CHAPTER TWO

CELL ADAPTATIONS ,CELL INJURY

AND CELL DEATH
Dr Noura H:Abdirahman
CELL
 Cells are the basic units of tissues, which form
organs and systems in the human body.
 Traditionally, body cells are divided in to two main
types: epithelial and mesenchymal cells.
 The study of abnormalities in structure and
function of cells in disease has remained the
focus of attention in understanding of diseases.
 Thus, most forms of diseases begin with cell
injury followed by consequent loss of cellular
function. Cell injury is defined as a variety of
stresses a cell encounters as a result of changes
in its internal and external environment.
OVERVIEW OF CELLULAR
RESPONSES

TO STRESS AND NOXIOUS STIMULI.
 Cells are active participants in their environment,
constantly adjusting their structure and function
to accommodate changing demands and
extracellular stresses.
 Cells normally maintain a steady state called
homeostasis in which the intracellular milieu is
kept within a fairly narrow range of physiologic
parameters.
 As cells encounter physiologic stresses or
pathologic stimuli, they can undergo adaptation,
achieving a new steady state and preserving
viability and function.
 The principal adaptive responses are hypertrophy,
hyperplasia, atrophy, and metaplasia.
 If the adaptive capability is exceeded or if the
external stress is inherently harmful, cell injury
develops .
 Within certain limits, injury is reversible, and cells
return to a stable baseline; however, if the stress
is severe, persistent and rapid in onset, it results
in irreversible injury and death of the affected
cells.
Cellular adaptation
 Adaptations are reversible changes in the number,
size, phenotype, metabolic activity, or functions of
cells in response to changes in their environment.
 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.
Types of cellular adaptation

 The types of cellular adaptation include

1 Hypertrophy.
2 Hyperplasia.
3 Atrophy.
4 Metaplasia .
5 Displasia
 Hypertrophy
Definition :hypertrophy is an increase in
the size of cells resulting in increase in
the size of the organ.
Hypertrophy can be physiologic or
pathologic and is caused either by
increased functional demand or by growth
factor or hormonal stimulation.
Examples: the enlargement of the left
ventricle in hypertensive heart disease &
the increase in skeletal muscle during
sternous exercise.
 Hyperplasia
Definition :hyperplasia is an increase in the number
of cell in a tissue or organ .
 Hyperplasia can be physiologic or pathologic. In
both situations, cellular proliferation is
stimulated by growth factors that are produced
by a variety of cell types.
 The two types of physiologic hyperplasia are
(1) hormonal hyperplasia, exemplified by the
proliferation of the glandular epithelium of the
female breast at puberty and during pregnancy.
(2) Compensatory hyperplasia, that is, hyperplasia
that occurs when a portion of the tissue is
removed or diseased.
Cont…
 Most forms of pathologic hyperplasia are
caused by excessive hormonal or growth
factor stimulation.
 Atrophy

 Definition :Shrinkage in the size of the cell by the loss

of cell substance is known as atrophy.
Causes
 Decreased workload .
 Loss of innervations.
 Diminished blood supply.
 Inadequate nutrition .
 Loss of endocrine stimulation .
 Aging (senile atrophy).
 metaplasia
Metaplasia is the replacement of one differentiated
tissue by another differentiated tissue. There are
different types of metaplasia include:
1. Squamous metaplasia
This is replacement of another type of epithelium
by squamous epithelium. For example, the
columnar epithelium of the bronchus can be
replaced by squamous epithelium in cigarette
smokers
2. Osseous metaplasia
This replacement of a connective tissue by bone,
for example at sites of injury
Dysplasia
Definition : dysplasia is an abnormal
proliferation of cells that is
characterized by changes in cell size ,
shape and loss of cellular organization.
Dysplasia is not cancer but may
progress to cancer .
Example cervical dysplasia.
 CELL INJURY

Define cell injury.

