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Faculty of Medicine
Department of
Pathology
Khairat Battah,MD
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Cells are active participants in their
environment, constantly adjusting their
structure and function to accommodate
changing demands and extracellular stresses.
Cells tend to maintain their intracellular
milieu within a fairly narrow range of
physiologic parameters; that is, they maintain
normal homeostasis.
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As cells encounter physiologic stresses or
pathologic stimuli, they can undergo adaptation,
achieving a new steady state and preserving
viability and function.
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, severe or
persistent stress results in irreversible injury and
death
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Adaptive mechanisms to stresses.
Causes of cell injury.
Reversible and irreversible cell injury.
Mechanism of cell injury
Patterns of cell death (apoptosis and
necrosis).
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Reversible changes in size, number,
phenotype, metabolic activity or function in
response to changes in environment.
Adaptation can be both physiologic and
pathologic.
principal adaptive responses:
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Hypertrophy.
Hyperplasia.
Atrophy.
Metaplasia.
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Hypertrophy is an increase in cell size
resulting in an increase in the size of the
organ.
Increased amount of structural proteins and
organelle without increasing the number of
cells.
Occurs in cells that have limited capacity to
divide.
Physiologic vs pathologic.
Caused by increased functional demand
(workload) or stimulation by hormones or
growth factors.
Heart: left ventricle hypertrophy(pathologic).

In skeletal and cardiac muscles (pure
hypertrophy)
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Uterus smooth muscles in pregnancy
(hypertrophy and hyperplasia) (physiologic)
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There is a limit for hypertrophy, beyond
which the muscle is no longer able to
compensate for the increased burden.
Some times subcellular organelle may
undergo selective hypertrophy, Example:
drugs cause smooth ER hypertrophy.
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Increased number of cells resulting in
increased mass of the organ or tissue.
Takes place in cells capable of dividing.
Physiologic vs pathologic.
•
•
Physiological hyperplasia
compensatory)
Examples:
(hormonal
– Uterine enlargement during pregnancy
– Female breast in puberty & lactation
– Compensatory hyperplasia in the liver after partial
resection.
or
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Pathological hyperplasia
◦ Hyperplasia of the endometrium (excessive hormone
stimulation).
◦ Nodular prostatic hyperplasia
◦ Wound healing (Effects of growth factors).
◦ Infection by papillomavirus (HPV)
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Pathologic hyperplasia can be a fertile soil for
development of neoplasia
Prostate
Endometrium
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Reduced size of an organ or tissue as a result
from a decrease in cell size .
Mechanism of atrophy include combination of
decreased protein synthesis and increased
protein degradation in cells.
reduced metabolic activity and degradation of
cellular proteins
Autophagy (“self-eating”) is the process in
which the starved cell eats its own
components in an attempt to survive with
resulting increases in the number
of autophagic vacuoles.
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Physiologic :
-Embryonic development.
-Gravid uterus involution.
-Hormonal withdrawal after menopause.
Pathologic:
-Decreased workload (Disuse atrophy)
-Loss of innervation (Denervation atrophy)
-Diminished blood supply.
-Inadequate nutrition.
-Loss of endocrine stimulation.
-Aging (senile atrophy
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Metaplasia is a “reversible” change in which one
differentiated cell type is replaced by another cell
type.
New cell type is better has survival advantage with
the current stress or irritation but important
protective mechanisms are lost
Persistence of factors causing metaplasia may lead
to progression into malignant transformation.
Vitamin A is essential for normal epithelial
differentiation, its deficiency may also induce
squamous
metaplasia
in
the
respiratory
epithelium.
Examples: respiratory , esophagus, cervix, muscle.

Replacement
of
ciliated
columnar
epithelium
with
stratified
squamous
epithelium in the respiratory tract of a
smoker.
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Oxygen Deprivation: hypoxia and ischemia
Chemical agents & Drugs.
Physical agents: trauma, extremes of
tempreture, radiation, chemicals.
Infectious Agents: viruses to worms.
Immunological reactions.
Genetic factors: chromosomal to single
aminoacid defect
Nutritional Imbalances: Deficiency vs
excess.
Aging.
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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.
The morphologic changes of cell injury (or
death) occur very late.
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cellular swelling .
and
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fatty change.
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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
various forms of toxic or metabolic injury,
and is manifested by the appearance of small
or large lipid vacuoles (hepatocytes and
myocardial cells)
1. Cellular swelling , the first manifestation of
almost all forms of injury to cells.
Difficult to appreciate with the light
microscope, appears as small clear vacuoles
within the cytoplasm.
(Hydropic change or vacuolar degeneration).
2.Fatty change is manifested by the appearance of
lipid vacuoles in the cytoplasm. These changes
are seen in cells involved in fat metabolism as
hepatocytes and myocardial cells.
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(1) plasma membrane alterations such as
blebbing, blunting or distortion of microvilli,
and loosening of intercellular attachments.
(2) mitochondrial changes such as swelling
and the appearance of phospholipid-rich
amorphous densities.
(3) dilation of the ER with detachment of
ribosomes and dissociation of polysomes.
(4) nuclear alterations, with clumping of
chromatin.
Kidney tubules
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© 2005 Elsevier
,‫الجسيم الحال‬
‫يحلول‬
‫الشبكة الهيولية‬
‫الباطنة‬
‫النواة‬
‫المتقدرة‬
‫خلية طبيعية‬
Slide 1.5
W.B. Saunders Company items and
derived items Copyright (c) 1999
by W.B. Saunders Company
‫تكدس‬
‫الجسيمات‬
‫داخل الغشائية‬
‫مجلة(فقاعة)‬
‫تورم الشبكة‬
‫الهيولية الباطنة‬
‫تورم عام‬
‫تبعثر الريباسات‬
‫تالزن(تراكم)الكروماتين(الصبغين)النووي‬
‫تورم متقد ري‬
‫التهام ذاتي‬
‫بالجسيمات‬
‫الحالة‬
‫كثافات صغيرة‬
‫األذية العكوسة‬
‫‪Slide 1.6‬‬

