Only a few techniques are being used to determine the occurrence
of cell death, e.g. in pathological mouse models. A fast and
easy way to determine the occurrence of cell death in tissues and
organs is by measuring the presence in plasma of cellular content
such as LDH or mitochondrial DNA [69]. Release of other cellular
components such as HMGB1 [70], IL-1a [71], IL-33 [72] and Cyclophillin
A [73] is considered to be a necrosis marker, but this is not
exclusively linked to cell death, as other conditions such as macrophage
activation can also trigger their release [74]. Circulating
histones were also detected in the sera of septic patients [75],
and they might have been linked to cell death. As the release of cellular
content is a typical hallmark of necrosis, circulating levels of
these cellular contents are likely to reflect necrotic cell death.
However, when apoptosis is extensive, this cell death mode in
pathological conditions might also proceed to secondary necrosis.
Therefore, the release of markers should be combined with the
detection of posttranslational modifications, such as specific proteolytic
events. Detection of CK18 or its cleavage product is discussed
in Section 5.4. To identify the precise location of cell death, one can
use TUNEL or staining with an antibody against caspase-3 on sections
of different organs. Activation of caspase-3 in TUNEL-positive
cells strongly indicates the occurrence of apoptosis. Currently,
there is no unique marker for necrosis, and therefore discriminative
criteria are additionally applied to define necrosis as cell death
in the absence of caspase activation.