API

Event: 1724

Key Event Title

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Acinar cell proliferation

Short name

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Acinar cell proliferation

Biological Context

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Level of Biological Organization
Cellular

Cell term

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Organ term

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Key Event Components

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Process Object Action

Key Event Overview


AOPs Including This Key Event

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AOP Name Role of event in AOP
TI-induced AC tumors KeyEvent

Stressors

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Taxonomic Applicability

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Term Scientific Term Evidence Link
Homo sapiens Homo sapiens Moderate NCBI
Macaca fascicularis Macaca fascicularis Moderate NCBI
Rattus norvegicus Rattus norvegicus High NCBI
Mus musculus Mus musculus High NCBI

Life Stages

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Life stage Evidence
All life stages High

Sex Applicability

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Key Event Description

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The major function of pancreatic exocrine secretion is secretion of digestive enzymes, fluid, and bicarbonate in response to food intake. Zymogen granules located at the apical site of pancreatic acinar cells contain the precursors of multiple digestive enzymes, such as trypsinogen, chymotrypsinogen, proesterase, procarboxypeptidase A and B, as well as pancreatic lipase and amylase α. These precursors are secreted into the small intestine, where trypsinogen is converted to trypsin by enteropeptidase, and the newly generated trypsin activates more trypsinogen molecules and other proenzymes [Berg JM et al, 2002].

Pancreatic exocrine secretion is regulated mainly by CCK released from CCK-producing I cells located within the mucosa of the small intestine. CCK stimulates exocrine secretion either directly via CCK receptors expressed on acinar cells or indirectly by the vagovagal reflex via CCK receptors. There are species differences in these CCK regulatory mechanisms [Singer MV and Niebergall-Roth E, 2009; Chandra R and Liddle RA, 2009].

There are two types of CCK receptors: CCK1 (CCK-A) and CCK2 (CCK-B or gastrin) receptors. The CCK1 receptor exhibits high affinity to all CCK isoforms, whereas the CCK2 receptor exhibits affinity to both CCK and gastrin, in which the last five amino acid sequences at the C-terminus end are identical [Dufresne M et al, 2006; Rehfeld JF, 2017].

In rats, pancreatic acinar cells express mainly CCK1 receptors, and blood CCK directly stimulates exocrine secretion and acinar cell proliferation [Dufresne M et al, 2006]. Moreover, the vagal afferent nerves also stimulate pancreatic exocrine secretion; CCK stimulates CCK1 receptors expressed on the vagal afferent nerve fibers of the vago–vagal reflex loop, and the acetylcholine generated acts on M3 muscarinic cholinergic receptors to promote pancreatic exocrine secretion [Bourassa J et al, 1999; Adler G, 1997; Ji B et al, 2001; Li Y et al, 1997; Owyang C, 1996]. Moreover, when the gastric wall is distended with ingested food, the vagus nerve is stimulated to promote pancreatic exocrine secretion [Dufresne M et al, 2006].

In humans, the density of CCK receptors expressed on acinar cells is lower than that in rodents, whereas CCK2 receptors are dominantly expressed. Therefore, the responses of acinar cells to CCK seem to be weaker compared with rodents, and pancreatic exocrine secretion in humans is regulated mainly by vagal afferent nerves expressing CCK1 receptors [Wang BJ and Cui ZJ, 2007; Owyang C, 1996; Pandiri AR, 2014].


How It Is Measured or Detected

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Ex vivo procedure for measuring secretion from pancreatic acini is reported [Geron E, 2014], where ex vivo culture of pancreatic acini isolated from mice is used for amylase secretion assay as a global measure and direct imaging of pancreatic secretion with subcellular resolution.

The release of amylase was measured in dispersed acini from human pancreas [Miyasaka K et al, 2002].

Pancreatic exocrine secretion was measured in rats with chronic pancreatitis and pancreatic and biliary fistulas [Green GM and Miyasaka K, 1983]. Pancreatic juice was collected from the jejunum and the amounts of protein and pancreatic enzymes were measured.

Pancreatic enzyme activities in pancreatic outlet were measured after CCA injection [Folsch UR et al, 1978]. After repeated subcutaneous injections of CCK in rats, pancreatic enzymes were collected by perfusing duodenum. trypsin in the perfusate was activated with enterokinase and its activity was measured photometrically using benzoyl arginine as substrate. Amylase activity in the perfusate was measured using Zulkovsky starch as substrate. The concentration of protein per weight of DNA, the total level of pancreatic DNA, and the pancreatic levels of amylase and trypsin were also measured in rats after repeated CCK administration.

In the rats fed the TI camostat, pancreatic weight and protein, DNA, and enzyme contents and trypsinogen, chymotrypsinogen, and amylase levels in the pancreatic homogenates prepared 24 hours after the last administration were measured [Goke B et al, 1986]. Levels of trypsinogen and chymotrypsinogen were measured as trypsin and chymotrypsin after activation.


Domain of Applicability

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CCK1 and CCK2 receptors are expressed in various organs and tissues including the digestive and nervous systems, and there are species differences in the expression localization and levels of these receptors.

