A mathematical model of the pancreatic duct cell generating high bicarbonate concentrations in pancreatic juice.
OBJECTIVE
To develop a simple, physiologically based mathematical model of pancreatic duct cell secretion using experimentally derived parameters that generates pancreatic fluid bicarbonate concentrations of >140 mM after CFTR activation.


METHODS
A new mathematical model was developed simulating a duct cell within a proximal pancreatic duct and included a sodium-2-bicarbonate cotransporter (NBC) and sodium-potassium pump (NaK pump) on a chloride-impermeable basolateral membrane, CFTR on the luminal membrane with 0.2 to 1 bicarbonate to chloride permeability ratio. Chloride-bicarbonate antiporters (Cl/HCO3 AP) were added or subtracted from the basolateral (APb) and luminal (APl) membranes. The model was integrated over time using XPPAUT.


RESULTS
This model predicts robust, NaK pump-dependent bicarbonate secretion with opening of the CFTR, generates and maintains pancreatic fluid secretion with bicarbonate concentrations >140 mM, and returns to basal levels with CFTR closure. Limiting CFTR permeability to bicarbonate, as seen in some CFTR mutations, markedly inhibited pancreatic bicarbonate and fluid secretion.


CONCLUSIONS
A simple CFTR-dependent duct cell model can explain active, high-volume, high-concentration bicarbonate secretion in pancreatic juice that reproduces the experimental findings. This model may also provide insight into why CFTR mutations that predominantly affect bicarbonate permeability predispose to pancreatic dysfunction in humans.
Whitcomb
David C
DC
Department of Medicine, University of Pittsburgh, UPMC Presbyterian, Pittsburgh, Pennsylvania 15213, USA. whitcomb@pitt.edu
Ermentrout
G Bard
GB
D000818:Animals; D001639:Bicarbonates / Q000378:metabolism*; D002463:Cell Membrane Permeability; D002712:Chlorides / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D004563:Electrochemistry; D006168:Guinea Pigs; D006801:Humans; D017136:Ion Transport; D008954:Models, Biological; D010183:Pancreatic Ducts / Q000166:cytology / Q000378:metabolism*; D010189:Pancreatic Juice / Q000737:chemistry* / Q000378:metabolism; D027982:Sodium-Bicarbonate Symporters / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
D001639:Bicarbonates; C505032:CFTR protein, human; D002712:Chlorides; D027982:Sodium-Bicarbonate Symporters; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000254:Sodium-Potassium-Exchanging ATPase