Stages in The Cellular Response To Stress & Injurious Stimuli

Blok BBS 2
Departemen Patologi Anatomi Fakultas

Kedokteran Universitas Sumatera Utara
Medan - 2011
Stages in the cellular response to stress &

injurious stimuli
DEPARTEMEN PATOLOGI ANATOMI FK-

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Table 1-1. Cellular Responses to Injury
Nature &Severity of Injurious Stimulus Cellular Response
Altered physiologic stimuli: Cellular adaptations:
• ↑demand, ↑ trophic stimulation (e.g. growth
• Hyperplasia, hypertrophy
factors, hormones)
• ↓ nutrients, stimulation • Atrophy
• Chronic irritation (chemical /physical) • Metaplasia
↓ O2 supply; chemical injury; microbial
Cell injury:
infection
• Acute & self-limited • Acute reversible injury
• Progessive & severe (including DNA damage) • Irreversible injury ➙ cell death
Necrosis
Apoptosis
• Mild chronic injury • Subcellular alterations in various organelles
Metabolic alterations (genetic / acquired) Intracellular accumulations; calcifications
Prolonged life span with cumulative
Cellular aging
sublethal injury

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Stresses/pathologic stimuli the cell

Can undergo
Adaptation
• Atrophy
• Hypertrophy
• Hyperplasia
• Metaplasia
Irreversible injury & dies
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Perubahan sel & jaringan
Agenesis Hyperplasia
Aplasia Metaplasia
Hypoplasia Dysplasia
Atrophy Anaplasia
Hypertrophy Granuloma

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Agenesis Aplasia
• Complete absent of • Is present

organ • But never develops
• e.g. : • e.g. :
– Renal agenesis – Lung aplasia with tissue
– Ovarial agenesis containing rudimentary
– Tubal agenesis, etc. duct & connective tissue

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Hypoplasia
• Developved incompletly
• But the tissue histhologicaly normal
• e.g. : microcephaly

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Atrophy
• Decrease in the:
– Size
– Function of a cell
• But not dead

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Causes of atrophy :
1. ↓ functional demand (immobilitation in fracture, prolonged
bed rest)
2. Inadequate supply O2 (ischemia)
3. Insufficient nutrients (starvation, inadequate nutrition,
chronic disease)
4. Interruption of trophic signals transmitted by chemical
mediators (endocrine system/neuromusculator transmission)
e.g. : thyroid, adrenal cortex, ovarium, testis.
5. Persistent cell injury by chronic inflamation
e.g. : chronic gastritis, prolonged pressure
6. Aging : brain, heart (Senile Atrophy)

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Atrophy
A section of heart muscle (myocardium). The spaces between muscle fibers are not present in normal
myocardium. The muscle fibers are thinner than normal
DEPARTEMEN creating
PATOLOGI ANATOMIspaces
FK- between them, a finding
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suggesting 10
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The mechanism of atrophy :
↓ Synthesis
↑ Catabolism
↑ Hormones
e.g. :
• Insulin
• Tyroid stimulating hormon
• Glucocorticoids

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Hypertrophy
• ↑ size of cell accompanied by ↑ functional

capacity
• Is a response to trophic signals
• Commonly a normal procesess

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… hypertrophy
Physiological (hormonal) hypertrophy
• in puberty
• ↑ production of sex hormon
• Hypertrophy breast tissue
• Abnormal hormon production in cancer
↑ Functional demands
• Exercise
• Pathological conditions (myocardial cell)
• Kidney hypertrophy on surgical removed

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Hypertrophy
Myocardium in an area adjacent to a
healed MCI ("heart attack").
Cardiac muscle cannot regenerate, fibrous
connective tissue fills in the defect.
Viable muscle cells, ↑ size to compensate
for cells that died.
Nuclei ↑ indicate the cells have
undergone hypertrophy (↑ in volume
of cells).
Hypertrophy At higher magnification

↑ cardiac muscle cells & nuclei.
Cardiac muscle cells cannot divide adapt by
↑size (hypertropy).

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Hyperplasia
↑ the number of cells in an organ / tissue

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Hyperplasia can be :
Physiologic hyperplasia Pathologic hyperplasia
• Hormonal hyperplasia • ↑ hormonal / growth

• Compensatory factor stimulation
hyperplasia • e.g. :
• Endometrial
hyperplasia

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Metaplasia
1 adult cell type another adult cell type

(convertion of 1 differentiated cell type of another)
Most common is the replacment of a glandular epithelium

by a squamous cell.
• Squamous metaplasia of the bronchial epithelium to tobacco

• Lower oesophagus by reflux acidic gastric
• Endocervical metaplasia
Usually reversible if the stimulus is removed

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Metaplasia of normal columnar (left) to squamous epithelium

(right) in a bronchus, (A) schematically and (B) histologically

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Dysplasia
Cellular alteration in the

size, shape & organization of the cellular component of a
tissue
1. Size & shape of cells variation

2. Nuclei : >>, irregular & hyperchromatism
3. Disorderly arrangement of the cells within the
epithelium
The most common in the cervix & bronchus

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Dysplasia is a preneoplastic lession

Necessary stage in the multistep cellular evolution
to cancer.

