Notes

Cell death
also is a normal and essential process in embryogenesis,
the development of organs, and the maintenance of
homeostasis.
Whether a specific form of stress induces
adaptation or causes reversible or irreversible injury
depends not only on the nature and severity of the stress
but also on several other variables, including basal cellular
metabolism and blood and nutrient supply
Physiologic adaptations
usually represent responses of cells to normal stimulation
by hormones or endogenous chemical mediators
(e.g., the hormone-induced enlargement of the breast and
uterus during pregnancy). Pathologic adaptations are
responses to stress that allow cells to modulate their structure
and function and thus escape injury. Such adaptations
can take several distinct forms.
Thus, reversibly
injured myocytes are not dead and may resemble normal
myocytes morphologically; however, they are transiently
noncontractile, so even mild injury can have a significant
The mechanisms driving cardiac hypertrophy involve
at least two types of signals: mechanical triggers, such as
stretch, and trophic triggers, which typically are soluble
mediators that stimulate cell growth, such as growth factors
and adrenergic hormones.
When a cell is deprived of
growth factors, or the cell’s DNA or proteins are
damaged beyond repair, typically the cell kills itself by
another type of death, called apoptosis
There may also be a switch of
contractile proteins from adult to fetal or neonatal forms.
For example, during muscle hypertrophy, the α-myosin
heavy chain is replaced by the β form of the myosin heavy
chain, which produces slower, more energetically economical
contraction.
The variables that limit continued hypertrophy and
cause the regressive changes are incompletely understood.
There may be finite limits of the vasculature to adequately
supply the enlarged fibers, of the mitochondria to supply
adenosine triphosphate (ATP), or of the biosynthetic
machinery to provide the contractile proteins or other cytoskeletal
elements
Most forms of pathologic hyperplasia are caused by excessive
hormonal or growth factor stimulation. For example after a normal menstrual period there is a burst of
uterine epithelial proliferation that is normally tightly
regulated by stimulation through pituitary hormones
and ovarian estrogen and by inhibition through progesterone.
Stimulation
by growth factors also is involved in the hyperplasia
that is associated with certain viral infections; for
example, papillomaviruses cause skin warts and mucosal
lesions composed of masses of hyperplastic epithelium
the
hyperplastic process remains controlled; if the signals that initiate
it abate, the hyperplasia disappears. It is this responsiveness
to normal regulatory control mechanisms that distinguishes
pathologic hyperplasias from cancer, in which the
growth control mechanisms become dysregulated or ineffective
the ubiquitin-proteasome pathway.is also thought to be responsible
for the accelerated proteolysis seen in a variety of catabolic
conditions, including the cachexia associated with
cancer.
the influences that induce metaplastic change, if persistent,
may predispose to malignant transformation of the epithelium
Since vitamin A is
essential for normal epithelial differentiation, its deficiency
may also induce squamous metaplasia in the respiratory
Metaplasia
may also occur in mesenchymal cells but in these situations
it is generally a reaction to some pathologic alteration
and not an adaptive response to stress. For example, bone
is occasionally formed in soft tissues, particularly in foci of
injury.
Whereas necrosis is always a pathologic
process, apoptosis serves many normal functions and is
not necessarily associated with pathologic cell injury. Furthermore,
in keeping with its role in certain physiologic processes,
apoptosis does not elicit an inflammatory response.
Agents commonly
known as poisons cause severe damage at the cellular level
by altering membrane permeability, osmotic homeostasis,
or the integrity of an enzyme or cofactor, and exposure to
such poisons can culminate in the death of the whole
organism
All stresses and
noxious influences exert their effects first at the molecular
or biochemical level. Cellular function may be lost long before
cell death occurs, and the morphologic changes of cell injury (or
death) lag far behind both (Fig. 1–7). For example, myocardial
cells become noncontractile after 1 to 2 minutes of ischemia,
although they do not die until 20 to 30 minutes of
ischemia have elapsed. These myocytes may not appear
dead by electron microscopy for 2 to 3 hours, or by light
microscopy for 6 to 12 hours
two phenomena consistently
characterize irreversibility: the inability to correct mitochondrial
dysfunction (lack of oxidative phosphorylation
and ATP generation) even after resolution of the original
injury, and profound disturbances in membrane function
The two main morphologic correlates of reversible cell
injury are cellular swelling and fatty change.
The two main morphologic correlates of reversible cell
injury are cellular swelling and fatty change. Cellular swelling
is the result of failure of energy-dependent ion pumps
in the plasma membrane, leading to an inability to maintain
ionic and fluid homeostasis. Fatty change occurs in
hypoxic injury and in various forms of toxic or metabolic
injury and is manifested by the appearance of small or
large lipid vacuoles in the cytoplasm.
ethanol is Social stimuli for injury
in Necrosos The enzymes responsible for digestion of the cell may be
derived from the lysosomes of the dying cells themselves
and from the lysosomes of leukocytes that are recruited as
part of the inflammatory reaction to the dead cells.

Cytoplasmic changes. Necrotic cells show increased
eosinophilia
patterns, all due to breakdown of DNA and chromatin.
The basophilia of the chromatin may fade (karyolysis),
presumably secondary to deoxyribonuclease (DNase)
activity. A second pattern is pyknosis, characterized by
nuclear shrinkage and increased basophilia; the DNA condenses
into a solid shrunken mass. In the third pattern,
karyorrhexis, the pyknotic nucleus undergoes fragmentation.
In 1 to 2 days, the nucleus in a dead cell may
completely disappear. Electron microscopy reveals profound
nuclear changes culminating in nuclear dissolution.
• Fates of necrotic cells. Necrotic cells may persist for
some time or may be digested by enzymes and disappear.
Dead cells may be replaced by myelin figures, which are
either phagocytosed by other cells or further degraded
into fatty acids. These fatty acids bind calcium salts,
which may result in the dead cells ultimately becoming
calcified.
Coagulative necrosis is a form of necrosis in which the
underlying tissue architecture is preserved for at least
several days .Coagulative necrosis is characteristic of infarcts
(areas of ischemic necrosis) in all of the solid organs
except the brain.
Liquefactive necrosis is seen in focal bacterial or,
occasionally, fungal infections, because microbes stimulate
the accumulation of inflammatory cells and the enzymes
of leukocytes digest (“liquefy”) the tissue. For obscure
reasons, hypoxic death of cells within the central nervous
system often evokes liquefactive necrosis
When bacterial infection is superimposed,
coagulative necrosis is modified by the liquefactive action
of the bacteria and the attracted leukocytes (resulting in
so-called wet gangrene).

Caseous necrosis is encountered most often in foci of
tuberculous infection. Caseous means “cheese-like.The area of
caseous necrosis is often enclosed within a distinctive
inflammatory border; this appearance is characteristic
of a focus of inflammation known as a granuloma
Fibrinoid necrosis is a special form of necrosis, visible
by light microscopy, usually in immune reactions in which
complexes of antigens and antibodies are deposited in
the walls of arteries.

Leakage of intracellular proteins through the damaged cell
membrane and ultimately into the circulation provides a means
of detecting tissue-specific necrosis using blood or serum samples.
Cardiac muscle, for example, contains a unique isoform of
the enzyme creatine kinase and of the contractile protein
troponin, whereas hepatic bile duct epithelium contains a
temperature-resistant isoform of the enzyme alkaline phosphatase,
and hepatocytes contain transaminases. Irreversible
injury and cell death in these tissues result in increased
serum levels of such proteins, and measurement of serum
levels is used clinically to assess damage to these tissues