Apoptosis is a major mechanism of programmed cell death used by
to eliminate superfluous and irreparably damaged cells. It has a crucial
role in shaping organs during development and controls homeostasis and
integrity of tissues throughout life. Apoptosis can be triggered by a wide
variety of stimuli, including developmental cues, severe cellular stress or
damage to essential cellular components, caused by heat shock, radiation,
cytotoxic drugs, infection and oncogenic transformation.
Apoptosis induction occurs through two distinct pathways: intrinsic
and extrinsic. The intrinsic pathway is activated by intracellular events
and depends on the release of proapoptotic factors from the mitochondria.
The extrinsic pathway receives signals through the binding of
extracellular protein ligands to proapoptotic death receptors (DRs),
located on the cell surface. Both pathways lead to hierarchical activation
of specialized proteases called caspases. Apoptotic signals first activate
initiator caspases, including caspase-2, -9 and -10. Once stimulated,
initiator caspases proteolytically activate the downstream effector
caspases, including caspase-3, which in turn cleave numerous essential
cellular proteins, thereby leading to the unique morphological and
biochemical features of apoptosis, such as plasma membrane ‘blebbing’,
cell shrinkage, chromatin condensation and DNA fragmentation.
Apoptosis is regulated by numerous genes and factors such as Fas,
TNF, perforin ⁄ granzyme B, Bcl-2, NF-κB and p53. Aberrant regulation
of apoptotic cell death mechanisms is an important pathological factor in
variety of major human diseases. Deficiency in apoptosis is one of the
key hallmarks of cancer and also contributes to certain autoimmune
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diseases and metabolic disorders. In contrast, excessive apoptosis is an
important component in neurodegenerative disorders, infertility and
inflammatory diseases.
Keratinocyte apoptosis is believed to play an important role in the
pathogenesis of spongiotic dermatitis, in particular for the formation of
spongiosis. The present study investigates changes in the expression level
of the apoptosis regulatory proteins caspase-3, Fas, Bcl-2, NF-κB and p53
in skin samples of patients with spongiotic disorders.
This study was carried out on 2 groups:
(1) Patients group that included 50 patients divided into five
subgroups:
Group (A): atopic dermatitis
Group (B): allergic contact dermatitis
Group (C): irritant contact dermatitis
Group (D): nummular eczema
Group (E): dyshidrotic eczema
(2) Control group that included 10 healthy subjects.
All studied individuals were subjected to history taking and clinical
examination; we investigated expression of apoptotic regulatory
molecules with variable parameters including duration of cutaneous
lesions and age of the patients.
The result of this work showed the following:
1. Caspase-3 cleavage occurs in keratinocytes of the spinous
layers of the epidermis in acute spongiotic lesions and that
particular high levels are present in spongiotic areas.
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2. Positive Fas expression of keratinocytes in acute spongiotic
lesions. The ring-like staining pattern suggested that a large
proportion of the expressed Fas molecules were located on the
surface of these cells.
3. Bcl-2 expression was absent or weak in suprabasal cells in
lesional skin. This decrease in epidermal Bcl-2 expression with
its antiapoptotic effect may explain the increased sensitivity of
keratinocytes to apoptotic stimuli.
4. NF-κB expression was absent or weak in suprabasal cells in
lesional skin. This decrease in epidermal NF-κB expression
with its antiapoptotic effect may also explain the increased
sensitivity of keratinocytes to apoptotic stimuli.
5. P53 expression was absent or weak in suprabasal cells in
lesional skin. This indicates that p53 has no role in
keratinocytes apoptosis that occurred in spongiotic dermatitis.
Conclusion:
KC apoptosis is the initiating event in the development of the
epidermal pathology seen in spongiotic dermatitis (in studied diseases).
Most notably, KC apoptosis occurs in suprabasal cells, where spongiosis
takes place. Apoptosis of individual KC is the first event leading to
disruption of epidermal continuity and vesicle formation. Damage to KCs
leads to the loss of intercellular cohesion (acantholysis) and subsequent
cleft formation. Fluid influx from the dermis and intercellular edema
contributes to spongiosis. The knowledge of this molecular basis is
pivotal in understanding the development of pathology in spongiotic
disorders, and opens a future for more focused therapeutic applications.
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