Page 20 - Color Atlas Of Pathophysiology (S Silbernagl Et Al, Thieme 2000)

Necrotic Cell Death
The survival of the cell is dependent on the also occur when the energy supply is compro-
+
maintenance of cell volume and the intracellu- mised, or when Na entry exceeds the maxi-
+
+
lar milieu (→ A). As the cell membrane is high- mal transport capacity of the Na /K -ATPase.
ly permeable to water and water follows the Numerous endogenous substances (e.g., the
osmotic gradient (→ A1), the cell depends on neurotransmitter glutamate) and exogenous
osmotic equilibrium to maintain its volume. poisons (e.g., oxidants) increase the entry of
+
In order to counterbalance the high intracellu- Na and/or Ca 2+ via the activation of the re-
lar concentration of proteins, amino acids, and spective channels (→ B).
+
other organic substrates, the cell lowers the The increase in intracellular Na concentra-
cytosolic ionic concentration. This is done by tion not only leads to cell swelling, but also, via
+
+
+
+
Na /K -ATPase, which pumps Na out of the impairment of the 3Na /Ca 2+ exchanger, to an
+
cell in exchange for K (→ A2). Normally the increase in cytosolic Ca 2+ concentration. Ca 2+
cell membrane is only slightly permeable for produces a series of cellular effects (→ p. 6ff.);
+
+
Na (→ A3), but highly permeable for K , so among others it penetrates into the mitochon-
+
+
that K diffuses out again (→ A4). This K -ef-
dria and, via inhibition of mitochondrial res-
Fundamentals flux creates an inside negative potential piration, leads to ATP deficiency (→ B).
–
(→ A5) which drives Cl out of the cell (→
If there is a lack of O 2 , energy metabolism
A6). In this ionic shift, which uses up adeno-
switches to anaerobic glycolysis. The forma-
sine 5′-triphosphate (ATP), reduction of the cy-
tion of lactic acid, which dissociates into lac-
+
–
+
terferes with the functions of the intracellular
up to ca. 230 mosm/L) is much greater than
1 tosolic concentration of Na and Cl (adding tate and H , causes cytosolic acidosis that in-
the rise in cytosolic K + concentration (ca. enzymes, thus resulting in the inhibition of the
140 mosm/L). glycolysis so that this last source of ATP dries
Reduction in intracellular Na + concentra- up (→ B).
+
+
tion by Na /K -ATPase is necessary not only to If an energy deficiency arises, the cell is
avoid cell swelling, but also because the steep more likely to be exposed to oxidative damage,
+
electrochemical gradient for Na is utilized for because the cellular protective mechanisms
+
+
a series of transport processes. The Na /H ex- against oxidants (O 2 radicals) are ATP-depen-
+
changer (→ A9) eliminates one H for one Na , + dent (→ B). There is then a risk of the cell
+
while the 3 Na /Ca 2+ exchanger (→ A8) elimi- membrane being destroyed (lipid peroxida-
+
+
nates one Ca 2+ for 3 Na . Na -bound transport tion) and intracellular macromolecules being
processes also allow the (secondarily) active released in the intracellular space. As the im-
uptake of amino acids, glucose, etc. into the mune system is not normally exposed to intra-
cell (→ A7). Lastly, depolarization achieved by cellular macromolecules, there is no immune
+
opening the Na channels (→ A10) serves to tolerance to them. The immune system is acti-
regulate the function of excitable cells, e.g. the vated and inflammation occurs, resulting in
signal processing and transmission in the ner- further cell damage.
vous system and the triggering of muscle con- The time-span before necrotic cell death oc-
tractions. curs due to interruption of energy supply de-
+
+
As the activity of Na -transporting carriers pends on the extent of Na entry, thus, for ex-
+
and channels continuously brings Na into the ample, on the activity of excitable cells or the
cell, survival of the cell requires the continu- transport rate of epithelial cells. As the volt-
+
+
+
ous activity of Na /K -ATPase. This intracellu- age-gated Na channels of excitable cells are
+
lar Na homeostasis may be disrupted if the activated by depolarization of the cell mem-
+
+
activity of Na /K -ATPase is impaired by ATP brane, depolarization can accelerate cell death.
deficiency (ischemia, hypoxia, hypoglycemia).
+
The intracellular K decreases as a result, ex-
+
tracellular K rises, and the cell membrane is
–
10 depolarized. As a consequence, Cl enters the
cell and the cell swells up (→ B). These events
Silbernagl/Lang, Color Atlas of Pathophysiology © 2000 Thieme
All rights reserved. Usage subject to terms and conditions of license.