not open for comment. Do not cite||Under Development|
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
In rats, an increased blood level of CCK stimulates pancreatic acinar cells to secrete digestive enzymes directly via surface CCK1 receptors and indirectly via innervation of vagal afferent nerves expressing CCK1 receptors. A persistent increase in the blood CCK level stimulates pancreatic acinar cell proliferation directly via surface CCK1 receptors. On the other hand, human pancreatic acinar cells express CCK2 receptors, which do not respond to CCK in terms of secretion and proliferation. Pancreatic enzyme secretion in humans is innervated by afferent vagal nerves expressing CCK1 receptors; however, its involvement in acinar cell proliferation is unclear.
Evidence Supporting this KER
CCK-induced pancreatic acinar cell proliferation
An increased plasma level of CCK directly induces proliferation of pancreatic acinar cells via surface CCK1 receptors as well as exocrine secretion in rodents. Consuming raw soya flour for 30 days, administration of trypsin inhibitor in drinking water for 7 days, or repeated injection of cholecystokinin for 7 days induced pancreatic hypertrophy and hyperplasia [Yanatori Y and Fujita T, 1976]. Repeated administration of CCK for 21 days [Folsch UR et al, 1978] and treatment with the CCK8 and CCK1 receptor agonist A-71623 for 3 weeks [Povoski SP et al, 1994] also induced pancreatic hyperplastic changes in mice [Tashiro M et al, 2004]. Addition of 0.1% camostat in the diet for 10 days increased pancreatic weight and protein and DNA levels in a time-dependent manner in mice [Tashiro M et al, 2004].
The CCK1 receptor agonist GI181771X induced pancreatitis due to abnormal basolateral secretion of Zymogen granules at the high dose and acinar cell hypertrophy at the middle and low doses in ratsan. The author mentioned JAK1/2–STAT1/3 activation leading to p38MAPK activation as a mechanism underlying acinar cell proliferation.
Direct effect of CCK on acinar cell proliferation via CCK receptors
In rats, the trypsin inhibitor FOY-305 increased pancreatic weight and induced acinar cell hypertrophy, and denervation of vagal nerves had little effect on these hypertrophic changes [Aki T et al, 1989]. Administration of CCK-8 at physiological doses induced exocrine secretion, and atropine and vagal nerve denervation suppressed this exocrine secretion but not that induced by non-physiological doses of CCK-8 [Li Y and Owyang C, 1993]. These results suggest that the involvement of vagal nerve innervation in acinar cell proliferation under an increased blood CCK level might be low, and this may also be the case in humans, but the evidence is unclear [Chandra R and Liddle RA, 2009].
Uncertainties and Inconsistencies
A8947, a broadleaf herbicide with trypsin inhibitory action, was fed to male rats for up to 28 days, at doses of 0, 300, 10,000, and 30,000 ppm. A8947 at 10,000 and 30,000 ppm induced significant increases in acinar cell proliferation after 7 days, followed by a decrease to control levels by 28 days [Obourn JD et al, 1997]. The reason why the TI-induced increase in acinar cell proliferation is transient is unclear.
In humans, the involvement of innervation of vagal nerves in acinar cell proliferation under an increased blood level of CCK might be low, but this is unclear [Chandra R and Liddle RA, 2009].
KE3 and KE4 in rats injected with CCK
In rats repeatedly injected subcutaneously with CCK at 7.5 or 30 Ivy dog units (IU) twice daily for 20 days, pancreatic wet weight and DNA content / 100g BW increased with a same manner compared with saline-treated rats, however, pancreatic output of amylase and trypsin in response to submaximal intravenous stimulation with CCK at 15 IU/kg/hour increased with dose-dependent manner. [Folsch UR et al, 1978].
KE3 and KE4 in rats treated with TIs
A8947, a broadleaf herbicide with trypsin inhibitory action, was fed to male rats for up to 28 days, at doses of 0, 300, 10,000, and 30,000 ppm, or 56 days, at 0 and 30,000 ppm. A8947 at 10,000 and 30,000 ppm induced significant increases in pancreatic weight, acinar cell proliferation, diffuse acinar cell hypertrophy, and the plasma CCK level after 7 days. The increases in pancreatic weight and the CCK level were maximum at day 14 and then maintained throughout the study, whereas acinar cell proliferation peaked at day 7 but then decreased to control levels by day 28 [Obourn JD et al, 1997]. MK-329, a specific CCKA receptor antagonist, completely abolished the increase in pancreatic weight induced by 30,000 ppm A8947 after 7 days [Obourn JD et al, 1997].
