CELULAR

ADAPTATION,
INJURY, AND
DEATH
Sesilia Andriani Keban, MSi., Apt.

CELULAR
ADAPTATION
Cells

are the structural and functional units

of tissues and organs. They are capable of
adjusting their structure and functions in
response to various physiological and
pathological conditions.
If these changes and stimuli are minor or
brief, the cell adapts.
Cellular
adaptations
include
atrophy,
hypertrophy, hyperplasia, and metaplasia.
Prolonged or intense stimuli can cause cell
injury or death

TYPES OF ADAPTATIONS
1-Physiological adaptations
They represent response of cells to normal stimulation by hormones
or endogenous chemical substances e.g. :
an increase in skeletal muscle cells in athletes due to exercise and
increased metabolic demand
the increase in number and size of epithelial cells in breasts of
women resulting from endocrine stimulation during pregnancy.
2-Pathological adaptations
When these cells or tissues are damaged, the body attempts to adapt
and repair or limit the harmful effects. Often the adaptive changes
result in cells or organs that can not function normally.Examples :
Change from ciliated columnar epithelium to non-ciliated squamous
epithelium in the trachea and bronchi of cigarette smokers. The
replacement of squamous epithelium can better withstand the
irritation of the cigarette smoke. However, the loss of cilia and
mucous secretions of columnar epithelium diminish the tracheobronchial defense mechanisms.
Replacement of normal liver cells by fibrotic cells in chronic
alcoholics (known as cirrhosis of the liver). A severely cirrhotic liver
is incapable of normal metabolism, maintenance of nutrition, and
detoxification of xenobiotics.

Cellular adaptation to toxic agents is of three basic types:

Increase in cell activity
Decrease in cell activity
Alteration in cell morphology (structure and appearance) or cell
function
Adaptive changes in cell growth and differentiation include:
Atrophy
Hypertrophy
Hyperplasia
Metaplasia
Dysplasia

ADAPTATION

Atrophy:
Decrease in size or number of
cells leading to reduction in
tissue mass

Causes

Physiologic--due to decreased
work load (e.g., decreased size
of uterus following child birth,
or disease), loss of endocrine
stimulation, aging
Pathologic--primarily due to
denervation of muscle,
diminished blood supply,
nutritional deficiency

ADAPTATION

Hypertrophy:
Increase in size of cells leading to increase in size of organ
It is mostly seen in cells that cannot divide, such as:
skeletal muscle (in exercise),
cardiac muscle (hypertension).
These changes usually revert to normal if the cause is
removed.
It can also be caused by Specific hormonal stimulation
uterus in pregnancy

ADAPTATION

Hyperplasia:
Increase in number of cells
leading to increase size of organ

Physiologic

Hormonal (breast during

pregnancy)

Pathologic

Excessive hormonal / growth factor

absolute or relative increase in estrogen

over progesterone--endometrial
hyperplasia (the excessive thickening of the
lining of the uterus caused by an increase in
the number of endometrial glands)

ADAPTATION

Metaplasia:

Is the replacement of one type of cells by

another

Squamous Metaplasia

Intestinal Metaplasia

In the habitual cigarette smoker, the normal ciliated columnar

epithelial cells of the trachea and bronchi are often replaced
focally or widely by stratified squamous epithelial cells.
Stones in the excretory ducts of the salivary glands, pancreas,
or bile ducts may cause replacement of the normal secretory
columnar epithelium by nonfunctioning stratified squamous
epithelium.
A deficiency of vitamin A (retinoic acid) induces squamous
metaplasia in the respiratory epithelium, and vitamin A excess
suppresses keratinization.

Metaplasia from squamous to columnar type may

also occur, as in Barrett esophagus, in which the
esophageal squamous epithelium is replaced by
intestinal-like columnar cells under the influence of
refluxed gastric acid. Cancers may arise in these
areas.
Osseous metaplasia: it is the formation of new bone at
sites of tissue injury (muscle).

Metaplastic changes usually result from chronic irritation.

Metaplastic changes seem to precede the development of
cancer, in some instances.
Metaplasia is thought to arise from reprogramming of stem
or undifferentiated cells that are present in adult tissue.