In rats, it has been reported that pancreatic acinar cells express mainly CCK1 receptors but not CCK2 receptors [Bourassa J et al, 1999]. CCK1 receptors are also expressed in vagal afferent nerve fibers of the gastroduodenal tract; stimulation of the vagus nerve via CCK1 receptors as well as via physical stimulation of stomach wall distention by ingested food also promotes pancreatic exocrine secretion [Dufresne M et al, 2006].

Meanwhile, in humans, CCK2 receptors are dominantly expressed in pancreatic acinar cells, with low expression of CCK1 receptors [Nishimori I et al, 1999]. Ji reported the following using human pancreatic acini: 1) the mRNA level of the CCK2 receptor is higher than that of the CCK1 receptor, 2) an in situ hybridization experiment showed no expression of either receptor type, and 3) human pancreatic cells did not show any response to the CCK1 receptor agonist CCK8 or the CCK2 receptor agonist gastrin in vitro [Ji B et al, 2001]. Therefore, human pancreatic acinar cells respond to CCK more weakly compared with rodents, because the CCK receptor subtypes expressed in the pancreas are different between humans and rodents, and CCK receptor expression levels are lower in humans than rodents.

In addition, exocrine secretion from the human pancreas is regulated mainly by innervation of vagal afferent nerves via CCK1 receptors and less so by direct stimulation of acinar cells via CCK receptors [Wang BJ and Cui ZJ, 2007; Owyang C, 1996; Pandiri AR, 2014]. Although the distribution of CCK receptors is different between humans and rodents, the structures of CCK1 receptors are highly conserved among mammalian species, with 98% homology between rats and mice, 90% between rats and humans, 98% between cynomolgus monkeys and humans, and 89% between dogs and humans [Wang BJ and Cui ZJ, 2007].

Multiple molecular forms of CCKs, including CCK-83, -58, -39, -33, -22, -8 among others, have been identified; all of these isoforms have a highly conserved region of 5 amino acid sequences at the C-terminal, and all are ligands for CCK1 receptors [Wank SA, 1995].


References

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 1.    Adler G: Regulation of human pancreatic secretion. Digestion 58 Suppl 1:39-41,1997

 2.    Berg JM, Tymoczko JL, Stryer L: Many enzymes are activated by specific proteolytic cleavage. Biochemistry. 5th edition. New York: W H Freeman, Section 10.5,2002

 3.    Bourassa J, Laine J, Kruse ML, Gagnon MC, Calvo E, Morisset J: Ontogeny and species differences in the pancreatic expression and localization of the CCK(A) receptors. Biochem Biophys Res Commun 260:820-828,1999

 4.    Chandra R, Liddle RA: Neural and hormonal regulation of pancreatic secretion. Curr Opin Gastroenterol 25:441-446,2009

 5.    Dufresne M, Seva C, Fourmy D: Cholecystokinin and gastrin receptors. Physiol Rev 86:805-847,2006

 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.     Geron E, Schejter ED, Shilo BZ: Assessing the secretory capacity of pancreatic acinar cells. J Vis Exp,2014

 8.    Goke B, Printz H, Koop I, Rausch U, Richter G, Arnold R, Adler G: Endogenous CCK release and pancreatic growth in rats after feeding a proteinase inhibitor (camostate). Pancreas 1:509-515,1986

 9.    Green GM, Miyasaka K: Rat pancreatic response to intestinal infusion of intact and hydrolyzed protein. Am J Physiol 245:G394-8,1983

10.    Ji B, Bi Y, Simeone D, Mortensen RM, Logsdon CD: Human pancreatic acinar cells lack functional responses to cholecystokinin and gastrin. Gastroenterology 121:1380-1390,2001

11.    Li Y, Hao Y, Owyang C: High-affinity CCK-A receptors on the vagus nerve mediate CCK-stimulated pancreatic secretion in rats. Am J Physiol 273:G679-85,1997

12.    Miyasaka K, Shinozaki H, Jimi A, Funakoshi A: Amylase secretion from dispersed human pancreatic acini: neither cholecystokinin A nor cholecystokinin B receptors mediate amylase secretion in vitro. Pancreas 25:161-165,2002

13.    Nishimori I, Kamakura M, Fujikawa-Adachi K, Nojima M, Onishi S, Hollingsworth MA, Harris A: Cholecystokinin A and B receptor mRNA expression in human pancreas. Pancreas 19:109-113,1999

14.    Owyang C: Physiological mechanisms of cholecystokinin action on pancreatic secretion. Am J Physiol 271:G1-7,1996

15.    Pandiri AR: Overview of exocrine pancreatic pathobiology. Toxicol Pathol 42:207-216,2014

16.    Rehfeld JF: Cholecystokinin-from local gut hormone to ubiquitous messenger. Front Endocrinol (Lausanne) 8:47,2017

17.    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

18.    Wang BJ, Cui ZJ: How does cholecystokinin stimulate exocrine pancreatic secretion? From birds, rodents, to humans. Am J Physiol Regul Integr Comp Physiol 292:R666-78,2007

19.    Wank SA: Cholecystokinin receptors. Am J Physiol 269:G628-646,1995