Weanling male Wistar rats were fed 15 diets consisting of four concentrations of purified soybean TIs (93, 215, 337, and 577 mg/100 g diet) and three protein concentrations (10%, 20%, and 30%), as well as raw and heat-treated soy flour containing 10% protein. Rats were sacrificed at 3-month intervals, starting at 6 months, over a period of 22 months [Rackis JJ et al, 1985]. Trypsin and chymotrypsin activities per 100g BW, RNA and DNA contents of pancreas indicative of pancreatic hypertrophy and hyperplasia, respectively, were already increased in all of the TI and protein-fed animals after 6-month dosing, although pancreatic nodules were increased in number at 15 months of dosing or later at 215 mg TI/100 g diet or higher [Liener IE et al, 1985].
In rats in which bile and pancreatic juice had been returned to the duodenum, intraduodenal administration of 30 mg RSF stimulated a 1-h integrated increase in pancreatic protein output of 2.2 ± 1.1 mg/h (mean ± SE) [Jordinson M et al, 1996].
Pancreatic hypertrophy was observed in rats fed an RSF-containing diet within 9 days [Rackis JJ, 1965; Watanapa P and Williamson RC, 1993].
Rats fed RSF showed a biphasic increase in acinar and duct cell proliferation, as determined by [3H]-thymidine incorporation into pancreatic DNA, on days 2–4 and again on days 7–28 after the start of RSF feeding. The first peak in DNA synthesis may represent a regenerative response to tissue damage. The second more delayed peak appears to represent the development of hyperplasia in response to a trophic stimulus [Oates PS and Morgan RG, 1984].
Rats administered TIs in drinking water for 7 days or repeatedly injected with CCK for 7 days [Yanatori Y and Fujita T, 1976] exhibited mitotic figures in the acinar, centroacinar, and intercalated portions of the pancreas and in excretory duct cells, as well as marked pancreatic hypertrophy [Oates PS and Morgan RG, 1984].
A8947, a broadleaf herbicide with trypsin inhibitory action, was fed to male rats for up to 28 days, at doses of 0, 300, 10,000, and 30,000 ppm. A8947 at 10,000 and 30,000 ppm induced significant increases in acinar cell proliferation after 7 days, followed by a decrease to control levels by 28 days [Obourn JD et al, 1997].
In the abovementioned studies [Rackis JJ et al, 1985; Liener IE et al, 1985], the increases in exocrine activity and acinar cell hyperplasia and hypertrophy were found at the earliest sacrifice (6 months). The exocrine activities and hypertrophic changes remained unchanged thereafter, whereas the hyperplastic changes became more pronounced until the final sacrifice (22 months).
These findings show that pancreatic exocrine secretion and increased acinar cell proliferation were found at 1 h and 7 days, respectively, after the start of TI or CCK treatment.
CCK was released within 1 h after intraduodenal administration of RSF, and acinar cell proliferation was elevated approximately 7 days after the start of RSF feeding, although some TIs induced transient acinar cell proliferation within 7 days as a regenerative change to acute pancreatic injury.
Known modulating factors
TIs including RSFs are reported to induce pancreatic acinar cell proliferation as well as acinar cell hypertrophy due to increased pancreatic protein secretion in rats. Administration of CCK receptor agonist and CCK also induce acinar cell hyperplasia and hypertrophy as follows.
Acinar cell changes induced by a CCK receptor agonist
A novel CCK1 receptor agonist, GI181771X, was administered to mice and/or rats at doses of 0.25–250 mg/kg/day from 7 days to 26 weeks, and pancreatic acinar cell responses were examined. The treated animals showed a wide range of morphological changes in the pancreas that were dose and time dependent, including necrotizing pancreatitis, acinar cell hypertrophy/atrophy, zymogen degranulation, focal acinar cell hyperplasia, and interstitial inflammation [Myer JR et al, 2014].
