Model number
0200
Four and two region BTEX models without heterogeniety used to compare serotonin uptake in the pulmonary endothelium and beyond. From Jardine et al. 2013 paper.
Description
A four-region (capillary plasma, endothelium, ISF, cell) blood-tissue exchange model
was configured to describe data from serotonin uptake studies in dog lungs. Data from
the Multiple Indicator Dilution experiments of Rickaby et al. (JAP 51: 405, 1981),
Rickaby et al. (JAP 56:1170,1984), and Malcorps et al. (JAP 57: 720, 1984) were analyzed
to distinguish facilitated transport into the endothelial cells (EC) from permeation into
the interstitial fluid space via interendothelial clefts. The permeability-surface area
products, PS, for the inter-EC clefts were low, about 0.3 ml/(g·min). The serotonin
endothelial transporter kinetic parameters were Km = ~ 0.3 uM and Vmax = ~ 4 nmol/(g·min),
equivalent to a maximum PS of 13 ml/(g·min), similar to values found by Rickaby et al. 1981
using a simpler two-region, plasma/endothelium model not accounting for cleft permeation.
Because the cleft PS is so small, less than 10% of that in cardiac capillaries and ~ 2%
of the maximum EC serotonin PS, their model fits the data as well as our four-region one.
Our estimates of serotonin PS’s for transporters and for inter-EC clefts from fits to the
data of Malcorps et al and Rickaby et al 1984 were similar. While this argues that the use
of a simpler model to characterize the transporter capacity in lung capillary endothelium
gave a good approximation, our deeper analyses provides affirmation on the tightness of
the clefts and the low peri-endothelial permeability for hydrophilic solutes during normal
physiological conditions and reveals the weakness in the two region model describing
conditions of transporter inhibition and constant infusion of serotonin through the
pulmonary vasculature.
The two models in this JSim project file have no heterogeniety and are simplifications of the
four and two region models used to compare the effects of PSg on serotonin uptake. Please see
models JardineSerotonin_FourRegion (model #0198) and JardineSerotonin_TwoRegion (model #0199) for more details.
See Notes page for steps to reproduce figures in the Jardine paper (in Press).
Three curve model used to fit physiological variables to three
sets of data simulataneously.
- each separate curve has aaa, bbb, ccc, suffix on the model variable.
- Example: CMpaaa(t,x): Conc curve one for mother in plasma.
- CMpbbb(t,x): Conc curve two
- CMpccc(t,x): Conc curve three
- PSg: Passive conductance channel between Plasma and ISF
- PSecl: Concentration dependent transporter between Plasma and EC
- PSeca: Concentration dependent trans between ISF and EC
- PSpc: Conc dependent transporter between ISF and PC
- Gec: EC consumption, can be set to zero.
- Gpc: PC consumption
Constant infusion:
- Model can accomadate constant infusion of Mother substrate into system.
- At time t.min the arteriol has a concentration of CMpaaa_init.
- WHen a bolus is injected then at x1.min = Cin + CMpaaa_init.
- Can have three different infusion rates, oA four-region (capillary plasma, endothelium, ISF, cell) blood-tissue exchange model was
configured to describe data from serotonin uptake studies in dog lungs. Data from the
Multiple Indicator Dilution experiments of Rickaby et al. (JAP 51: 405,1981), Rickaby et al.
(JAP 56:1170, 1984), and Malcorp et al. (JAP 57: 720, 1984) were analyzed to distinguish
facilitated transport into the endothelial cells (EC) from permeation into the interstitial
fluid space via interendothelial clefts. The permeability-surface area products, PS, for
the inter-EC clefts were low, about 0.2 ml/(g*min). The serotonin endothelial transporter
kinetic parameters were Km = ~ 0.3 M and Vmax = ~ 4 nmol/(g*min) , equivalent to a PS of
20 ml/(g*min), similar to values found by Rickaby et al. 1981 using a simpler two-region,
plasma/endothelium model not accounting for cleft permeation. Because the cleft PS is so
small, less than 10% of that in cardiac capillaries and ~ 1% of the EC serotonin PS, their
model fits the data as well as our four-region one. Our estimates of serotonin PS’s for
transporters and for inter-EC clefts from fits to the data of Malcorps et al and Rickaby
et al 1984 were similar. While this argues that the use of a simpler model by Linehan,
Dawson et al (e.g Linehan et al: Whole Organ Approaches to Cellular Mechanism: p.427, 1998) to
characterize the transporter capacity in lung capillary endothelium gave a good approximation,
our deeper analyses provide affirmation, plus new information on the tightness of the clefts
and the low peri-endothelial permeability for hydrophilic solutes.ne for each curve.