ADAPTATION

Dysplasia :
Dysplasia is a condition of abnormal cell changes or deranged cell growth in which the cells are
structurally changed in size, shape, and appearance from the original cell type.

Their relationship to one another is also abnormal.

Dysplasia of epithelial cells may result from chronic irritation or inflammation.

In some cases, dysplasia may progress to formation of a tumor; this is called neoplasia.

The epithelium covering the uterine cervix is a common site of dysplasia, and cervical
epithelial dysplasia sometimes progresses to cervical cancer.

CELL INJURY
When the cell is exposed to an injurious agent or
stress, a sequence of events follows that is loosely
termed cell injury.
Cell injury is reversible up to a certain point
If the stimulus persists or is severe enough from
the beginning, the cell reaches a point of no
return and suffers irreversible cell injury and
ultimately cell death.
Cell death, is the ultimate result of cell injury

Normal
cell

+ Stress

Injury

+Stress

Reversibly
injured cell

Irreversibly
Injured cell

- Stress

Adapted
Cell

- Stress

Apoptosis
Necrosis

Dead cell

CAUSES OF CELL INJURY

Oxygen deprivation.
Physical agents eg:mechanical trauma,burns,deep
cold,barotrauma,electric shock.
Chemical agents & drugs eg:poisons,environmental
pollutants,CO,asbestos,alcohol,narcotic drugs etc.
Infectious agentsviruses,rickettsiae,bacteria,fungi,protozoa and
helminths.
Immunologic reactions-anaphylaxis, autoimmune
disorders.
Genetic derangements.
Nutritional imbalances- obesity,specific vitamin
deficiencies etc.

INJURY

CELL INJURY AND

DEATH

Reversible Injury
o

Cell swelling develops when cells are incapable of

fluid and ion homeostasis ( function of ATP
dependant pumps).
Fatty change the accumulation of lipid vacuoles in
the cytoplasm.

Irreversible injury (Necrosis)

o

Two basic processes underlie the morphologic

changes of necrosis

Denaturation of protein
Enzymatic digestion of cell components

Reversible Injury

1. Cellular swelling

Also

called hydropic change or

vacuolar degeneration

change
Grossly: organ pallor, increased
weight
Microscopy: small, clear cytoplasmic
vacuoles

Normal kidney tubules

Earliest

Adenosine triphosphate (ATP) depletion

water influx ---Cellular swelling

Rversible cell injury

Reversible Injury

2. Fatty change

Lipid vacuoles in the cytoplasm.

In cells participating in fat metabolism (e.g.,
hepatocytes and myocardial cells).

Normal liver

Fatty liver

ISCHEMIC INJURY

CELL INJURY AND DEATH

Reversible hypoxic/ ischemic injury

o

o
o

Loss of ATP generation by mitochondria

initially results in reversible events:
Na+/K+ ATPase membrane pump leads to a
loss of ionic and osmotic gradient
( edCa+2+ Na+, ed K+ and osmotic
gain of water) resulting cell swelling &
Endoplasmic reticulum dilatation)
ed anaerobic glycolysis results in glycogen
depletion and lactate accumulation (ed pH).
Reduced protein synthesis due to ribosome
detachment from the rough endoplasmic
reticulum

CELL INJURY AND DEATH

Irreversible hypoxic/ ischemic injury

These changes are reversible if O2 and flow are

reinstated, the transition to irreversible injury depends
on the extent of ATP depletion and membrane
dysfunction especially of mitochondria.
ATP depletion results in mitochondrial permeability
transition (MPT) with loss of the H+ gradient
ATP depletion releases cytochrome c that can induce
apoptosis
ed Ca+2 activates
o membrane
phospholipases
with
resulting
membrane damage
o Intracellular proteases leading to cytoskeletal
degradation
Phospholipid degradation products that accumulate
are directly toxic to the cell

