KELAINAN SELKelainan Retrogresif, Progresif,

Degenerasi, Nekrosis, Apoptosis, dan Onkogenesis

Bagian Patologi Anatomi

Fakultas Kedokteran Universitas Islam Sumatera Utara

2010 /2011Dr. H. Soekimin, SpPADr. T. Ibnu Alferraly, SpPA

CELL INJURY, DEATH, AND ADAPTATION

DefinitonsPathology is a dicipline bridging clinical practiceand basic sience

To render diagnosis and guide therapy- Identity changes in gross- Morphology ( microscopy ) appearance of cell tissues

The scientific focus of pathology is :Etiology : on the cause of diseasePathogenesis : mechanisme of its development and the pathways by which morphologic changes occur

Normal homeostasis if cell adjusting structure and function to accommodate changing demands andextracellular stresses

Stresses or pathologic stimuli the cell can :- undergo adaptation

eg.: atrophy, hypertrophy, hyperplasia andmetaplasia

- irreversible injury and ultimately dies

Two principal pattern of cell death :

1.NECROSIS, commonly coagulative necrosis

- cellular swelling- protein denaturation- organellar breakdown2. APOPTOSIS, - regulated event

- programmed death

CAUSES OF CELL INJURY1. Hypoxia :-Anemia-Ischemia-Intoxication CO2

-Aerobic oxidative respiration

2. Physical Agent :- mechanical trauma

- extreme temprature- radiation- electric shock- athmosphere pressure

3. Chemical and drugs : - sufficiently concentrated glucose, salt, O2

- air pollutants- insecticides- asbestosis- ethanol

4. Microbilogy Agents- tape worms- rickettsia- virus- bacteria- fungi

5. Immunologic Reaction- anaphylactic reaction- autoimmune diseases

6. Genetic Defects- congenital Malformation- sicle cell anemia

7. Nutritional Inbalance- protein calori insufficiency- vitamins defficiency- diabetes

8. Aging

Mechanism of Cell Injury• Cellular response to injurious stimuli

depens on the : - injury type - duration - severity

• Current Status : ~ nutrional

~ hormonal ~ adaptibility of the cell

• Intercellular systems

> cell membrane integrity> aerobic respiration> protein synthesis> integrity genetic apparatus

• Oxygen and oxygen derived free radicals: ischemic and hypoxic injury

Reversible InjuryRediced oxidative phosphorylation in mitochondria.Activity Natrium Pump is reducedProducing cellular swelling. Loss of microvilli

Glycogen depleted Reduction in protein synthesis Formation of cell surface blebs

Irreversible Injury Severe vacuolization of the mitochondria Demage of the mitochondrial matrix

Demage of plasma membrane

Swelling of lysosomes

Accumulation of amorphous calcium

Rich dentities in mitochondrial matrix

Forms and Morphology of Cell Injury

1. Reversible acute cell injury

2. Necrosis ( Cell death after irreversible injury )

3. Cell death by suicide = Apoptosis

4. Subcellular alteration as a respond to chronic orpersistent injury stimuli

5. Intracellular accumulations of a number of sub-stances : lipid, carbohidrat, protein, as a result of dearangment

in cell metabolism or excessive storage.

Sublethal Damage

1. Recoverable – necrosis is not

2. Ultrastructural damage to mitochondria

3. Swelling of cellular organelles ( hydrophic deg.)

4. Fatty change is impairment of metabolism

NECROSIS

Refers to a sequence of morphologic changes that follow cell death in living tissue

1. Intense eosinophilia of the dead cell is due to loss of RNA and coagulation of protein.

2. Nuclei undergo phase of pyknosis, karyorhexis and karyolysis leaving a shrunken cell devoid of nucleus

3. Protein may be liberated from the dead cell

The morphologic appearance of necrosis is the result of two essentially processes :

1. Ensymic digestion of the cell2. Denaturation of protein

Autolysis is a dead cell themselves by hydrolitic enzymes

Heterolysis from the lysosomes of invading inflammatory cells

Morphologic Evidence of Necrosis

A Early Change1 – 3 hour before changes of necrosis are

recognizable on electron microscopy6 – 8 hour on light microscopy organelle

degenerationB. Nuclear Change Pyknosis : The chromatine clumps into coare strands

