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Event: 1724

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. More help

Acinar cell proliferation

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. The short name should be less than 80 characters in length. More help
Acinar cell proliferation

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help

Cell term

Further information on Event Components and Biological Context may be viewed on the attached pdf.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable. More help

Organ term

Further information on Event Components and Biological Context may be viewed on the attached pdf.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable. More help

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signalling by that receptor).Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. More help
Process Object Action

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
TI-induced AC tumors KeyEvent Shigeru Hisada (send email) Under development: Not open for comment. Do not cite Under Development

Stressors

This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
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

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help
Life stage Evidence
All life stages High

Sex Applicability

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Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. More help

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

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?

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

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information.  More help

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

List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide (https://www.oecd.org/about/publishing/OECD-Style-Guide-Third-Edition.pdf) (OECD, 2015). More help

 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