Extracellular acidosis delays onset of cell death in ATP-depleted hepatocytes

Gregory James Gores, A. L. Nieminen, K. E. Fleishman, T. L. Dawson, B. Herman, J. J. Lemasters

Research output: Contribution to journalArticle

180 Citations (Scopus)

Abstract

A fluorometric assay using propidium iodide total fluorescence was utilized to quantitate cell viability in hepatocyte suspensions continuously. For viable hepatocytes exposed to KCN, fluorescence was linearly proportional to lactate dehydrogenase release and to nuclear labeling by propidium iodide. In KCN-treated hepatocytes, iodoacetate eliminated the protective effect of the fed state and fructose against the onset of cell death. A model of cell death with KCN and iodoacetate was developed to mimic the ATP depletion of anoxia. This 'chemical hypoxia' was used to investigate the role of pH in cell death. At pH 7.4, cell viability decreased to 10% after 120 min, whereas at pH 5.5-7.0, cell viability was 65-85%, nearly the same as normoxic cells. During chemical hypoxia under acidotic conditions, a return of pH to 7.4 resulted in a rapid acceleration of cell killing, a 'pH paradox.' Inhibition of Na+-H+ exchange increased survival, whereas promoting exchange of intracellular Cl- for extracellular HCO3- potentiated cell killing. Monensin, a Na+-H+ ionophore, potentiated cell killing at pH 7.4 but not at pH 6.2. The results show that extracellular acidosis markedly protects against cell killing after ATP depletion, an effect that appears mediated through cytoplasmic acidification.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Cell Physiology
Volume255
Issue number3
StatePublished - 1988
Externally publishedYes

Fingerprint

Cell death
Acidosis
Hepatocytes
Cell Death
Adenosine Triphosphate
Cells
Iodoacetates
Cell Survival
Propidium
Fluorescence
Monensin
Acidification
Ionophores
Fructose
L-Lactate Dehydrogenase
Labeling
Assays
Suspensions
Hypoxia

ASJC Scopus subject areas

  • Cell Biology
  • Clinical Biochemistry
  • Physiology

Cite this

Gores, G. J., Nieminen, A. L., Fleishman, K. E., Dawson, T. L., Herman, B., & Lemasters, J. J. (1988). Extracellular acidosis delays onset of cell death in ATP-depleted hepatocytes. American Journal of Physiology - Cell Physiology, 255(3).

Extracellular acidosis delays onset of cell death in ATP-depleted hepatocytes. / Gores, Gregory James; Nieminen, A. L.; Fleishman, K. E.; Dawson, T. L.; Herman, B.; Lemasters, J. J.

In: American Journal of Physiology - Cell Physiology, Vol. 255, No. 3, 1988.

Research output: Contribution to journalArticle

Gores, GJ, Nieminen, AL, Fleishman, KE, Dawson, TL, Herman, B & Lemasters, JJ 1988, 'Extracellular acidosis delays onset of cell death in ATP-depleted hepatocytes', American Journal of Physiology - Cell Physiology, vol. 255, no. 3.
Gores, Gregory James ; Nieminen, A. L. ; Fleishman, K. E. ; Dawson, T. L. ; Herman, B. ; Lemasters, J. J. / Extracellular acidosis delays onset of cell death in ATP-depleted hepatocytes. In: American Journal of Physiology - Cell Physiology. 1988 ; Vol. 255, No. 3.
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