 Normal cells are in a state of
homeostasis .
Injury is defined as a set of biochemical
and/or morphologic changes that occur
when the state of homeostasis is
perturbed by adverse influences.
Cell injury occurs as a result of physical ,
chemical or biological insults or as a result
of vital substrate deficiency .
Cell injury may be reversible or irreversible.
The differences are mostly quantitative. Reversible
injury is usually mild, and, following the removal of the
adverse influences, the cell reverts to its normal steady
state. If the cell cannot recover, the injury is considered
to be irreversible.
or
Reversible cell injury denotes pathological cell changes
that can be restored to normalcy if the stimuli is
removed or if the cause of injury is mild .
Irreversible cell injury occurs when stressors exceed
the capacity of the cell to adapt and denotes
permanent pathologic changes that cause cell death.
 The two morphologic and mechanistic patttern of
cell death are:
 Necrosis
Apoptosis
 Necrosis is the more common type of cell death
involving severe cell swelling,denaturation and
coagulation of proteins .
 Apoptosis occur when a cell dies by activation of an
internal suicide program involving an cellular
component.
 Causes of cell injury
 The most common cause cell injury are
hypoxia
The other causes of cell injury are classified as
exogenous or endogenous.
 Exogenous causes include : physical, chemical,
and biological factors, such as heat and cold,
toxins and drugs, and viruses and bacteria.
 Endogenous causes include :genetic defects,
metabolites, hormones.
 Nutritional Imbalances.
 Immunologic Reactions.
Mechanism of cell injury
1) Physical
a) ionizing radiation
b) temperature
c) mechanical
2) Chemical
Drugs
Poisons
3) Biological
Enzymes
Cytokines
Cell death
Death of cells occurs in two ways:
Necrosis--(irreversible injury) changes
produced by enzymatic digestion of
dead cellular elements
Apoptosis--vital process that helps
eliminate unwanted cells--an internally
programmed series of events effected
by dedicated gene products .
Causes of necrosis

Necrosis occurs by the following mechanisms:

A. Hypoxia
B. Free radical-induced cell injury
C. Cell membrane damage
D. Increased intracellular calcium level
Hypoxia is decreased oxygen supply to tissues. It can
be caused by:
1. Ischemia
Ischemia is decreased blood flow to or from an organ.
Ischemia can be caused by obstruction of arterial
blood flow – the most common cause, or by
decreased perfusion of tissues by oxygen-carrying
blood as occurs in cardiac failure, hypotension, &
shock.
2.Anemia
Anemia is a reduction in the number of oxygen-carrying
red blood cells.
3. Carbon monoxide poisoning
CO decreases the oxygen-capacity of red blood cells
by chemical alteration of hemoglobin
4. Poor oxygenation of blood due to pulmonery disease
 The cell injury that results following hypoxia can be
divided into early & late stages
1. Early (reversible) stages of hypoxic cell injury
At this stage, hypoxia results in decreased
oxidative phosphorylation & ATP synthesis.
 Decreased ATP leads to
A .. Failure of the cell membrane Na – K pump,
which leads to increased intracellular Na & water,
which cause cellular & organelle swelling.
Cellular swelling (hydropic change) is
characterized by the presence of large vacuoles
in the cytoplasm.
The endoplasmic reticulum also swells. The
mitochondria show a low amplitude swelling.
All of the above changes are reversible if the
hypoxia is corrected.
B .. Disaggregation of ribosomes & failure of
protein synthesis.
Late (irreversible) stages of hypoxic cell injury.
 This is caused by severe or prolonged injury. It
is caused by massive calcium influx & very
low pH, which lead to activation of enzymes,
which damage the cell membrane& organelle
membranes. Irreversible damage to the
mitochondria, cell membranes, & the nucleus
mark the point of no return for the cell, that is
after this stage, the cell is destined to die.
Severe cell injury is typically associated with a
release of cytoplasmic enzymes into the blood.
For example:
Creatine kinase may indicate cardiac or skeletal
muscle cell injury.
Aspartate aminotransferase (AST) and alanine
aminotransferase (ALT) are released from
damaged liver cells.
Lactate dehydrogenase (LDH) is released from
ruptured red blood cells and many other cells.
B. Free radical-induced injury

 Free radical is any molecule with a single unpaired

electron in the outer orbital. Examples include
superoxide & the hydroxyl radicals. Free radicals
are formed by normal metabolism, oxygen toxicity,
ionizing radiation, & drugs & chemicals.
 When the production of free radicals exceeds
their degradation, the excess free radicals cause
membrane pump damage, ATP depletion, & DNA
damage. These can cause cell injury & cell death.
C. Cell membrane damage

Direct cell membrane damage as in extremes

of temprature, toxins, or viruses.
Indirect cell membrane damage as in the case
of hypoxia can lead to cell death by disrupting
the homeostasis of the cell.
D. Increased intracellular calcium level

 Increased intracellular calcium level is a

common pathway via which different causes of
cell injury operate. For example, the cell
membrane damage leads to increased
intracellular calcium level.
 The increased cytosolic calcium, in turn,
activates enzymes in the presence of low pH.
This activated enzymes
will degrade the cellular organelles.
 Types of necrosis
Necrosis is death of cells or tissues caused
most often by ischemia or the action of toxic
substances and infectious pathogens.