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Anaplasia
• Normal cell primitive cell

• E.g. : Malignant cell
– Carcinoma
– Sarcoma
– Adenocarcinoma
– Lymphoma
– Etc.

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CELL INJURY

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2 principal pattern of cell death :
• Commonly : coagulative necrosis
• Cellular swelling
NECROSIS •
•
Protein denaturation
Organellar breakdown
• Cell rupture
• Regulated event
APOPTOSIS • Programmed death

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Term Definition
Necrosis Antemortem pathologic cell death
Apoptosis Antemortem programmed cell death
Autolysis Postmortem cell death

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CAUSES OF CELL INJURY
Hypoxia
Physical Agent
Chemical and drugs
Microbiology Agents
Immunologic Reaction
Genetic Defects
Nutritional Inbalance
Aging
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… CAUSES OF CELL INJURY
Hypoxia Physical Agent
• Anemia • Mechanical trauma

• Ischemia • Extreme temprature :
• Intoxication CO2 heat, cold
• Aerobic oxidative • Radiation: X-ray, sun light
respiration • Electric shock
• Athmosphere pressure

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Chemical agent & drugs Microbiology Agents
• Sufficiently concentrated : • Tape worms

Glucose, Salt, O2 • Rickettsia
• Air pollutants • Virus
• Insecticides • Bacteria
• Asbestosis • Fungi
• Ethanol
• Cellular metabolism (i.e.
waste products)

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Immunologic Reaction
• Anaphylactic reaction
• Autoimmune diseases

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Genetic Defects
• Congenital malformation
• Sickle cell anemia
• G-6-PD
Nutritional Imbalance
• Protein calori insufficiency
• Vitamins defficiency
• Diabetes
Aging

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Mechanism of Cell Injury
Cellular Current Intercellular O2 & oxygen

response to systems : derived free
Status :
injurious • Cell membrane radicals :
stimuli • Nutritional integrity
• Aerobic
• Ischemic
depends on : • Hormonal
respiration • Hypoxic
• Injury type • Adaptibility • Protein synthesis injury
• Duration of the cell • Integrity genetic
apparatus
• Severity
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Normal cell & changes in reversible & irreversible cell injury
(necrosis)
The ultrastructuralDEPARTEMEN
3/28/2011 features PATOLOGI ANATOMI FK-
USUof these stages of cell injury.
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Reversible injury Irreversible injury
• Reduced of : • Severe vacuolization of
– Oxidative mitochondria
phosphorylation in
mitochondria
• Damage of :
– Activity Na Pump – Mitochondrial matrix
• Cellular swelling – Plasma membrane
• Loss of microvilli • Swelling of lysosomes
Glycogen depleted • Accumulation of
↓ protein synthesis
Formation of cell surface
amorphous calcium
blebs • Rich dentities in
mitochondrial matrix
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Figure 1-6.
Cellular features of
necrosis (left) &
apoptosis (right)

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Feature Necrosis Apoptosis
Cell size Enlarged (swelling) Reduced (shrinkage)
Nucleus Pyknosis → karyorrhexis Fragmentation into
→ karyolysis nucleosome-size
fragments
Plasma membrane Disrupted Intact; altered structure,
especially orientation of
lipids
Cellular contents Enzymatic digestion; may Intact; may be released in
leak out of cell apoptotic bodies
Adjacent inflammation Frequent No
Physiologic or pathologic Invariably pathologic Often physiologic, means
role (culmination of of eliminating unwanted
irreversible cell injury) cells; may be pathologic
after some forms of cell
injury, especially DNA
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damage 37
Forms & Morphology of Cell Injury