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The type of cell death that is associated with
loss of membrane integrity and leakage of
cellular contents
Denaturation of intracellular proteins and
enzymatic digestion of cells.
Digestion enzymes are derived from
lysosomes of dying cells and leukocytes.

1.
2.
3.
Discontinuities in plasma and organelle
membranes.
Marked dilation of mitochondria with the
appearance of large amorphous densities.
Disruption of lysosomes.
Intracytoplasmic myelin figures (aggregates
of damaged cell membranes
(phospholipids)).

1.
2.
3.
Profound nuclear changes culminating in nuclear
dissolution. Nuclear changes assume one of
three patterns:
karyolysis: The basophilia of the chromatin may
fade), presumably secondary to
deoxyribonuclease (DNase) activity.
pyknosis, characterized by nuclear shrinkage
and increased basophilia; the DNA condenses
into a solid shrunken mass.
karyorrhexis, the pyknotic nucleus undergoes
fragmentation then completely disappears
‫أشكال نخاعينية‬
‫تمزق الجسيمات‬
‫الحالة والتحلل‬
‫الذاتي‬
‫تحلل الشبكة‬
‫الهيولية الباطنة‬
‫عيوب في الغشاء‬
‫الخلوي‬
‫تغلظ النواة‬
‫أو‬
‫تكثفات كبيرة‬
‫تحلل النواة‬
‫تورم متقد ري‬
‫أو‬
‫تجزؤ النواة‬
‫األذية الغير عكوسة‬
‫‪Slide 1.7‬‬
Patterns of Tissue
Necrosis
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preservation of the architecture of dead
tissue for at least some days.
Denaturation of structural proteins and
enzymes.
Eosiniphilic anucleated cells that persist for
days.
Cells are removed by inflammatory
leukocytes.
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Ischemia in all solid organs except the brain
may lead to coagulative necrosis.
Infarction: localised area of coagulative
necrosis.
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digestion of the dead cells resulting into a
liquid jelly-like mass.
In focal bacterial or fungal infections and in
hypoxic death in central nervous system.
Acute inflammation: Creamy yellow material
due to accumulation of dead leukocytes (pus).
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Not a distinctive pattern of cell death, used
in clinical practice.
It is usually applied to a limb, generally the
lower leg, that has lost its blood supply.
When bacterial infection is superimposed,
coagulative necrosis is modified by the
liquefactive action of the bacteria and the
attracted leukocytes ( wet gangrene).
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White cheeselike friable necrosis.
The tissue architecture is completely
obliterated and cellular outlines cannot be
discerned.
Prototype: Tuberculosis
Typical finding is granuloma :Collection of
fragmented or lysed cells with amorphous
granular eosinophilic debris surrounded by
macrophages.
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usually used in clinical terms and it is not a
specific type.
Necrosis (destruction) of fat.
Typical example: pancreatic enzymes (lipases)
release in acute pancreatitis.
The fatty acids result from the breakdown of
fat combine with calcium leading to the
formation of white chalky areas
(Saponification).
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Immune reactions involving blood vessels.
Complexes of antigens and antibodies
deposited in the walls of blood vessels.
Immune complexes deposits along with fibrin
result in a bright pink material on light
microscopy.
Example: vasculitis (polyarteritis nodosa)
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Phagocytosis.
Replacement by scar.
Regeneration.
Calcification.
several general principles are relevant to most
forms of cell injury:
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The cellular response to injurious stimuli
depends on the type of injury, its duration, and
its severity.
The consequences of an injurious stimulus
depend on the type, status, adaptability, and
genetic makeup of the injured cell
Cell injury results from functional and
biochemical abnormalities in one or more of
several essential cellular components
Multiple biochemical alterations may be triggered
by any one injurious insult.
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Depletion of ATP
Mitochondrial Damage and Dysfunction
Influx of Calcium
Accumulation of Oxygen-Derived Free
Radicals (Oxidative Stress)
Defects in Membrane Permeability
Damage to DNA and Proteins
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The activity of plasma membrane ATPdependent sodium pumps is reduced –
cellular swelling
compensatory increase in anaerobic
glycolysis- lactic acid accumulates decreased intracellular pH and decreased
activity of many cellular enzymes.
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Failure of ATP-dependent Ca2+ pumps influx of Ca2+ - with damaging effects on
numerous cellular components
structural disruption of the protein synthetic
apparatus
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Failure of oxidative phosphorylation leads to
progressive depletion of ATP
formation of reactive oxygen species
The mitochondria also contain several
proteins that, when released into the
cytoplasm, tell the cell there is internal injury
and activate a pathway of apoptosis.
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Cytosolic free calcium is normally maintained
at lower concentration than that of
extracellular calcium or of sequestered
intracellular mitochondrial and ER calcium.
Increased cytosolic Ca2+ activates a number
of enzymes, with potentially deleterious
cellular effects (phospholipases, proteases ,
endonucleases)
Increased intracellular Ca2+ levels may also
induce apoptosis
This is seen in the following situations:
 Ischemia-reperfusion
 chemical and radiation injury
 toxicity from oxygen and other gases
 cellular aging
 microbial killing by phagocytic cells and
tissue injury caused by inflammatory cells.
Several biochemical mechanisms may
contribute to membrane damage:
 Decreased phospholipid synthesis
 Increased phospholipid breakdown
 Oxygen free radicals
 Cytoskeletal abnormalities.
 Lipid breakdown products.
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Pathway of cell death induced by a tightly
regulated suicide program in which cells
activate enzymes capable of degrading the
cells' own nuclear DNA and nuclear and
cytoplasmic proteins.
Fragments of the apoptotic cells then break
off, giving the appearance that is responsible
for the name (apoptosis, "falling off").
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The plasma membrane of the apoptotic cell
remains intact.
Apoptotic bodies (contain portions of the
cytoplasm and nucleus) become targets for
phagocytosis before their contents leak out
and so there would be no inflammatory
reaction.