- Assumption: THere is no uptake of Mother in Arteriols.
- Note: if just want system at a const Mother conc then modify the BCs
- so that: when (t=t.min) { CMvaa1 = 0; } becomes:
- when (t=t.min) { CMvaa1 = CMpaaa_init; }
Competitve inhibitor on PSecl, PSeca:
- Ki is the inhibitor constant (k_i/ki) , where k_i is the off rate of the
reaction: ki
E + I <-> EI
k_i
Other models in Jardine 2012 paper:
Equations
The equations for this model may be viewed by running the JSim model applet and clicking on the Source tab at the bottom left of JSim's Run Time graphical user interface. The equations are written in JSim's Mathematical Modeling Language (MML). See the Introduction to MML and the MML Reference Manual. Additional documentation for MML can be found by using the search option at the Physiome home page.
Download JSim model project file
- Download JSim model MML code (text):
- Download translated SBML version of model (if available):
- No SBML translation currently available.
- Information on SBML conversion in JSim
Model Feedback
We welcome comments and feedback for this model. Please use the button below to send comments:
References
(Primary) Jardine B, Bassingthwaighte JB, Modeling serotonin uptake in the lung shows endothelial tranporters dominate over cleft permeation, Am J Physiol Lung Cell Mol Physiol 305: L42-L55, 2013, PMID:23645496 Audi SH, Krenz GS, Linehan JH, Rickaby DA, and Dawson CA. Pulmonary Capillary Transport Function from Flow-Limited Indicators. J Appl Physiol 77: 332-351, 1994. Audi SH, Linehan JH, Krenz GS, and Dawson CA. Accounting for the heterogeneity of capillary transit times in modeling multiple indicator dilution data. Ann Biomed Eng 26: 914-930, 1998. Bassingthwaighte JB and Chaloupka M. Sensitivity Functions in the Estimation of Parameters of Cellular-Exchange. Federation Proceedings 43: 180-184, 1984. Bassingthwaighte JB, Chan ISJ, and Wang CY. Computationally Efficient Algorithms for Convection-Permeation-Diffusion Models for Blood-Tissue Exchange. Ann Biomed Eng 20: 687-725, 1992. Bassingthwaighte JB, Wang CY, and Chan IS. Blood-Tissue Exchange Via Transport and Transformation by Capillary Endothelial-Cells. Circ Res 65: 997-1020, 1989. Bassingthwaighte JB. A practical extension of hydrodynamic theory of porous transport for hydrophilic solutes. Microcirc 13: 111-118, 2006. Bassingthwaighte JB, Raymond GR, Ploger JD, Schwartz LM, and Bukowski TR. GENTEX, a general multiscale model for in vivo tissue exchanges and intraorgan metabolism. Phil Trans Roy Soc A: Mathematical, Physical and Engineering Sciences 364: 1423-1442, 2006. Brenner B, Harney JT, Ahmed BA, Jeffus BC, Unal R, Mehta JL, and Kilic F. Plasma serotonin levels and the platelet serotonin transporter. J Neurochem 102: 206-215, 2007. Brigham KL, Harris TR, and Owen PJ. [Urea-[C-14] and [Sucrose-[C-14] as Permeability Indicators in Histamine Pulmonary-Edema. J Appl Physiol 43: 99-101, 1977. Bronikowski TA, Dawson CA, Linehan JH, and Rickaby DA. A Mathematical-Model of Indicator Extraction by the Pulmonary Endothelium Via Saturation Kinetics. Mathematical Biosciences 61: 237-266, 1982. Bundgaard M. The 3-dimensional organization of tight junctions in a capillary endothelium revealed by serial-section electron-microscopy. J Ultrastructure Res 88: 1-17, 1984. Chan IS, Goldstein AA, and Bassingthwaighte JB. Sensop - a Derivative-Free Solver for Nonlinear