1. Reversible acute cell injury
2. Necrosis (cell death after irreversible injury)
3. Apoptosis (cell death by suicide)
4. Subcellular alteration as a respond to chronic

or persistent injury stimuli
5. Intracellular accumulations of a number of

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substanceDEPARTEMEN PATOLOGI ANATOMI FK- 38
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Necrosis
Morphologic changes that follow cell death in living tissue
1. Intense eosinophilia of the dead cell is due to

loss of RNA & coagulation of protein
2. Nuclei undergo:
1. Pyknosis
2. Karyorhexis
3. Karyolysis
Leaving a shrunken cell devoid of nucleus
3. Protein may be liberated from the dead cell
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The morphologic appearance of necrosis is

the result of 2 essentially processes :
1. Enzymatic digestion of the cell

2. Denaturation of protein
Autolysis : is a cell death by hydrolitic

enzymes
Heterolysis : cell death by the lysosomes of

invading inflammatory cells.
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Nuclear Changes: This nucleus is faded -- karyolysis.
Karyolytic DEPARTEMEN
nuclei suggest that PATOLOGI
cells have diedANATOMI FK-
(undergone necrosis).
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Nuclear Changes: Pyknosis While cytoplasmic changes associated with cell death are not
specific, nuclear changes are. The large arrow indicates a normal-appearing nucleus while the
smaller arrow indicates a nucleus that
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is small PATOLOGI
DEPARTEMEN and darkANATOMI
-- features
FK- of "pyknosis." Pyknotic nuclei
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suggest that cells have died (are undergoing necrosis).
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Fragmented nuclei suggest that cells have died. Karyorrhexis is the term used for this
circumstance. The nucleus indicated by the large arrow may be undergoing karyorrhexis. The
smaller arrow indicates a fragmented
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nucleus:
DEPARTEMEN it could
PATOLOGI be karyorrhexis
ANATOMI FK- or a mitotic figure (a
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cell undergoing mitosis). USU 2011

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Morphologic changes in reversible and irreversible cell injury
(necrosis).
A, Normal kidney tubules B, Early (reversible) C, Necrotic (irreversible) injury

with viable epithelial ischemic injury of epithelial cells
cells

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Types of Necrosis
Depends on :
1. Cells compotitions
2. Speed of necrosis
3. Type of injuries

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Coagulative Necrosis
• The structural protein & enzymatic protein thus

blocking cellular proteolysis
• Cahareteristic of hypoxic death of cells in all

tissue except the brain
e.g. : Myocardial Infarction (occlusion of arterial
supply)

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• Liquefactive/Colliquativa Necrosis
• Dead tissue
• Appears semi liquid
• Result of dissolution of tissue by the action of
hydrolytic enzymes
e.g.: cerebral infarction, necrosis caused by bacterial
inf.
• Caseous Necrosis
• Dead cell
• Form amorphous proteinaceaus mass
• No original architecture can be seen (histologic)
• Soft & white resembling cream cheese
• Most often in TBC infection with central necrosis

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Coagulative & liquefactive necrosis
A. Kidney infarct B. Liquefactive necrosis (kidney

(coagulative necrosis) caused by fungal infection).

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• Gumatous Necrosis
• Dead tissue, it is firm & rubbery like caseous necrosis in the
spirochetal infection syphilis.
• Hemorrhagic Necrosis
• Dead tissue suffused with extravasated red cell, when cell
death is due to blockage
• Fat Necrosis
• Not really necrosis.
• Focal areas of fat destruction tipically occuring following
pancreatic injury /after trauma to fat for (ex. in the breast)
• Describes foci of hard yellow material seen in dead adipose
tissue
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• Fibrinoid Necrosis
• Fibrin deposited in damage necrotic vessel
walls in hypertension and vasculitis
• Gangrene
• Extensive tissue necrosis ; is complicated to
a variable degree by secondary bacterial
infection

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Fibrinoid necrosis in an artery

(polyarteritis nodosa)

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APOPTOSIS
• Responsible for the programmed cell death in several
important physiology processes
• Including :
– During embryogenesis (in implantation, organogenesis, &
developmental involution)
– Hormon dependent physiologic involution (endometrium,
lactating, prostate after castration)
– Cell deletion in proliferating population (intestinal crypt
epithelium / cell dead in tumor)
– Deletion of autoreactive T cell in the thymus,
cell death of cytokine starved lymphocytes

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Apoptosis of epidermal cells in an immune-

mediated reaction
A. Apoptotic cells are visible in the
epidermis with eosinophilic cytoplasm B. High power of apoptotic cell in liver in
and small, dense nuclei. immune-mediated hepatic cell injury.
DEPARTEMEN
(Courtesy of Dr. Scott Granter, Brigham and Women's PATOLOGI
Hospital, Boston, ANATOMI
AM.) (Courtesy FK- Jain, Yale University, New Haven, CT.)
of Dr. Dhanpat
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Granuloma
• Special type of chronic inflamation in tissue

reaction.
• Cause :
syphilis,
infection : TBC fungal
etc
non- sarcoidosis
Crohn’s
infection : disease

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NECROBIOSIS
Necrobiosis is physiological death of a cell, and

can be caused by certain conditions
Such as :
• Basophilia
• Erythema or
• Presence of a tumor
It can be identified both with/without necrosis

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… Necrobiosis
• Gradual cell damage

• Progressive
• Singly / small group cells
• Reversible (+/-)
• Example :
– Hepar cell deg.
– Cell death healing fibrosis.

