Model number


Four region BTEX model used to describe serotonin uptake in the pulmonary endothelium and beyond. From Jardine et al. 2013 paper.


 A four-region (capillary plasma, endothelium, ISF, cell) multipath model was configured to
describe the kinetics of blood-tissue exchange for small solutes in the lung, accounting for
regional flow heterogeneity, permeation of cell membranes and through interendothelial
clefts, and intracellular reactions. Serotonin uptake data from the Multiple Indicator
Dilution “bolus sweep” 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) and the inhibition of tracer transport by
non-tracer serotonin in the bolus of injectate from the free uninhibited permeation through
the clefts into the interstitial fluid space. The permeability-surface area products, PS, for
serotonin via the inter-EC clefts were about 0.3 ml/(g·min), low compared to the
transporter-mediated maximum PS of 13 ml/(g·min), (with Km = ~ 0.3 uM and Vmax = ~4
nmol/(g·min)). The estimates of serotonin PS’s for EC transporters from their multiple data
sets were similar, and were influenced only modestly by accounting for the cleft
permeability in parallel. The cleft PS estimates in these Ringer-perfused lungs are less than
half of those for anesthetized dogs (Yipintsoi, Circ Res 39:523, 1976) with normal
hematocrits, but are compatible with passive non-carrier-mediated transport observed later
in the same laboratory (Dawson et al. ABE 15: 217, 1987; Peeters et al. JAP 66:2328, 1989)
The identification and quantitation of the cleft pathway conductance from these studies
affirms the importance of the cleft permeation.

 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

 Capillary heterogeneity is taken into account. 
 - This is done by creating separate paths and assigning a relative mass to each, 
 - creating a simple probabilty density function based on flow (Fp).
 - Currently, seven (7) paths used.
 - Example paths for first curve (CMpaaa(t,x)): CMpaa1(t,x), CMpab1(t,x), CMpac1(t,x)
 - Path flows are relative to average plasma flow.

 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, one 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

Other models referenced in Jardine 2013 paper:

Supplemental modeling information for Jardine 2013 paper:


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.

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 (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, 

 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. Permeability of capillaries in various organs as determined by use of indicator 
 diffusion method. Acta Physiologica Scandinavica 58:292-305, 1963a.

 Crone C. Does ‘restricted diffusion’ occur in muscle capillaries? PSEMB 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. J Appl Physiol 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, Am J Physiol Heart Circ 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.

 Kellen MR, and Bassingthwaighte JB. Transient transcapillary exchange of water driven by osmotic 
 forces in the heart. Am J Physiol Heart Circ 285: H1317-H1331, 2003

 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.

 Kuikka J, Levin M, and Bassingthwaighte JB. Multiple tracer dilution estimates of 
 D- and 2-deoxy-D-glucose uptake by the heart. Am J Physiol Heart Circ 250: H29-H42, 1986.)

 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

 Parker JC. Hydraulic conductance of lung endothelial phenotypes and Starling safety factors against 
 edema. Am J Physiol-Lung Cell Mol Physiol 292: L378-L380, 2007

 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. J Appl Physiol 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.

 Tancredi R, Caldini P, Shanoff M, Permutt S, and Zierler K. The pulmonary microcirculation 
 evaluated by tracer dilution techniques. Chapter 17 in Cardiovascular Nuclear Medicine, 
 Ed HW Strauss, B Pitt, and AE James, CV Mosby, St Louis 255-260, 1974.

 Tancredi RG and Yipintsoi T. Interrelationships of flow, intravascular pressure, and tissue 
 perfusion in the measurement of capillary permeability to sodium in isolated dog lung lobes. 
 Circ Res 46: 669-680, 1980.

 Watts SW. 5-HT in systemic hypertension: foe, friend or fantasy? Clinical Science 108: 399-412, 2005.

 Yipintsoi T. Single-passage extraction and permeability estimation of sodium in normal dog lungs. 
 Circ Res 39: 523-531, 1976.

Key terms
transport modeling
pulmonary capillary permeability
capillary-tissue exchange
hydroxy-tryptamine receptors

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.