Computer Model of Transporting Epithelial Cells. Analysis of Current-Voltage and Current-Time Curves

Larsen, Erik Hviid; Rasmussen, Bjørn E.; Willumsen, Niels J.

doi:10.1016/b978-0-08-026815-6.50015-7

Cited by 3 publications

(1 citation statement)

References 16 publications

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“…Both models focused on the electric driving forces of the airway epithelium but did not take into account the liquid transport (Latta et al, 1984). This aspect was addressed in physiological models designed to simulate the in vivo airway epithelium and to study the ion and water balance in this tissue (Hodgkin & Huxley, 1952; Larsen et al, 1981; Lew et al, 1979). For example, Novotny and Jakobsson (1996a, 1996b) proposed a model with 12 variables representing concentrations, volumes, and membrane potentials and including all osmotically significant membrane transport processes known at the time: passive apical Na + and Cl − movement, basolateral Na + –K + pumping, basolateral Na + –K + –Cl − cotransport, passive basolateral K + movement, nonselective passive paracellular ion motion, and water transport across all membranes.…”

Section: Anchor Models Of Cfmentioning

confidence: 99%

Mathematical models of cystic fibrosis as a systemic disease

Olivença

Davis

Kumbale

et al. 2023

WIREs Mechanisms of Disease

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Cystic fibrosis (CF) is widely known as a disease of the lung, even though it is in truth a systemic disease, whose symptoms typically manifest in gastrointestinal dysfunction first. CF ultimately impairs not only the pancreas and intestine but also the lungs, gonads, liver, kidneys, bones, and the cardiovascular system. It is caused by one of several mutations in the gene of the epithelial ion channel protein CFTR. Intense research and improved antimicrobial treatments during the past eight decades have steadily increased the predicted life expectancy of a person with CF (pwCF) from a few weeks to over 50 years. Moreover, several drugs ameliorating the sequelae of the disease have become available in recent years, and notable treatments of the root cause of the disease have recently generated substantial improvements in health for some but not all pwCF. Yet, numerous fundamental questions remain unanswered. Complicating CF, for instance in the lung, is the fact that the associated insufficient chloride secretion typically perturbs the electrochemical balance across epithelia and, in the airways, leads to the accumulation of thick, viscous mucus and mucus plaques that cannot be cleared effectively and provide a rich breeding ground for a spectrum of bacterial and fungal communities. The subsequent infections often become chronic and respond poorly to antibiotic treatments, with outcomes sometimes only weakly correlated with the drug susceptibility of the target pathogen. Furthermore, in contrast to rapidly resolved acute infections with a single target pathogen, chronic infections commonly involve multi‐species bacterial communities, called “infection microbiomes,” that develop their own ecological and evolutionary dynamics. It is presently impossible to devise mathematical models of CF in its entirety, but it is feasible to design models for many of the distinct drivers of the disease. Building upon these growing yet isolated modeling efforts, we discuss in the following the feasibility of a multi‐scale modeling framework, known as template‐and‐anchor modeling, that allows the gradual integration of refined sub‐models with different granularity. The article first reviews the most important biomedical aspects of CF and subsequently describes mathematical modeling approaches that already exist or have the potential to deepen our understanding of the multitude aspects of the disease and their interrelationships. The conceptual ideas behind the approaches proposed here do not only pertain to CF but are translatable to other systemic diseases.This article is categorized under: Congenital Diseases > Computational Models

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Section: Anchor Models Of Cfmentioning

confidence: 99%

Mathematical models of cystic fibrosis as a systemic disease

Olivença

Davis

Kumbale

et al. 2023

WIREs Mechanisms of Disease

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Exchange diffusion, electrodiffusion and rectification in the chloride transport pathway of frog skin

Kristensen¹

1983

J. Membrain Biol.

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Measurements of chloride flux ratios across frog skin at different clamping voltages showed that chloride transport at clamping voltages from 0 mV to and beyond the spontaneous potential is probably electrodiffusion. At reversed potentials a significant fraction of chloride transport could be described formally as exchange diffusion. Chloride conductance was found to be highly voltage dependent, being largest at hyperpolarizing clamping voltages. The transition from the less conducting state to the more conducting one was studied by recording the time course of the current after a step change in clamping voltage from 0 mV to hyperpolarizing voltages. The shape of the curve is sigmoidal, and the relative rate of change of current increases with increasing hyperpolarization. It is proposed that the change in conductance is governed by the same mechanism as in the toad skin, namely a change in chloride permeability due to voltage gating of chloride channels. The time course of transepithelial conductance after addition of amiloride to the outside solution indicates that a fraction of the decrease in conductance is due to closure of chloride channels caused by the change in intracellular potential due to the inhibition of the sodium channels.

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Chloride channels in toad skin

Larsen

Be²

1982

Phil. Trans. R. Soc. Lond. B

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A study of the voltage and time dependence of a transepithelial Cl- current in toad skin (Bufo bufo) by the voltage-clamp method leads to the conclusion that potential has a dual role for Cl- transport. One is to control the permeability of an apical membrane Cl-pathway, the other is to drive Cl- ions through this pathway. Experimental analysis of the gating kinetics is rendered difficult owing to a contamination of the gated currents by cellular ion redistribution currents. To obtain insight into the effects of accumulation-depletion currents on voltage clamp currents of epithelial membranes, a mathematical model of the epithelium has been developed for computer analysis. By assuming that the apical membrane Cl- permeability is governed by a single gating variable (Hodgkin-Huxley kinetics), the model predicts fairly well steady-state current-voltage curves, the time course of current activations from a closed state, and the dependence of unidirectional fluxes on potential. Other predictions of the model do not agree with experimental findings, and it is suggested that the gating kinetics are governed by rate coefficients that also depend on the holding potential. Evidence is presented that Cl- transport through open channels does not obey the constant-field equation.

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Computer Model of Transporting Epithelial Cells. Analysis of Current-Voltage and Current-Time Curves

Cited by 3 publications

References 16 publications

Mathematical models of cystic fibrosis as a systemic disease

Mathematical models of cystic fibrosis as a systemic disease

Exchange diffusion, electrodiffusion and rectification in the chloride transport pathway of frog skin

Chloride channels in toad skin

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