The nucleus becomes a shrunken dense, basophilic mass

Karyorrhexis : The pyknotic nucleus break up

into numerous small basophilic

massKaryolysis : The nucleus lysis as a result

of the action of lysosome deoxy

– ribonucleases

C. Cytoplasmic ChangeAbout 6 hour after cell necrosisCytoplasma becomes homogenous and

deeply` acidophilic. Enzymatic digestion

D. Biochemical ChangesActively transports calcium ions out of the

cell

Tipes of NecrosisDepends on :

1. Cells compotitions2. Speed of necrosis3. Type of injuries

> Coagulative Necrosis

Implies preservation of basic structural outline of the coagulated cell or tissue for a span of days. The structural protein and the enzymatic protein thus blocking cellular proteolysis Coagulation necrosis is cahareteristic of hypoxic death of cells in all tissue except the brain eq. Myocardial Infarction ( occlusion of arterial supply )

Liquefactive or Colliquativa Necrosis

Dead tissue that appears semi liquid as a result of dissolution of tissue by the action of hydrolytic enzymes eq.: - cerebral infarction

- necrosis caused by bacterial inf.

Caseous Necrosis

Dead cell form an amorphous proteinaceaus mass, no original architecture can be seen histologically ( soft and white resembling cream cheese ) Most often in fact of tuberculous infection with central necrosis

> Gumatous Necrosisdescribes dead tissue when it is firm and

rubberylike caseous necrosis in the spirochetal infectionsyphilis.

> Hemorrhagic Necrosisdescribes dead tissue that are suffused withextravasated red cell, when cell death is due toblockage

> Fat Necrosis does not really necrosis. It describes focal areas of fat destruction

tipically occuring following pancreatic injury.

Or after trauma to fat for example in the breast

Describes foci of hard yellow material seen indead adipose tissue

> Fibrinoid Necrosiswhen fibrin is deposited in damage necroticvessel walls in hypertension and vasculitis

> Gangreneextensive tissue necrosis ; is complicated to avariable degree by secondary bacterial

infection

A P O P T O S I Sis responsible for the programmed cell death inseveral important physiology processes

including : The programmed destruction of cells during embryo- genesis as in implantation, organogenesis, and developmental involution Hormon dependent physiologic involution such as the endometrium, lactating, as in the prostate after castration

Cell deletion in proliferating population such as intestinal crypt epithelium or cell dead in tumor

Deletion of autoreactive T cell in the thymus, cell death of cytokine starved lymphocytes

CELL DEATH APOPTOSIS vs. NECROSIS

What is DEATH? (What is LIFE?)

DEATH is IRREVERSIBLE

So the question is….

…NOT what is life or death, but what is REVERSIBLE or IRREVERSIBLE injury

REVERSIBLE CHANGESREDUCED oxidative phosphorylation

ATP depletion

Cellular “SWELLING”

IRREVERSIBLE CHANGESMITOCHONDRIAL IRREVERSIBILITY

IRREVERSIBLE MEMBRANE DEFECTS

LYSOSOMAL DIGESTION

REVERSIBLE = INJURY

IRREVERSIBLE = DEATH

SOME INJURIES CAN LEAD TO DEATH IF PROLONGED

and/or SEVERE enough

INJURY CAUSES (REVERSIBLE)

THE

USUAL

SUSPECTS

But…WHO are

the THREE

WORST?

INJURY CAUSES (REVERSIBLE)

Hypoxia, (decreased O2)

PHYSICAL Agents

CHEMICAL Agents

INFECTIOUS Agents

Immunologic

Genetic

Nutritional

INJURY MECHANISMS (REVERSIBLE)

DECREASED ATP

MITOCHONDRIAL DAMAGE

INCREASED INTRACELLULAR CALCIUM

INCREASED FREE RADICALS

INCREASED CELL MEMBRANE PERMEABILITY

What is Death?What is Life?

DEATH is IRREVERSIBLE MITOCHONDRIAL

DYSFUNCTION PROFOUND MEMBRANE DISTURBANCES

LIFE is……..???