REVERSIBLE VS IRREVERSIBLE CELL

INJURY
Reversible injury
* Decreased ATP levels

Irreversible injury
* Amorphous densities in

* Ion imbalance
* Swelling
Decreased pH
Fatty change (liver)

mitochondria
* Severe membrane damage
* Lysosomal rupture
Extensive DNA damage

NECROSIS
Necrosis refers to a spectrum of morphologic
changes that follow cell death in living tissue,
due to degradative action of enzymes on the
injured cell.
It occurs in irreversible injury.
This may elicit inflammation in the surrounding
tissue.
There is denaturation of intracellular proteins
and enzymatic digestion of the cell.
The enzymes are derived either from the
lysosomes of the dead cells themselves, in which
case the enzymatic digestion is referred to as
autolysis, or from the lysosomes of immigrant
leukocytes, during inflammatory reactions.

PATHOLOGY OF NECROTIC
CELLS
Increased

eosinophilia with a glassy

homogeneous appearance as a result of
glycogen particles.
Moth-eaten appearance in cells with
vacuolated cytoplasm due to enzymatic
digestion of cytoplasmic organelles.
Calcification of dead cells.
Replacement of dead cells by whorled
phospholipid masses called myelin figures
(ultrastructurally).

NUCLEAR CHANGES IN NECROTIC

CELLS:
Nuclear changes show one of three patterns, all due to
nonspecific breakdown of DNA
1- Karyolysis : basophilia of the chromatin may fade
2-Pyknosis, (also seen in apoptotic cell death) is
characterized by nuclear shrinkage and increased
basophilia. Here the DNA apparently condenses into a
solid, shrunken basophilic mass.
3- Karyorrhexis: fragmentation of the nucleus.
With the passage of time (a day or two), the nucleus in
the necrotic cell totally disappears

TYPES OF NECROSIS
There are different types of necrosis :
Coagulative necrosis,
Liquefactive necrosis,
Caseous necrosis and
Fat necrosis

COAGULATIVE NECROSIS:
The affected tissues has a firm texture e.g.
myocardial infarct
The necrotic myocardial cells are removed by
fragmentation and phagocytosis of the cellular
debris by scavenger leukocytes and by the action
of proteolytic lysosomal enzymes brought in by
the immigrant white cells.
Coagulative necrosis, with preservation of the
general tissue architecture, is characteristic of
hypoxic death of cells in all tissues except the
brain.

Here is myocardium in which the cells are dying. The nuclei of the myocardial fibers are
being lost. The cytoplasm is losing its structure, because no well defined cross-striations
are seen.

LIQUEFACTIVE NECROSIS
Is characteristic of focal bacterial or, occasionally,
fungal infections.
It is also seen in hypoxic death of cells within the
central nervous system.
Liquefaction completely digests the dead cells.
The end result is transformation of the tissue
into a liquid viscous mass.
If
the process was initiated by acute
inflammation, the material is frequently creamy
yellow because of the presence of dead white cells
and is called pus.

The liver shows a small abscess here filled with many neutrophils.
This abscess is an example of localized liquefactive necrosis.

GANGRENOUS NECROSIS
It is usually applied to a limb, generally the lower
leg, that has lost its blood supply and has
undergone coagulation necrosis.

When bacterial infection is superimposed,

coagulative necrosis is modified by the
liquefactive action of the bacteria and the
attracted leukocytes (so-called wet gangrene).

GANGREN

CASEOUS NECROSIS
Is a type of coagulative necrosis, seen in
tuberculous infection.
The term caseous is derived from the cheesy
white gross appearance of the area of necrosis.
On microscopic examination, the necrotic area
appears as amorphous pink granular debris
surrounded by granuloma (small area of
inflamation in tissue).

This is a caseating granuloma. Epithelioid cells surround a

central area of necrosis that appears irregular, amorphous,
and pink. Grossly, areas of caseation appear cheese-like.

FAT NECROSIS
Is focal areas of fat destruction, due to release of
activated pancreatic lipases into the substance of
the pancreas and the peritoneal cavity.
This occurs in acute pancreatitis.
The released fatty acids combine with calcium to
produce grossly visible chalky white areas (fat
saponification).
On histologic examination:
The necrosis takes the form of foci of shadowy
outlines of necrotic fat cells, with basophilic
calcium deposits, surrounded by an inflammatory
reaction

1. Microscopically, fat necrosis adjacent to pancreas is seen here. There are some
remaining steatocytes at the left which are not necrotic. The necrotic fat cells at
the right have vague cellular outlines, have lost their peripheral nuclei, and
their cytoplasm has become a pink amorphous mass of necrotic material.

