Stages in the cellular response to stress & injurious...

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Departemen Patologi Anatomi Fakultas Kedokteran Universitas Sumatera Utara

Medan - 2011

Blok BBS 2

Stages in the cellular response to stress &

injurious stimuli

3/28/2011 2DEPARTEMEN 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

factors, hormones)• Hyperplasia, hypertrophy

• ↓ nutrients, stimulation • Atrophy

• Chronic irritation (chemical /physical) • Metaplasia

↓ O2 supply; chemical injury; microbial

infectionCell injury:

• 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

sublethal injuryCellular aging


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Stresses/pathologic stimuli the cell

Adaptation

• Atrophy

• Hypertrophy

• Hyperplasia

• Metaplasia

Irreversible injury & dies


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Can undergo

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Perubahan sel & jaringan

Agenesis

Aplasia

Hypoplasia

Atrophy

Hypertrophy

Hyperplasia

Metaplasia

Dysplasia

Anaplasia

Granuloma


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• Complete absent of

organ

• e.g. :

– Renal agenesis

– Ovarial agenesis

– Tubal agenesis, etc.

Agenesis Aplasia

• Is present

• But never develops

• e.g. :

– Lung aplasia with tissue

containing rudimentary

duct & connective tissue


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• Developved incompletly

• But the tissue histhologicaly normal

• e.g. : microcephaly

Hypoplasia


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• Decrease in the:

– Size

– Function of a cell

• But not dead

Atrophy


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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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AtrophyA section of heart muscle (myocardium). The spaces between muscle fibers are not present in normal myocardium. The muscle fibers are thinner than normal creating spaces between them, a finding suggesting atrophy.3/28/2011 10

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The mechanism of atrophy :

e.g. :

• Insulin

• Tyroid stimulating hormon

• Glucocorticoids


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↓ Synthesis

↑ Catabolism

↑ Hormones

• ↑ size of cell accompanied by ↑ functional capacity

• Is a response to trophic signals

• Commonly a normal procesess

Hypertrophy


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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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HypertrophyMyocardium 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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Physiologic hyperplasia

• Hormonal hyperplasia

• Compensatory hyperplasia

Pathologic hyperplasia

• ↑ hormonal / growth factor stimulation

• e.g. :

• Endometrial hyperplasia

Hyperplasia can be :


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Metaplasia

1 adult cell type � another adult cell type

(convertion of 1 differentiated cell type of another)

Usually reversible if the stimulus is removed

• Squamous metaplasia of the bronchial epithelium to tobacco

• Lower oesophagus by reflux acidic gastric

• Endocervical metaplasia

Most common is the replacment of a glandular epithelium by a squamous cell.


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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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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

Dysplasia

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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• Normal cell � primitive cell

• E.g. : Malignant cell

– Carcinoma

– Sarcoma

– Adenocarcinoma

– Lymphoma

– Etc.

Anaplasia


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CELL INJURY

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2 principal pattern of cell death :

• Commonly : coagulative necrosis

• Cellular swelling

• Protein denaturation

• Organellar breakdown

• Cell rupture

NECROSIS

• Regulated event

• Programmed deathAPOPTOSIS


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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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• Anemia

• Ischemia

• Intoxication CO2

• Aerobic oxidative

respiration

• Mechanical trauma

• Extreme temprature :

heat, cold

• Radiation: X-ray, sun light

• Electric shock

• Athmosphere pressure

Hypoxia Physical Agent

… CAUSES OF CELL INJURY


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• Sufficiently concentrated :

Glucose, Salt, O2

• Air pollutants

• Insecticides

• Asbestosis

• Ethanol

• Cellular metabolism (i.e.

waste products)

• Tape worms

• Rickettsia

• Virus

• Bacteria

• Fungi


Chemical agent & drugs Microbiology Agents


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• Anaphylactic reaction

• Autoimmune diseases

Immunologic Reaction


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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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Cellular response to injurious stimuli depends on :

• Injury type

• Duration

• Severity

Current

Status :

• Nutritional

• Hormonal

• Adaptibilityof the cell

Intercellular systems :

• Cell membrane integrity

• Aerobic respiration

• Protein synthesis

• Integrity genetic apparatus

O2 & oxygen derived free radicals :

• Ischemic

• Hypoxic injury

Mechanism of Cell Injury


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The ultrastructural features of these stages of cell injury.