REVERSIBLE IRREVERSIBLEDEATHEMLIGHT MICROSCOPYGROSS APPEARANCES

DEATH:ELECTRON MICROSCOPY

DEATH:LIGHT MICROSCOPY

NECROSIS BROTHERS: Liquefactive (Brain)

Gangrenous (Extremities, Bowel, non-specific) WET DRY

Fibrinoid (Rheumatoid, non-specific)

Caseous (cheese) (Tuberculosis)

Fat (Breast, any fat)

Ischemic (non-specific)

Avascular (aseptic), radiation, organ specific, papillary

LIQUEFACTIVE NECROSIS, BRAIN

MORE LIQUID MORE WATER MORE PROTONS

CASEOUS NECROSIS, TB

FIBRINOID NECROSIS

“WET” GANGRENE

“DRY” GANGRENE

EXAMPLES of Cell INJURY/NECROSIS

Ischemic (Hypoxic)

Ischemia/Reperfusion

Chemical

ISCHEMIC INJURY

REVERSIBLE IRREVERSIBLE

DEATH (INFARCT)

ISCHEMIA/RE-PERFUSION INJURY

NEW Damage “Theory”

CHEMICAL INJURY“Toxic” Chemicals, e.g CCl4 Drugs, e.g tylenol

Dose Relationship

Free radicals, organelle, DNA damage

APOPTOSISNORMAL (preprogrammed)

PATHOLOGIC (associated with Necrosis)

“NORMAL” APOPTOSIS Embryogenesis

Hormonal “Involution”

Cell population control, e.g., “crypts”

Post Inflammatory “Clean-up”

Elimination of “HARMFUL” cells

Cytotoxic T-Cells cleaning up

“PATHOLOGIC” APOPTOSIS

“Toxic” effect on cells, e.g., chemicals, pathogens

Duct obstruction

Tumor cells

Apoptosis/Necrosis spectrum

APOPTOSIS MORPHOLOGYDE-crease in cell size, i.e., shrinkage

IN-crease in chromatin concentration, i.e., hyperchromasia, pyknosis karyorhexis karyolysis

IN-crease in membrane “blebs”

Phagocytosis

SHRINKAGE/HYPERCHROMASIA

PHAGOCYTOSIS

APOPTOSIS BIOCHEMISTRYProtein Digestion (Caspases)

DNA breakdown

Phagocytic Recognition

SUB-Cellular Responses to Injury(APOPTOSIS/NECROSIS)

Lysosomal Auto-DigestionSmooth Endoplasmic Reticulum (SER) activation

Mitochondrial “SWELLING”Cytoskeleton Breakdown

Thin Filaments (actin, myosin) Microtubules Intermediate Filaments (keratin, desmin,

vimentin, neurofilaments, glial filaments)

INTRAcellular ACCUMULATIONS

Lipids Neutral Fat Cholesterol

“Hyaline” = any “proteinaceous” pink “glassy” substance

GlycogenPigments (EX-ogenous, END-ogenous)

Calcium

LIPID LAW

ALL Lipids are YELLOW grossly and WASHED out (CLEAR) microscopically

FATTY LIVER

FATTY LIVER

PIGMENTSEX-ogenous--- (tattoo, Anthracosis)

END-ogenous--- they all look the same, (e.g., hemosiderin, melanin, lipofucsin, bile), in that hey are all golden yellowish brown on “routine” Hematoxylin & Eosin (H&E) stains

Hemosiderin/Melanin/etc.

CLINICAL EFFECTS OF NECROSIS Abnormal function

Kidney : renal failureCortex in brain : muscle paralysisHeart : heart failureLung : hemoptysis

Bacterial infection : gangrene

Realease of contens of necrotic cellsLiver : elevation SGOTHeart : creatine kinase

Systemic effectsFeverInflamatoir Reaction

Local effectsHemorrhageUlceration

CELLULAR ADAPTATIONS OF GROWTH ANDDIFFENTIATION

Environment adaptation of the cell1. Physiologic Adaptation

- Hormones- Endogenous chemical mediators

2. Pathologic Adaptation- Induction of new protein synthesis by target

cell

Cell Injury :• Death of cells ( permanent organ injury )• Sublethal injury ( adaptation )

Perubahan sel dan jaringan :

1. Agenesis 2. Aplasia3. Hypoplasia4. Atrophy5. Hypertrophy6. Hyperplasia7. Metaplasia8. Dysplasia9. Anaplasia10.Granuloma

The –plasia brothers HYPER- HYPO- (A-) NORMO- META-

DYS- ANA- Frank ANA-

Agenesis Complet absen of an organ Exc : - renal agenesis - ovarial agenesis - tubal agenesis, etc

Aplasia

Anlarge is present but never develops

Exc : lung aplasia with tissue containing rudimentary duct and connective tissue

HYPO-PLASIADE-CREASE IN NUMBER OF CELLS

Hypoplasia Anlarge develoved incompletly but the

tissue histhologicaly normal

Exc : microcephaly

The –trophy brothers HYPER- HYPO- (A-)