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Cellular Aging
Alterations in structure & function that may lead
to cell death, or at least diminished capacity of the
cell to respond an injury
• Reduced cell in :
– Pleomorphic vacuolated mitochondria
– Repair of chromosomal damage

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… Cellular Aging
Morphologic alteration in :
• Pleomorphic vacuolated mitochondria
• ↓ endoplasmic reticulum
• Disorted Golgi Apparatus
• Accumutaion of lipofuscin pigment

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Cellular senescence is multifactorial :
The cumulative effects of :

1. Extrinsic influences : free radical damage
2. Intrinsic molecular program of cellular aging

cell have a finite life span

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DEGENERATION
Cloudy Fatty
Hydropic Atropy
swelling change
Hyaline Mucoid Amyloid Calcification

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Ballooning
degeneration
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Hydropic change
of gestational
mole

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Fatty Change At higher

magnification the
intracytoplasmic fat
droplets are clearly
evident.

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Hyaline Droplet Degeneration Sometimes protein droplets appear within the
cy_toplasm of sick cells. These
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dropletsPATOLOGI
DEPARTEMEN appear ANATOMI
homogeneous,
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structures -- an apearance known as "hyaline.”
THANK YOU
SELAMAT BELAJAR

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Blok BBS 2

Departemen Patologi Anatomi Fakultas

Stages in the cellular response to stress &

DEPARTEMEN PATOLOGI ANATOMI FK-

DEPARTEMEN PATOLOGI ANATOMI FK-

Stresses/pathologic stimuli the cell

DEPARTEMEN PATOLOGI ANATOMI FK-

• Complete absent of • Is present

DEPARTEMEN PATOLOGI ANATOMI FK-

DEPARTEMEN PATOLOGI ANATOMI FK-

DEPARTEMEN PATOLOGI ANATOMI FK-

DEPARTEMEN PATOLOGI ANATOMI FK-

DEPARTEMEN PATOLOGI ANATOMI FK-

• ↑ size of cell accompanied by ↑ functional

DEPARTEMEN PATOLOGI ANATOMI FK-

DEPARTEMEN PATOLOGI ANATOMI FK-

Hypertrophy At higher magnification

DEPARTEMEN PATOLOGI ANATOMI FK-

↑ the number of cells in an organ / tissue

DEPARTEMEN PATOLOGI ANATOMI FK-

Physiologic hyperplasia Pathologic hyperplasia

• Hormonal hyperplasia • ↑ hormonal / growth

DEPARTEMEN PATOLOGI ANATOMI FK-

1 adult cell type another adult cell type

Most common is the replacment of a glandular epithelium

• Squamous metaplasia of the bronchial epithelium to tobacco

Usually reversible if the stimulus is removed

DEPARTEMEN PATOLOGI ANATOMI FK-

Metaplasia of normal columnar (left) to squamous epithelium

DEPARTEMEN PATOLOGI ANATOMI FK-

Cellular alteration in the

1. Size & shape of cells variation

The most common in the cervix & bronchus

Dysplasia is a preneoplastic lession

DEPARTEMEN PATOLOGI ANATOMI FK-

• Normal cell primitive cell

DEPARTEMEN PATOLOGI ANATOMI FK-

DEPARTEMEN PATOLOGI ANATOMI FK-

DEPARTEMEN PATOLOGI ANATOMI FK-

Necrosis Antemortem pathologic cell death

Apoptosis Antemortem programmed cell death

Autolysis Postmortem cell death

DEPARTEMEN PATOLOGI ANATOMI FK-

Chemical and drugs

… CAUSES OF CELL INJURY

Hypoxia Physical Agent

• Anemia • Mechanical trauma

DEPARTEMEN PATOLOGI ANATOMI FK-

Chemical agent & drugs Microbiology Agents

• Sufficiently concentrated : • Tape worms

DEPARTEMEN PATOLOGI ANATOMI FK-

… CAUSES OF CELL INJURY

DEPARTEMEN PATOLOGI ANATOMI FK-

DEPARTEMEN PATOLOGI ANATOMI FK-

Mechanism of Cell Injury

Cellular Current Intercellular O2 & oxygen

DEPARTEMEN PATOLOGI ANATOMI FK-