Normal cell & changes in reversible & irreversible cell injury

(necrosis)


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• Reduced of :– Oxidative

phosphorylation in

mitochondria

– Activity Na Pump

• Cellular swelling

• Loss of microvilli� Glycogen depleted

� ↓ protein synthesis

� Formation of cell surface

blebs

• Severe vacuolization of

mitochondria

• Damage of :

– Mitochondrial matrix

– Plasma membrane

• Swelling of lysosomes

• Accumulation of

amorphous calcium

• Rich dentities in

mitochondrial matrix

Reversible injury Irreversible injury


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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

→ karyolysis

Fragmentation into

nucleosome-size

fragments

Plasma membrane Disrupted Intact; altered structure,

especially orientation of

lipids

Cellular contents Enzymatic digestion; may

leak out of cell

Intact; may be released in

apoptotic bodies

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

damage3/28/2011 37DEPARTEMEN PATOLOGI ANATOMI FK-

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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

substance

Forms & Morphology of Cell Injury


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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

Necrosis


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The morphologic appearance of necrosis isthe result of 2 essentially processes :

1. Enzymatic digestion of the cell2. Denaturation of protein

Autolysis : is a cell death by hydroliticenzymes

Heterolysis : cell death by the lysosomes of invading inflammatory cells.


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Nuclear Changes: This nucleus is faded -- karyolysis.

Karyolytic nuclei suggest that cells have died (undergone necrosis).3/28/2011 41DEPARTEMEN PATOLOGI ANATOMI FK-

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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 is small and dark -- features of "pyknosis." Pyknotic nuclei 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 nucleus: it could be karyorrhexis or a mitotic figure (a cell undergoing mitosis).


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Morphologic changes in reversible and irreversible cell injury

(necrosis).

A, Normal kidney tubules with viable epithelial cells

B, Early (reversible) ischemic injury

C, Necrotic (irreversible) injury of epithelial 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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• The structural protein & enzymatic protein thus blocking cellular proteolysis

• Cahareteristic of hypoxic death of cells in all tissue except the braine.g. : Myocardial Infarction (occlusion of arterial supply)

Coagulative Necrosis


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• Liquefactive/Colliquativa Necrosis• Dead tissue• Appears semi liquid • Result of dissolution of tissue by the action of hydrolytic enzymese.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 (coagulative necrosis)

B. Liquefactive necrosis (kidney 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

and small, dense nuclei.

B. High power of apoptotic cell in liver in

immune-mediated hepatic cell injury.

(Courtesy of Dr. Scott Granter, Brigham and Women's Hospital, Boston, AM.) (Courtesy of Dr. Dhanpat Jain, Yale University, New Haven, CT.)3/28/2011 54DEPARTEMEN PATOLOGI ANATOMI FK-

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Granuloma

• Special type of chronic inflamation in tissue

reaction.

• Cause :

infection : TBC fungal syphilis,

etc

non-

infection :sarcoidosis

Crohn’s

disease


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NECROBIOSIS

Necrobiosis is physiological death of a cell, and can be caused by certain conditions


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It can be identified both with/without necrosis

Such as :

• Basophilia

• Erythema or

• Presence of a tumor

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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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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

Cellular Aging


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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 swelling

Fatty change

Hydropic Atropy

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 droplets appear homogeneous, glassy, bead-like structures -- an apearance known as "hyaline.”


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THANK YOU

SELAMAT BELAJAR


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