Physiologic situations:
To eliminate cells that are no longer needed OR
to maintain a steady number of various cell
populations in tissues.
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Embryogenesis.
involution of hormone-dependent tissues upon
hormone withdrawal. ( endometrial and breast
after pregnancy)
Cell loss in proliferating cell populations. (GIT)
Death of host cells after serving their useful
function. ( Neutrophils and lymphocytes in
inflammation)
Elimination of potentially harmful self-reactive
lymphocytes.
Cell death induced by cytotoxic T lymphocytes
(tumor cells and viraly infected cells)
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Examples:
DNA damaged cells.
Cells with accumulation of misfolded proteins.
Certain infections (viral ones): may be induced by
the virus (as in human immunodeficiency virus
infections) or by the host immune response (as in
viral hepatitis).
Pathologic atrophy in parenchymal organs after
duct obstruction (pancreas, parotid and kidney)
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Cell shrinkage: dense cytoplasm, tightly
packed organelles.
Chromatin condensation: peripherally under
the nuclear membrane.
Formation of cytoplasmic blebs and apoptotic
bodies: blebbing then fragmentation into
membrane bound apoptotic bodies composed
of cytoplasm and tightly packed organelles
with or without nuclear fragments.

Phagocytosis of apoptotic cells or cell bodies
by macrophages (quickly hence no
inflammation).
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The fundamental event in apoptosis is the
activation of enzymes called caspases .
Two main pathways:
1- Mitochondrial pathway (intrinsic)
2- Death receptor pathway (extrinsic)
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1- mitochondrial pathway (intrinsic)
responsible for apoptosis in most situations.
Leak of cytochrome c out of mitochondria
and activation of caspase 9…
2- death receptor pathway (extrinsic)
Involved in elimination of self-reactive
lymphocytes and in killing of target cells by
some cytotoxic T lymphocytes.
Activation of caspase 8.
Feature
Necrosis
Apoptosis
Cell size
Enlarged (swelling)
Reduced (shrinkage)
Nucleus
Pyknosis → karyorrhexis →
karyolysis
Fragmentation into
nucleosome-size fragments
Plasma membrane
Disrupted
Intact; altered structure,
especially orientation of
lipids
Cellular content
Enzymatic digestion; may
leak out of cell
Intact; altered structure,
especially orientation of
lipids
Adjacent inflammation
Frequent
No
Physiologic or pathologic role
Invariably pathologic
(culmination of irreversible
cell injury)
Often physiologic, means of
eliminating unwanted cells;
may be pathologic after
some forms of cell injury,
especially DNA damage
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