Acinar cell proliferation in rats injected with CCK
Rats 1) fed raw soybeans for 30 days, 2) administered TIs in drinking water for 7 days, or 3) repeatedly injected with CCK for 7 days exhibited increased mitotic figures in the acinar, centroacinar, and intercalated portions of the pancreas and in excretory duct cells, as well as marked pancreatic hypertrophy [Myer JR et al, 2014].
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
The effect of CCK on acinar cell proliferation differs between rodents and humans.
In rats, CCK stimulates pancreatic exocrine secretion directly via CCK1 receptors expressed on the cell surface and also via innervation of afferent vagal nerves expressing CCK1 receptors [Singer MV and Niebergall-Roth E, 2009; Pandiri AR, 2014]. Higher plasma levels of CCK might also directly stimulate acinar cell proliferation via surface CCK receptors [Yamamoto M et al, 2003].
In contrast to rats, monkeys receiving repeated doses of the CCK1 receptor agonist GI181771X for up to 52 weeks showed no hypertrophy or histopathological changes in the pancreas [Myer JR et al, 2014]. Regarding humans, obese patients treated with GI181771X for 24 weeks showed no abnormal changes in the pancreas by ultrasonography or MRI [Jordan J et al, 2008]. Moreover, some epidemiological surveys suggested that long-term ingestion of TI-containing foods does not increase the risk of pancreatic cancer [Miller RV, 1978], although oral ingestion of raw soya flour containing TIs was reported to stimulate CCK release in humans [Calam J et al, 1987].
These findings suggest that exocrine secretion in humans and primates is regulated exclusively by innervation of vagal afferent nerves expressing CCK1 receptors [Soudah HC et al, 1992; Beglinger C et al, 1992; Singer MV and Niebergall-Roth E, 2009], with little effect on acinar cell proliferation, although the possibility of direct stimulation of exocrine secretion from human pancreatic acinar cells has been suggested [Murphy JA et al, 2008].
Meanwhile, a strong relationship between pancreatic cancers and a history of subtotal gastrectomy [Mack TM et al, 1986], which induced a higher plasma CCK level in response to fat [Hopman WP et al, 1984], was reported. Therefore, the effect of CCK on acinar cell proliferation in humans is controversial.
1. Aki T, Baba N, Tobe T, Suzuki T, Nishimura I, Tsai G: [The influence of truncal vagotomy or surgical sympathectomy on the pancreatic trophic effect of trypsin inhibitor upon normal rats and major pancreatectomized rats]. Nihon Geka Gakkai Zasshi 90:586-597,1989
2. Beglinger C, Hildebrand P, Adler G, Werth B, Luo H, Delco F, Gyr K: Postprandial control of gallbladder contraction and exocrine pancreatic secretion in man. Eur J Clin Invest 22:827-834,1992
3. Calam J, Bojarski JC, Springer CJ: Raw soya-bean flour increases cholecystokinin release in man. Br J Nutr 58:175-179,1987
4. Chandra R, Liddle RA: Neural and hormonal regulation of pancreatic secretion. Curr Opin Gastroenterol 25:441-446,2009
5. Crass RA, Morgan RG: The effect of long-term feeding of soya-bean flour diets on pancreatic growth in the rat. Br J Nutr 47:119-129,1982
6. Folsch UR, Winckler K, Wormsley KG: Influence of repeated administration of cholecystokinin and secretin on the pancreas of the rat. Scand J Gastroenterol 13:663-671,1978
7. Hopman WP, Jansen JB, Lamers CB: Plasma cholecystokinin response to oral fat in patients with Billroth I and Billroth II gastrectomy Ann Surg 199:276-280,1984
