Upstream eventIncreased blood CCK level
Increased acinar cell exocrine secretion
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Trypsin inhibition leading to pancreatic acinar cell tumors||adjacent||High||High|
|Homo sapiens||Homo sapiens||High||NCBI|
|Macaca fascicularis||Macaca fascicularis||High||NCBI|
|Rattus norvegicus||Rattus norvegicus||High||NCBI|
|Mus musculus||Mus musculus||High||NCBI|
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
Pancreatic exocrine secretion is regulated mainly by cholecystokinin (CCK) released by CCK-producing I cells located in the mucosa of the upper small intestine. CCK stimulates exocrine secretion directly via CCK receptors expressed on acinar cell surfaces or indirectly via vagal afferent nerves expressing CCK receptors.
There are two types of CCK receptors: CCK1 (CCK-A) and CCK2 (CCK-B or gastrin) receptors. The former shows high affinity to CCK and the latter to both CCK and gastrin [Wang BJ and Cui ZJ, 2007; Dufresne M et al, 2006].
There are species differences in CCK-mediated pancreatic exocrine secretion. In rats, exocrine secretion from pancreatic acinar cells is regulated directly by CCK1 receptors expressed on the surface of acinar cells and indirectly by vagal afferent nerves expressing CCK1 receptors. Meanwhile, in humans, pancreatic exocrine secretion is regulated mainly by vagal afferent nerves expressing CCK1 receptors [Wang BJ and Cui ZJ, 2007].
The major function of pancreatic exocrine secretion is the production and secretion of digestive enzymes. Zymogen granules located at the apical site of pancreatic acinar cells contain the precursors of multiple digestive enzymes such as trypsinogen, chymotrypsinogen, proesterases, procarboxypeptidase A and B, as well as pancreatic lipase and amylase α. These precursors are secreted by acinar cells into the small intestine, where they are activated by pepsins and peptidases [Berg JM et al, 2002].
Evidence Supporting this KER
Pancreatic exocrine secretion
The major function of pancreatic exocrine secretion is the release 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].
Regulation of pancreatic exocrine secretion via CCK and CCK receptors
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].
CCK receptor subtypes
There are two types of CCK receptors: CCK1 (CCK-A) and CCK2 (CCK-B or gastrin receptor) receptors. The CCK1 receptor exhibits high affinity to all CCK isoforms, whereas the CCK2 receptor exhibits affinity to both CCKs and gastrin [Dufresne M et al, 2006; Rehfeld JF, 2017].
Direct and indirect innervation-mediated regulation of exocrine secretion from acinar cells via CCK receptors
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 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].
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].
In rats, diversion of bile pancreatic juice induced more than ten-times increase in plasma concentration of CCK at the end of two hours diversion and caused rapid and sustained increase in pancreatic protein secretion with more than two folds at 60 minutes of diversion compared with the basal levels [Li Y and Owyang C, 1994].
Repeated injections of CCK at 1390 IU s.c. for 3 weeks significantly increased the pancreatic levels and secretion of amylase and trypsin during stimulation with 60 IU/kg-hour of CCK. Peak secretion rates of the enzymes were obtained 45 minutes after the start of the stimulation [Folsch UR et al, 1978].
Trypsin-mediated feedback control of pancreatic enzyme secretion has also been observed in humans.
Intraduodenal perfusion of phenylalanine at 10mM, 5mL/min induced a several times increase in the plasma level of CCK within 15 minutes and a four-times increase in one-hour pancreatic outputs of trypsin and chymotrypsin. Simultaneous intraduodenal perfusion of trypsin with phenylalanine lowered plasma CCK level at 24% and pancreatic output of chymotrypsin at 63% compared with the perfusion of phenylalanine alone. Moreover, intravenous infusion of CCK-8 at 20 and 40 ng/kg/h for 60 minutes showed a dose-dependent increase in pancreatic output of chymotrypsin [Owyang C et al, 1986].
Uncertainties and Inconsistencies
Quantitative Understanding of the Linkage
CCK action on the stimulation of pancreatic secretion is dose dependent. Doses of CCK that induce physiological concentrations of plasma CCK (up to ~10 pM) stimulate the vagal afferent pathway, whereas doses that produce supraphysiological CCK levels act to stimulate intrapancreatic neurons and pancreatic acini. The brief summaries are as follows:
Intravenous infusion of CCK-8 at 20 and 40 pM/kg/hour or high affinity CCKR agonist CCK-JMV-189 at 22, 44 and 88 μg/kg/hour in rats induced dose-dependent increases in pancreatic protein secretion from 15 minutes of infusion, which was blocked by the CCK1 receptor antagonist L-364,718 [Li Y et al, 1997].
Physiological level of plasma CCK (up to ~10 pM) result in stimulation of the vagal afferent pathway originating from the gastroduodenal mucosa, whereas doses that induce supraphysiological CCK levels result in stimulation of intrapancreatic neurons and pancreatic acini [Owyang C, 1996].
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].
Bile-pancreatic juice diversion in rats increases pancreatic protein secretion with more than two fold 60 minutes after the start of diversion with elevated blood level of CCK [Li Y and Owyang C, 1994].