Least-Squares with Sensitivity Scaling. Ann Biomed Eng 21: 621-631, 1993. Cioffi DL, Moore TM, Schaack J, Creighton JR, Cooper DMF, and Stevens T. Dominant regulation of interendothelial cell gap formation by calcium-inhibited type 6 adenylyl cyclase. Journal of Cell Biology 157: 1267-1278, 2002. Cousineau DF, Goresky CA, Rouleau JR, and Rose CP. Microsphere and dilution measurements of flow and interstitial space in dog heart. J Appl Physiol 77: 113-120, 1994. Crone C. Does `restricted diffusion' occur in muscle capillaries?. PSEBM 112: 453-455, 1963b. Dash RK and Bassingthwaighte JB. Simultaneous blood-tissue exchange of oxygen, carbon dioxide, bicarbonate, and hydrogen ion. Ann Biomed Eng 34: 1129-1148, 2006. Dawson CA, Linehan JH, Rickaby DA, and Bronikowski TA. Kinetics of Serotonin Uptake in the Intact Lung. Ann Biomed Eng 15: 217-227, 1987. Dixon M and Webb EC. Enzymes. London: Longman Group Ltd, 1979. 332-336. Effros RM and Praker JC. Pulmonary vascular heterogeneity and the Starling hypothesis. Microvasc Res 78: 71-77, 2009. Flink JR, Pitt BR, Hammond GL, and Gillis CN. Selective effect of microembolization on pulmonary removal of biogenic-amines. Journal of Applied Physiology 52: 421-427, 1982. Geng WP, Schwab AJ, Hori T, Goresky CA, and Pang KS. Hepatic uptake of bromosulfophthalein-glutathione in perfused Eisai hyperbilirubinemic mutant rat liver: A multiple-indicator dilution study. J Pharm and Exp Therapeutics 284: 480-492, 1998. Gonzalez F and Bassingthwaighte JB. Heterogeneities in regional volumes of distribution and flows in the rabbit heart. Am J Physiol Heart Circ 258: H1012-H1024, 1990. Gorman MW, Bassingthwaighte JB, Olsson RA, Sparks HV, Endothelial-Cell Uptake of Adenosine in Canine Skeletal-Muscle, AJP 250:H482-489, 1986 Hodgson L and Tarbell JM. Solute transport to the endothelial intercellular cleft: The effect of wall shear stress. Ann Biomed Eng 30: 936-945, 2002. King RB, Raymond GM, and Bassingthwaighte JB. Modeling blood flow heterogeneity. Ann Biomed Eng 24: 352-372, 1996. Knopp TJ and Bassingthwaighte JB. Effect of Flow on Transpulmonary Circulatory Transport Functions. J Appl Physiol 27: 36-43, 1969. Linehan JH, Audi SH, and Dawson CA. The Uptake and Metabolism of Substrates in the Lung. In: Whole Organ Approaches to Cellular Mechanism, edited by Bassingthwaighte J, Goresky CA and Linehan JH. New York: Springer-Verlag, p. 427-437, 1998. Malcorps CM, Dawson CA, Linehan JH, Bronikowski TA, Rickaby DA, Herman AG, and Will JA. Lung Serotonin Uptake Kinetics from Indicator-Dilution and Constant-Infusion Methods. J Appl Physiol 57: 720-730, 1984. Marcos E, Adnot S, Pham MH, Nosjean A, Raffestin B, Hamon M, and Eddahibi S. Serotonin transporter inhibitors protect against hypoxic pulmonary hypertension. American Journal of Respiratory and Critical Care Medicine 168: 487-493, 2003 Meyer EC, Ottavian R, Right Lymphatic Duct Distribution Volume in Dogs – Relationship to Pulmonary Interstitial Volume, Circ Research, 35(2):197-203, 1974 Moffett TC, Chan IS, and Bassingthwaighte JB. Myocardial Serotonin Exchange - Negligible Uptake by Capillary Endothelium. Am J Physiol 254: H570-H577, 1988. Neufeld GR, Williams JJ, Graves DJ, Soma LR, and Marshall BE. Pulmonary Capillary-Permeability in Man and a Canine Model of Chemical Pulmonary-Edema. Microvasc Res 10: 192-207, 1975. Ochoa CD and Stevens T. Studies on the cell biology