Biomedical Engineering Reference
In-Depth Information
Fig. 1 Schematic
representation of important
cell responses versus
biomaterials or drugs
apoptosis
no visible
effects
o
v
i
i
l
cytotoxic
effects
necrosis
fuse
stress
stress
responses
hypertrophy
responses
trans/dedifferentiate
enlarge &
enlarge &
divide
divide
arrested
mode
shrink
change in cell-
cell interactions
change in
motility
cytoeffective
pathways by which the response may be (primarily) induced are summarized in
Fig.
2
. The importance of these pathways in the appearance of the cell responses
is strongly dependent on the exposure period and/or the period between start of
the exposure and the time-point at which the cell response is assessed (which
need not always to be the same). By prolonging the period between start of the
exposure and time-point at which effects are measured, the possible mechanisms
by which the cell responses are induced also increase, and thus the kind of
appearances of the effects in the test concentration range. If the period between
start of the exposure and measurement of the effects is very short, observed
effects are mainly based on acute responses, i.e. the induction of cell necrosis.
Apoptosis may also become manifest if the time period is prolonged, e.g. after 2
h when treating cardiomyocytes with 0.1 mM H
2
O
2
[
134
], or in the case of
treating SCC-9 cells with 50 lM quercetin after 72 h [
64
]. These two toxins
reveal one of the problematic points with regard to standard testing methods: the
appearance of the cell response is not a fixed event, but may vary tremendously
and is highly specific as to the function of the compound and the cell phenotype;
in this case the difference is a factor of 36. While necrosis and apoptosis are
early effects, the consequences for cell proliferation can be measured only if the
treatment period is further increased corresponding to the normal proliferation
rate of the cells used. The consequences becomes more visible by progressing
the treatment period. Effects on cell number manifest only after many days in
cell culture, e.g. six days for 300 lM and at least ten days for 30 lM AlCl
3
on
osteoprogenitor cells [
15
].
Compounds may interact in two different ways [
27
]. (1) By a direct interaction
with the target cell protein inducing the effects. For this kind of response, a single
moment of a critical concentration is needed to induce the effect. Cell necrosis is
an effect which is probably induced by direct interaction. (2) By accumulation of
the toxicant in a sensitive cell compartment. Effects are induced if a critical
concentration is reached. For this accumulation, the compound has to be taken
up by the cell and transported into the sensitive or target cell compartment.
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