A Biophysical Model for Cytotoxic Cell Swelling

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Abstract

We present a dynamic biophysical model to explain neuronal swelling underlying cytotoxic edema in conditions of low energy supply, as observed in cerebral ischemia. Our model contains Hodgkin—Huxley-type ion currents, a recently discovered voltage-gated chloride flux through the ion exchanger SLC26A11, active KCC2-mediated chloride extrusion, and ATP-dependent pumps. The model predicts changes in ion gradients and cell swelling during ischemia of various severity or channel blockage with realistic timescales. We theoretically substantiate experimental observations of chloride influx generating cytotoxic edema, while sodium entry alone does not. We show a tipping point of Na+/K+-ATPase functioning, where below cell volume rapidly increases as a function of the remaining pump activity, and a Gibbs–Donnan-like equilibrium state is reached. This precludes a return to physiological conditions even when pump strength returns to baseline. However, when voltage-gated sodium channels are temporarily blocked, cell volume and membrane potential normalize, yielding a potential therapeutic strategy.
Original languageUndefined
Pages (from-to)11881-11890
Number of pages10
JournalJournal of neuroscience
Volume36
Issue number47
DOIs
Publication statusPublished - 23 Nov 2016

Keywords

  • cytotoxic edema
  • EWI-27480
  • ATP
  • IR-103047
  • Electrodiffusion
  • osmosis
  • METIS-320829
  • Gibbs–Donnan equilibrium

Cite this

@article{7047225a15554fb2a976784b28df28cf,
title = "A Biophysical Model for Cytotoxic Cell Swelling",
abstract = "We present a dynamic biophysical model to explain neuronal swelling underlying cytotoxic edema in conditions of low energy supply, as observed in cerebral ischemia. Our model contains Hodgkin—Huxley-type ion currents, a recently discovered voltage-gated chloride flux through the ion exchanger SLC26A11, active KCC2-mediated chloride extrusion, and ATP-dependent pumps. The model predicts changes in ion gradients and cell swelling during ischemia of various severity or channel blockage with realistic timescales. We theoretically substantiate experimental observations of chloride influx generating cytotoxic edema, while sodium entry alone does not. We show a tipping point of Na+/K+-ATPase functioning, where below cell volume rapidly increases as a function of the remaining pump activity, and a Gibbs–Donnan-like equilibrium state is reached. This precludes a return to physiological conditions even when pump strength returns to baseline. However, when voltage-gated sodium channels are temporarily blocked, cell volume and membrane potential normalize, yielding a potential therapeutic strategy.",
keywords = "cytotoxic edema, EWI-27480, ATP, IR-103047, Electrodiffusion, osmosis, METIS-320829, Gibbs–Donnan equilibrium",
author = "Koen Dijkstra and Jeannette Hofmeijer and {van Gils}, {Stephanus A.} and {van Putten}, {Michel Johannes Antonius Maria}",
note = "eemcs-eprint-27480",
year = "2016",
month = "11",
day = "23",
doi = "10.1523/JNEUROSCI.1934-16.2016",
language = "Undefined",
volume = "36",
pages = "11881--11890",
journal = "Journal of neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
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}

A Biophysical Model for Cytotoxic Cell Swelling. / Dijkstra, Koen; Hofmeijer, Jeannette; van Gils, Stephanus A.; van Putten, Michel Johannes Antonius Maria.

In: Journal of neuroscience, Vol. 36, No. 47, 23.11.2016, p. 11881-11890.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - A Biophysical Model for Cytotoxic Cell Swelling

AU - Dijkstra, Koen

AU - Hofmeijer, Jeannette

AU - van Gils, Stephanus A.

AU - van Putten, Michel Johannes Antonius Maria

N1 - eemcs-eprint-27480

PY - 2016/11/23

Y1 - 2016/11/23

N2 - We present a dynamic biophysical model to explain neuronal swelling underlying cytotoxic edema in conditions of low energy supply, as observed in cerebral ischemia. Our model contains Hodgkin—Huxley-type ion currents, a recently discovered voltage-gated chloride flux through the ion exchanger SLC26A11, active KCC2-mediated chloride extrusion, and ATP-dependent pumps. The model predicts changes in ion gradients and cell swelling during ischemia of various severity or channel blockage with realistic timescales. We theoretically substantiate experimental observations of chloride influx generating cytotoxic edema, while sodium entry alone does not. We show a tipping point of Na+/K+-ATPase functioning, where below cell volume rapidly increases as a function of the remaining pump activity, and a Gibbs–Donnan-like equilibrium state is reached. This precludes a return to physiological conditions even when pump strength returns to baseline. However, when voltage-gated sodium channels are temporarily blocked, cell volume and membrane potential normalize, yielding a potential therapeutic strategy.

AB - We present a dynamic biophysical model to explain neuronal swelling underlying cytotoxic edema in conditions of low energy supply, as observed in cerebral ischemia. Our model contains Hodgkin—Huxley-type ion currents, a recently discovered voltage-gated chloride flux through the ion exchanger SLC26A11, active KCC2-mediated chloride extrusion, and ATP-dependent pumps. The model predicts changes in ion gradients and cell swelling during ischemia of various severity or channel blockage with realistic timescales. We theoretically substantiate experimental observations of chloride influx generating cytotoxic edema, while sodium entry alone does not. We show a tipping point of Na+/K+-ATPase functioning, where below cell volume rapidly increases as a function of the remaining pump activity, and a Gibbs–Donnan-like equilibrium state is reached. This precludes a return to physiological conditions even when pump strength returns to baseline. However, when voltage-gated sodium channels are temporarily blocked, cell volume and membrane potential normalize, yielding a potential therapeutic strategy.

KW - cytotoxic edema

KW - EWI-27480

KW - ATP

KW - IR-103047

KW - Electrodiffusion

KW - osmosis

KW - METIS-320829

KW - Gibbs–Donnan equilibrium

U2 - 10.1523/JNEUROSCI.1934-16.2016

DO - 10.1523/JNEUROSCI.1934-16.2016

M3 - Article

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SP - 11881

EP - 11890

JO - Journal of neuroscience

JF - Journal of neuroscience

SN - 0270-6474

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ER -