Review
Necrotic volume increase and the early physiology of necrosis

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Abstract

Whether a lethally injured mammalian cell undergoes necrosis or apoptosis may be determined by the early activation of specific ion channels at the cell surface. Apoptosis requires K+ and Cl efflux, which leads to cell shrinking, an active phenomenon termed apoptotic volume decrease (AVD). In contrast, necrosis has been shown to require Na+ influx through membrane carriers and more recently through stress-activated non-selective cation channels (NSCCs). These ubiquitous channels are kept dormant in viable cells but become activated upon exposure to free-radicals. The ensuing Na+ influx leads to cell swelling, an active response that may be termed necrotic volume increase (NVI). This review focuses on how AVD and NVI become conflicting forces at the beginning of cell injury, on the events that determine irreversibility and in particular, on the ion fluxes that decide whether a cell is to die by necrosis or by apoptosis.

Section snippets

To apoptose or to necrose?

Whether cells die by apoptosis or by necrosis can have profound implications for local homeostasis and this has much to do with tissue inflammation. Necrosis is pro-inflammatory, while apoptosis is anti-inflammatory. A mechanism to explain this contrast was suggested by the observation that necrotic cells and apoptotic cells elicit opposite effects on the cytotoxic and phagocitic activities of tissue macrophages (Voll et al., 1997, Fadok et al., 1998, Melcher et al., 1998). The

Early ionic events in cell death

Necrotic cell death is characterised by a relatively stereotyped sequence of events. Regardless of the primary insult, e.g. anoxia, metabolic inhibitors, free radicals, etc, ATP levels (or more critically [ATP]i/[ADP]i) drop to near zero in the matter of seconds. In anoxia or chemical hypoxia, energy depletion is adequately explained by defective ATP production in the face of continued ATP hydrolysis by ion pumps, protein synthesis and degradation, etc. In free radical-induced necrosis, the

Ion channels as effectors of cell death

In stressed cells, passive inhibition of the Na+/K+ pump have long been thought to play a major role in the intracellular accumulation of Na+ (Cotran et al., 1999). However, recent data from several laboratories are in conflict with such hypothesis. For example, the rate of accumulation elicited by menadione or KCN was 10-fold higher than that evoked by the pump blocker ouabain (Carini et al., 1999). In endothelial cells, exposure to tert-butyl hydroperoxide not only failed to inhibit but

Positive feedbacks and negative cross-talk in early cell death

Several positive feedback loops that close during early cell injury make of NVI a highly regenerative phenomenon. Upon activation of NSCCs by free-radicals or low [ATP]i, high [Na+]i will activate the Na+/K+ pump, which will in turn decrease cell ATP and further activate NSCCs. NSCC, by a mechanism that is not yet clear, can cause a massive increase in cytosolic Ca2+ (Fig. 1). High calcium will perpetuate ATP depletion by several mechanisms including Ca2+-ATPase activation, further NSCC

Acknowledgements

We thank Claudio Hetz for helpful discussions. This work was supported by Fondecyt 1990782. Institutional support to the Centro de Estudios Cientı́ficos (CECS) from Fuerza Aérea de Chile, I. Municipalidad de Las Condes and a group of chilean private companies (AFP Provida, CODELCO, Empresas CMPC, Telefónica del Sur y Masisa S.A.) is also acknowledged. We thank support obtained through the International Program of the Howard Hughes Medical Institute and Cátedra Presidencial en Ciencias (to

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