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.
  
  
  
  Cytotoxic edema most commonly results from energy shortage, such as in cerebral ischemia, and refers to the swelling of brain cells due to the entry of water from the extracellular space. We show that the principle of electroneutrality explains why chloride influx is essential for the development of cytotoxic edema. With the help of a biophysical model of a single neuron, we show that a tipping point of the energy supply exists, below which the cell volume rapidly increases. We simulate realistic time courses to and reveal critical components of neuronal swelling in conditions of low energy supply. Furthermore, we show that, after transient blockade of the energy supply, cytotoxic edema may be reversed by temporary blockade of Na+channels.
authors.affiliation: Departments of Applied Mathematics and koen.dijkstra@utwente.nl m.j.a.m.vanputten@utwente.nl.
authors.forename: Koen
authors.identifier: 0000-0002-4076-2662
authors.initials: K
authors.lastname: Dijkstra
authors.affiliation: Clinical Neurophysiology, University of Twente, 7522 NB Enschede, The Netherlands.|Department of Neurology, Rijnstate Ziekenhuis, 6815 AD Arnhem, The Netherlands, and.
authors.forename: Jeannette
authors.identifier: 0000-0002-7593-5674
authors.initials: J
authors.lastname: Hofmeijer
authors.affiliation: Departments of Applied Mathematics and.
authors.forename: Stephan A
authors.initials: SA
authors.lastname: van Gils
authors.affiliation: Clinical Neurophysiology, University of Twente, 7522 NB Enschede, The Netherlands, koen.dijkstra@utwente.nl m.j.a.m.vanputten@utwente.nl.|Department of Neurology and Clinical Neurophysiology, Medisch Spectrum Twente, 7512KZ Enschede, The Netherlands.
authors.forename: Michel J A M
authors.identifier: 0000-0001-8319-3626
authors.initials: MJ
authors.lastname: van Putten
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001929:Brain Edema / Q000378:metabolism* / Q000473:pathology; D048429:Cell Size; D018118:Chloride Channels / Q000378:metabolism*; D002713:Chlorine / Q000378:metabolism*; D003198:Computer Simulation; D006801:Humans; D015640:Ion Channel Gating; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
chemical_list: D018118:Chloride Channels; D015222:Sodium Channels; D002713:Chlorine; D000255:Adenosine Triphosphate; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase
keywords: ATP; Gibbs–Donnan equilibrium; cytotoxic edema; electrodiffusion; osmosis