Intravenous infusion of CCK at 60 IU/kg/hour induces the pancreatic secretion of amylase and trypsin with peak level at 45 minutes after the start of the stimulation [Folsch UR et al, 1978].
In human intraduodenal perfusion of phenylalanine at 10mM, 5mL/min induced a several times increase in the plasma level of CCK within 15 minutes and a four-times increase in one-hour pancreatic outputs of trypsin and chymotrypsin. Intravenous infusion of CCK-8 at 20 and 40 ng/kg/h for 60 minutes showed a dose-dependent increase in pancreatic output of chymotrypsin [Owyang C et al, 1986].
These results suggest that CCK-induced pancreatic exocrine secretion occur within a short time after CCK infusion or stimulation of CCK release.
Known modulating factors
Disruption of the CCK1 receptor in rats also affects pancreatic exocrine secretion [Miyasaka K et al, 1998].
Capsaicin and atropine inhibit cholinergic vagus nerve reflexes to reduce CCK-mediated pancreatic enzyme secretion [Li Y et al, 1997; Yamamoto M et al, 2003; Li Y and Owyang C, 1994; Soudah HC et al, 1992; Owyang C et al, 1986].
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Species differences in the mechanism of CCK release
Pancreatic exocrine secretion is controlled mainly by CCK released into the blood steam from intestinal mucosal I cells of the small intestine in response to the gastric contents transported to the intestine [Singer MV and Niebergall-Roth E, 2009; Rehfeld JF, 2017]. Peptides released from gastrointestinal digestion, along with fatty acids, are the main stimuli of CCK release involving several direct and indirect pathways [Caron J et al, 2017].
In humans and canines, amino acids and fatty acids in the gastric contents transported to the small intestine play a major role in stimulating CCK release, which regulates pancreatic exocrine secretion, but MP is not involved in exocrine regulation [Wang BJ and Cui ZJ, 2007]. CCK-stimulated pancreatic exocrine secretion seems to be regulated with negative feedback manner via LCRF.
In rats, however, different from other mammalian species, nutrient protein and protein hydrolysate stimulate CCK release and MP secreted by pancreatic acinar cells plays an active role in protein/protein hydrolysate-stimulated CCK release [Iwai K et al, 1988; Fushiki T et al, 1989]. Ingestion of trypsin inhibitors increases the intestinal level of MP, especially after all nutrient protein is digested in the intestines, causing a subsequent increase in the blood level of CCK. The increased CCK level stimulates pancreatic exocrine secretion of proteins including MP, which in turn further increases the release of CCK. This positive feedback response associated with MP secretion might lead to continuously elevated plasma levels of CCK [Liddle RA, 1995].
Species differences in CCKs
Several isoforms of CCK, including CCK-83, -58, -39, -33, -22, and -8, have been identified, and there are species differences in CCK isoforms (e.g., CCK-33, -22 and -58 are expressed in humans, CCK-58 in dogs, CCK-8, -33 and -58 in cats, CCK-22, -58, -3 and -8 in pigs, CCK-22 and -8 in rabbits, and CCK-58 in rats). All of these CCK isoforms have a highly conserved region of amino acids, and all are ligands of CCK1 receptors [Wang BJ and Cui ZJ, 2007].
Species differences in pancreatic exocrine secretion
In rats, CCK stimulates pancreatic exocrine secretion and acinar cell growth directly via CCK1 receptors expressed on the cell surface, and exocrine secretion is also innervated by vagal afferent nerves expressing CCK1 receptors [Singer MV and Niebergall-Roth E, 2009; Pandiri AR, 2014; Yamamoto M et al, 2003].
On the other hand, human pancreatic acinar cells do not express CCK1 receptors, and CCK-mediated exocrine secretion is regulated exclusively by innervation of vagal nerves expressing CCK1 receptors [Soudah HC et al, 1992; Beglinger C et al, 1992; Singer MV and Niebergall-Roth E, 2009], although there is some evidence of direct stimulation of exocrine secretion of human pancreatic acinar cells [Murphy JA et al, 2008].
Species differences in CCK receptors
CCK1 and CCK2 receptors are expressed in various organs and tissues including digestive and nervous systems, and there are species differences in distribution and expression levels of the receptors.
In rats, pancreatic acinar cells express mainly CCK1 receptors and no CCK2 receptors [Bourassa J et al, 1999]. CCK1 receptors are also expressed in vagal afferent nerve fibers of the gastroduodenal tract. Stimulation of the vagal nerve via CCK1 receptors as well as via physical stimulation by stomach wall distention from ingested food also promotes pancreatic exocrine secretion [Dufresne M et al, 2006].
In humans, on the other hand, CCK2 receptors are dominantly expressed in pancreatic acinar cells, with low expression of CCK1 receptors [Nishimori I et al, 1999]. Ji reported the following: 1) the mRNA level of the CCK2 receptor is higher than that of the CCK1 receptor in the human pancreas; 2) an in situ hybridization experiment showed no expression of either receptor type in the human pancreas, 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 the response in rodents.
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].
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