of interendothelial cell gaps. Am J Physiol-Lung Cell Mol Physiol 302: L275-L286, 2012. Parker JC, Stevens T, Randall J, Weber DS, King JA, Hydraulic conductance of pulmonary microvascular and macrovascular endothelial cell monolayers, Am J Physiol-Lung Cell Mol Physiol, 291:L30-L37, 2006 Peeters FAM, Bronikowski TA, Dawson CA, Linehan JH, Bult H, and Herman AG. Kinetics of Serotonin Uptake in Isolated Rabbit Lungs. J Appl Physiol 66: 2328-2337, 1989. Poulain CA, Finlayson BA, and Bassingthwaighte JB. Efficient numerical methods for nonlinear-facilitated transport and exchange in a blood-tissue exchange unit. Ann Biomed Eng 25: 547-564, 1997. Rickaby DA, Linehan JH, Bronikowski TA, and Dawson CA. Kinetics of Serotonin uptake in the dog lung. J Appl Physiol 51: 405-414, 1981. Rickaby DA, Dawson CA, and Linehan JH. Influence of Blood and Plasma-Flow Rate on Kinetics of Serotonin Uptake by Lungs. J Appl Physiol 53: 677-684, 1982. Rickaby DA, Dawson CA, and Linehan JH. Influence of Embolism and Imipramine on Kinetics of Serotonin Uptake by Dog Lung. J Appl Physiol 56: 1170-1177, 1984. Royston BD, Webster NR, and Nunn JF. Time course of changes in lung permeability and edema in the rat exposed to 100-percent oxygen. Journal of Applied Physiology 69: 1532-1537, 1990. Schwartz LM, Bukowski TR, Revkin JH, and Bassingthwaighte JB. Cardiac endothelial transport and metabolism of adenosine and inosine. Am J Physiol Heart Circ Physiol 277: H1241-H1251, 1999. Selinger SL, Bland RD, Demling RH, Staub NC, Distribution volumes of [131I]albumin, [14C]sucrose, and 36Cl in sheep lung, J Appl Physiol, 39(5):773-779, 1975 Sur C, Betz H, and Schloss P. Distinct effects of imipramine on 5-hydroxytryptamine uptake mediated by the recombinant rat serotonin transporter SERT1. Journal of Neurochemistry 70: 2545-2553, 1998. Talvenheimo J, Fishkes H, Nelson PJ, and Rudnick G. The Serotonin Transporter Imipramine Receptor - Different Sodium Requirements for Imipramine Binding and Serotonin Translocation. J Biol Chem 258: 6115-6119, 1983. Watts SW. 5-HT in systemic hypertension: foe, friend or fantasy? Clinical Science 108: 399-412, 2005.
Key terms
serotonin
endothelium
transport modeling
pulmonary capillary permeability
convection-diffusion
capillary-tissue exchange
hydroxy-tryptamine receptors
Data
PDE
Publication
Acknowledgements
Please cite https://www.imagwiki.nibib.nih.gov/physiome in any publication for which this software is used and send one reprint to the address given below:
The National Simulation Resource, Director J. B. Bassingthwaighte, Department of Bioengineering, University of Washington, Seattle WA 98195-5061.
Model development and archiving support at https://www.imagwiki.nibib.nih.gov/physiome provided by the following grants: NIH U01HL122199 Analyzing the Cardiac Power Grid, 09/15/2015 - 05/31/2020, NIH/NIBIB BE08407 Software Integration, JSim and SBW 6/1/09-5/31/13; NIH/NHLBI T15 HL88516-01 Modeling for Heart, Lung and Blood: From Cell to Organ, 4/1/07-3/31/11; NSF BES-0506477 Adaptive Multi-Scale Model Simulation, 8/15/05-7/31/08; NIH/NHLBI R01 HL073598 Core 3: 3D Imaging and Computer Modeling of the Respiratory Tract, 9/1/04-8/31/09; as well as prior support from NIH/NCRR P41 RR01243 Simulation Resource in Circulatory Mass Transport and Exchange, 12/1/1980-11/30/01 and NIH/NIBIB R01 EB001973 JSim: A Simulation Analysis Platform, 3/1/02-2/28/07.