The types of necrosis include:

1. Coagulative necrosis
2. Liquefactive necrosis
3. Fat necrosis
4. Caseous necrosis
5. Gangrenous necrosis
Coagulative necrosis
 Cogulative necrosis most often results from
sudden interruption of blood supply to an
organ, especially to the heart.
 It is, in early stages, characterized by general
preservation of tissue architecture. It is
marked by the following nuclear changes:
Pyknosis (which is chromatin clumping &
shrinking with increased basophilia),
karyorrhexis (fragmentation of chromatin), &
karyolysis (fading of the chromatin material).
Normal
Necrosis
Liquefactive necrosis
 Liquefactive necrosis is characterized by
digestion of tissue.
 It shows softening & liquefaction of tissue. It
characteristically results from ischemic injury
to the CNS. It also occurs in suppurative
infections characterized by formation of pus.
LIQUEFACTIVE
NECROSIS, BRAIN
 Fat necrosis
Fat necrosis can be caused by trauma to tissue
with high fat content, such as the breast or it can
also be caused by acute hemorrhagic pancreatitis
in which pancreatic enzymes diffuse into the
inflamed pancreatic tissue & digest it.
 The fatty acids released from the digestion form
calcium salts (soap formation or dystrophic
calcification).
In addition, the elastase enzyme digests the
blood vessels & cause the hemorrhage inside the
pancreas, hence the name hemorrhagic
pancreatitis
Caseous necrosis
 Caseous necrosis has a cheese-like (caseous,
white) appearance to the naked eye. And it
appears as an amorphous eosinophilic
material on microscopic examination.
 Caseouse necrosis is typical of tuberculosis.
CASEOUS NECROSIS, TB
 Gangrenous necrosis
This is due to vascular occlusion & most often
affects the lower extremities & the bowel.
 It is called wet gangrene if it is complicated by
bacterial infection which leads to superimposed
liquefactive necrosis.
Whereas it is called dry gangrene if there is only
coagulative necrosis without liquefactive necrosis.
Necrosis can be followed by release of
intracellular enzymes into the blood, inflammation
or dystrophic calcification.
“WET” GANGRENE
“DRY” GANGRENE
Apoptosis

Apoptosis is the death of single cells within

clusters of other cells. (Note that necrosis
causes the death of clusters of cells.) In
apoptosis, the cell shows shrinkage & increased
acidophilic staining of the cell. This is followed by
fragmentation of the cells. These fragments are
called apoptotic bodies.
Definition
 Apoptosis is a form of cell death based on
sequential activation of ‘‘death genes’’ and
‘‘suicide pathway enzymes.’’ It is also called
programmed cell death.
Apoptosis may be initiated through several pathways.
The two most important pathways are:
 Extrinsic pathway:
This pathway is activated by the
activation of the so-called death receptors on the
surface of the cell membrane.
 Intrinsic mitochondrial pathway: This pathway is
initiated by an increased permeability of
mitochondria, which release proapoptotic
molecules, such as cytochrome, that act on the
initiator caspases, such as the extrinsic pathway.
Many other mechanisms can initiate apoptosis,
such as radiation, drugs, hormones, immune
mechanisms (e.g., cytotoxic T lymphocytes).
Apoptosis VS necrosis

Apoptosis usually affects single cells, whereas

necrosis involves larger groups of cells or
tissues.
 During necrosis, there is no gene activity, and
most of the cytoplasmic maintenance
enzymes are inactivated.
During apoptosis, there is sequential,
genetically controlled enzyme activation and
inhibition.
Apoptosis is essential for normal
development of many organs, and if it does
not occur ,malformations may develop.
For example, apoptosis mediates the
disappearance of interdigital folds on fetal
limbs. If apoptosis does not occur, the fingers
will not develop normally
Apoptosis usually occurs as a physiologic process
for removal of cells during embryogenesis,
menstruation, etc… It can also be seen in
pathological conditions caused by mild injurious
agent
Apoptosis is not followed by inflammation or
calcification.