2. This is fat necrosis of the pancreas. Cellular injury to the pancreatic acini
leads to releaseof powerful enzymes which damage fat by the production of
soaps, and these appear grossly as the soft, chalky white areas seen here on
the cut surfaces.

APOPTOSIS
Apoptosis is programmed cell death.
It is a pathway of cell death that is induced by a
tightly regulated intracellular program in which
cells destined to die activate their own enzymes
to degrade their own nuclear DNA, nuclear
proteins and cytoplasmic proteins.
The cell's plasma membrane remains intact, but
its structure is altered in such a way that the
apoptotic cell sends signal to macrophages to
phagocytose it.

APOPTOSIS CONT.
The dead cell is rapidly phagocytosed and
cleared, before its contents have leaked out, and
therefore cell death by this pathway does not
elicit an inflammatory reaction in the host.
Thus, apoptosis is fundamentally different from
necrosis, which is characterized by loss of
membrane integrity, enzymatic digestion of cells,
and frequently a host reaction.
Apoptosis and necrosis sometimes coexist.

CAUSES OF APOPTOSIS
It occurs normally in many situations, and serves
to eliminate unwanted or potentially harmful
cells and cells that have outlived their usefulness.
It is also a pathologic event when cells are
damaged beyond repair, especially when the
damage affects the cell's DNA; in these
situations, the irreparably damaged cell is
eliminated.

APOPTOSIS IN PHYSIOLOGIC
SITUATIONS

The programmed destruction of cells during

embryogenesis.
Hormone-dependent involution in the adult, such as
endometrial cell breakdown during the menstrual
cycle
Cell deletion in proliferating cell populations,eg.
intestinal epithelia.
Death of host cells that have served their useful
purpose, such as neutrophils in an acute
inflammatory response, and lymphocytes at the end of
an immune response.
Cell death induced by cytotoxic T cells, a defense
mechanism against viruses and tumors that serves to
eliminate virus-infected and neoplastic cells

APOPTOSIS IN PATHOLOGIC
CONDITIONS
Cell death produced by a variety of injurious
stimuli eg. radiation and cytotoxic anticancer
drugs damage DNA.
Cell injury in certain viral diseases, such as viral
hepatitis.
Pathologic atrophy in parenchymal organs after
duct obstruction, such as occurs in the pancreas,
parotid gland, and kidney.
Cell death in tumors.

MORPHOLOGY OF
APOPTOSIS

Cell shrinkage.
Chromatin condensation. This is the most characteristic
feature of apoptosis. The chromatin aggregates
peripherally, under the nuclear membrane.
The nucleus itself may break up into fragments.
Formation of cytoplasmic blebs and apoptotic
bodies. The apoptotic cell first shows extensive surface
blebbing, then undergoes fragmentation into membranebound apoptotic bodies composed of cytoplasm and tightly
packed organelles, with or without nuclear fragments.
Phagocytosis of apoptotic cells or cell bodies,
usually by macrophages.
The apoptotic cell appears as a round or oval mass of
intensely eosinophilic cytoplasm with dense nuclear
chromatin fragments.
There is no inflammation.

Feature

Necrosis

Cell size

Enlarged (swelling)

Reduced (shrinkage)

Nucleus

Pyknosis karyorrhexis
karyolysis
Disrupted

Fragmentation into nucleosome

size fragments
Intact; altered structure,
especially orientation of lipids
Intact; may be released in
apoptotic bodies
No

Plasma
membrane
Cellular
contents
Adjacent
inflammation
Physiologic or
pathologic role

Enzymatic digestion; may

leak out of cell
Frequent
Invariably pathologic
(culmination of irreversible
cell injury)

Apoptosis

Often physiologic, means of

eliminating unwanted cells; may
be pathologic after some forms of
cell injury, especially DNA
damage

THE END