Page 22 - Color Atlas Of Pathophysiology (S Silbernagl Et Al, Thieme 2000)

Apoptotic Cell Death
Every day hundreds of billions of cells in our tor-independent stimulation of signaling cas-
body are eliminated and replaced by division cades. These events can be caused by ischemia,
of existing cells (→ p. 2ff.). Apoptosis, as op- toxins, massive osmotic cell shrinkage, radia-
posed to necrosis (→ p.10), is a programmed tion, or inflammation (infections, autoimmune
cell death and, like cell division (→ p. 2ff., 14), disease). This results in the inadequate death
is a finely regulated physiological mechanism. of functionally essential cells, leading to organ
It serves to adapt the tissue to changing de- insufficiency (→ B). In this way apoptosis will,
mands, to eliminate superfluous cells during for example, bring about transplant rejection,
embryonic development and to remove harmful neuronal degeneration (e.g., Parkinson’s or Alz-
cells such as tumor cells, virus-infected cells, or heimer’s disease, amyotrophic lateral sclerosis,
immune-competent cells that react against quadriplegia, multiple sclerosis) as well as
the body’s own antigens. toxic, ischemic, and/or inflammatory death of
Apoptosis is mediated by a signaling cas- liver cells (liver failure), of B cells of the pancre-
cade (→ A): protein-cleaving caspases activate atic islets (type 1 diabetes mellitus), of eryth-
sphingomyelinase that releases ceramide from
ropoietic cells (aplastic anemia), or of lympho-
Fundamentals sphingomyelin. One of the consequences is ac- cytes (immunodeficiency, e.g., in HIV infec-
tion).
tivation of the small G proteins Ras and Rac,
superoxide formation and destruction of the
Pathologically reduced apoptosis leads to
mitochondria together with liberation of cyto-
an excess of affected cells (→ C). Among the
+
–
regulation, genetic defects, or viral infections
amide inhibits K channels, activates Cl chan-
1 chrome c. By activating tyrosine kinases, cer- causes are disorders of endocrine or paracrine
nels, and acidifies the cells. MAP kinase cas- (e.g., with the Epstein–Barr virus). They pre-
cades and the cytosolic concentration of Ca 2+ vent physiological apoptosis by means of an
are also important in apoptosis. excess of antiapoptotically effective growth
Apoptosis can be encouraged by certain factors, via increased expression, for example,
genes (e.g., bax) or inhibited by others (e.g., of Bcl2, or decreased expression of functioning
bcl2). Ultimately, activation of an endonuclease p53 or CD95 ligand. Absent apoptosis of virus-
leads to DNA fragmentation, the cell loses infected cells can result in persistent infections.
electrolytes and organic osmolytes, proteins Cells that escape apoptosis can develop into
are broken down and the cell finally shrinks tumor cells. Insufficient apoptosis of immuno-
and disintegrates into small particles that are competent cells, directed against the body’s
easily taken up by macrophages. In this way own cells, is a cause of autoimmune disease. In
the cell disappears without intracellular mac- addition, an excess of cells can cause functional
romolecules being released and, therefore, abnormalities, for example, persistent proges-
without causing inflammation. terone formation in the absence of apoptosis
Apoptosis is triggered (→ A), for example, of the corpus luteum cells. Lack of apoptosis
by TNF-α, glucocorticoids, activation of the can also result in abnormal embryonic develop-
CD95(Fas/Apo1) receptor or the withdrawal of ment (e.g., syndactyly).
growth factors (GFs). DNA damage encourages
apoptosis via a p53-protein. In ischemia, for ex-
ample, the affected cells sometimes express
the CD95 receptor and thus become exposed
to apoptosis. In this way they “anticipate ne-
crotic cell death” and so at least prevent the re-
lease of intracellular macromolecules that
would cause inflammation (→ p.10).
Pathologically increased apoptosis (→ B)
can occur through the local formation of apo-
12 ptotically effective mediators, the (inappropri-
ate) expression of their receptors, or the recep-
Silbernagl/Lang, Color Atlas of Pathophysiology © 2000 Thieme
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