8. Jordan J, Greenway FL, Leiter LA, Li Z, Jacobson P, Murphy K, Hill J, Kler L, Aftring RP: Stimulation of cholecystokinin-A receptors with GI181771X does not cause weight loss in overweight or obese patients. Clin Pharmacol Ther 83:281-287,2008
9. Jordinson M, Deprez PH, Playford RJ, Heal S, Freeman TC, Alison M, Calam J: Soybean lectin stimulates pancreatic exocrine secretion via CCK-A receptors in rats. Am J Physiol 270:G653-9,1996
10. Li Y, Owyang C: Vagal afferent pathway mediates physiological action of cholecystokinin on pancreatic enzyme secretion. J Clin Invest 92:418-424,1993
11. Liener IE, Nitsan Z, Srisangnam C, Rackis JJ, Gumbmann MR: The USDA trypsin inhibitor study. II. Timed related biochemical changes in the pancreas of rats. Qual Plant Foods Hum Nutr 35:243-257,1985
12. Mack TM, Yu MC, Hanisch R, Henderson BE: Pancreas cancer and smoking, beverage consumption, and past medical history. J Natl Cancer Inst 76:49-60,1986
13. Miller RV: Epidemiology. Alan R. Liss, New York (pp) 39-57,1978
14. Murphy JA, Criddle DN, Sherwood M, Chvanov M, Mukherjee R, McLaughlin E, Booth D, Gerasimenko JV, Raraty MG, Ghaneh P, Neoptolemos JP, Gerasimenko OV, Tepikin AV, Green GM, Reeve JR Jr, Petersen OH, Sutton R: Direct activation of cytosolic Ca2+ signaling and enzyme secretion by cholecystokinin in human pancreatic acinar cells. Gastroenterology 135:632-641,2008
15. Myer JR, Romach EH, Elangbam CS: Species- and dose-specific pancreatic responses and progression in single- and repeat-dose studies with GI181771X: a novel cholecystokinin 1 receptor agonist in mice, rats, and monkeys. Toxicol Pathol 42:260-274,2014
16. Oates PS, Morgan RG: Short-term effects of feeding raw soya flour on pancreatic cell turnover in the rat. Am J Physiol 247:G667-73,1984
17. Obourn JD, Frame SR, Chiu T, Solomon TE, Cook JC: Evidence that A8947 enhances pancreas growth via a trypsin inhibitor mechanism. Toxicol Appl Pharmacol 146:116-126,1997
18. Pandiri AR: Overview of exocrine pancreatic pathobiology. Toxicol Pathol 42:207-216,2014
19. Povoski SP, Zhou W, Longnecker DS, Jensen RT, Mantey SA, Bell RH Jr: Stimulation of in vivo pancreatic growth in the rat is mediated specifically by way of cholecystokinin-A receptors. Gastroenterology 107:1135-1146,1994
20. Rackis JJ: Physiological properties of soybean trypsin inhibitors and their relationship to pancreatic hypertrophy and growth inhibition of rats.. Fed Proc 24:1488-1493,1965
21. Rackis JJ, Gumbmann MR, Liener IE: The USDA trypsin inhibitor study. I. Background, objectives, and procedural details. Qual Plant Foods Hum Nutr 35:213-24,1985
22. Singer MV, Niebergall-Roth E: Secretion from acinar cells of the exocrine pancreas: role of enteropancreatic reflexes and cholecystokinin. Cell Biol Int 33:1-9,2009
23. Soudah HC, Lu Y, Hasler WL, Owyang C: Cholecystokinin at physiological levels evokes pancreatic enzyme secretion via a cholinergic pathway. Am J Physiol 263:G102-107,1992
24. Tashiro M, Samuelson LC, Liddle RA, Williams JA: Calcineurin mediates pancreatic growth in protease inhibitor-treated mice. Am J Physiol Gastrointest Liver Physiol 286:G784-790,2004
25. Watanapa P, Williamson RC: Experimental pancreatic hyperplasia and neoplasia: effects of dietary and surgical manipulation. Br J Cancer 67:877-884,1993
26. Yamamoto M, Otani M, Jia DM, Fukumitsu K, Yoshikawa H, Akiyama T, Otsuki M: Differential mechanism and site of action of CCK on the pancreatic secretion and growth in rats. Am J Physiol Gastrointest Liver Physiol 285:G681-687,2003
27. Yanatori Y, Fujita T: Hypertrophy and hyperplasia in the endocrine and exocrine pancreas of rats fed soybean trypsin inhibitor or repeatedly injected with pancreozymin. Arch Histol Jpn 39:67-78,1976