DYS-

A-TROPHY DE-CREASE IN SIZE OF CELLS? YES

SHRINKAGE IN CELL SIZE DUE TO LOSS OF CELL

SUBSTANCE

ATROPHY

DECREASED WORKLOAD DENERVATION DECREASED BLOOD FLOW DECREASED NUTRITION AGING (involution) PRESSURE

A t r o p h y

is the decrease in the size and a function of a cell but are not dead

Causes of atrophy :

1. Reduced functional demanImmobilitation in fractureProlonged bed rest

2. Inadequate supply of oxygenIschemia

3. Insufficient nutrientsStarvationInadequate nutritionsChronic disease

4. Interrruption of trophic signalsThe functions of many cells depend on signaltransmitted by chemical mediators

-Endocrin system-Neuromucculator transmission eq. Thyroid

Adrenal cortexOvariumTestis

5. Persistant cell injuryCaused by chrinic inflamationeq. - chronic gastritis

- prolonged pressure

6. AgingParticularly in non replacating cells such brain,heart.> Senile Atrophy

The mechanism of atrophy :

• decreased synthesis

• increased catabolism

• influenced by a number of hormones eq. Insulin, tyroid stimulating hormon, glucocorticoids

HYPER-TROPHYIN-CREASE IN SIZE OF CELLS

H y p e r t r o p h y

Is an increase in the size of cell accompanied by

Augmented functional capacity

Hypertrophy is a response to trophic signals and

Commonly a normal procesess

I. Physiological ( Hormonal ) hypertrophy- in puberty an icreased production of sex hor –

mon - hypertrophy breast tissue - abnormal hormon production in cancer

II. Increased functional demands- exercise- pathological conditions

eq. Myocardial cell- kidney hypertrophy on surgical removed

HYPER-PLASIAIN-CREASE IN NUMBER OF CELLS

H Y P E R P L A S I Ais an increase in the number of cells in an organor tissue

Hyperplasia can be :

I . Physiologic hyperplasia- hormonal hyperplasia- compensatory hyperplasia

II. Pathologic hyperplasiaexcessive hormonal or growth factor stimulationeq. Endometrial hyperplasia

1. Hormonal stimulation- estrogen increased endometrium ( hyperplasia)- gynecomastia

2. Increased functional demand- secondary polycytemia- lymphocyte hyperplasia

3. Persistent Cell Injury- chronic inflammation in the skin and the epi –

thelium of viscera- hyperplasia of the bladder epithelium

METAPLASIA A SUBSTITUTION of one NORMAL CELL or TISSUE type, for ANOTHER COLUMNAR SQUAMOUS (Cervix) SQUAMOUS COLUMNAR (Glandular)

(Stomach) FIBROUS BONE

WHY?

M E T A P L A S I Ais a reversible change in which one adult celltype is replace by another adult cell type( Metaplasia is the convertion of one differentia – ted cell type of another )

It is almost invariably a response to persistent injuryand can be thought of as an adaptive mechanism.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

Metaplasia is usually reversible if the stimulus is removed

D Y S P L A S I Acellular dysplasia refers to an alteration in thesize, shape and organization of the cellular com –ponent of a tissue

The cells an epithelium exhibit uniformity of size, shapeAnd nucleus.

Dysplasia mean is disturbed by1. Variation in the size and shape of cells2. Enlargment, irregularity and hyperchromatism of the nuclei.3. Disorderly arrangement of the cells within the epi – thelium

The most common in the cervix and bronchus

It is established that dysplasia is a preneoplastic lession in the sense that it is a necessary stage in the multistep cellular evolution to cancer.

Dysplasia included in the morphological classification Of the stage if intraepithelial neoplasia

Anaplasia normal cell primitive cell Exc : malignan cell (carcinoma, sarcoma, adenocarcinoma, lymphoma, etc)

Granuloma

specialized type of chronic inflamation in tissue reaction

Cause : - infection : tbc, fungal, siphylis, etc - non-infection : sarcoidosis, Crohn’s disease, etc

C E L L U L A R A G I N GAlterations in structure and fuction that may leadto cell death, or at least diminished capacity ofthe cell to respond an injury

Reduced cell in : - pleomorphic vacuolated mitochondria - repair of chromosomal damage

Morphologic alteration in :• pleomorphic vacuolated mitochondria• decreased endoplasmic reticulum• disorted Golgi Apparatus• accumutaion of lipofuscin pigment

Cellular senescence is multifactorial :

1. The cumulative effects of extrinsic influences: free radical damage

2. Intrinsic molecular program of cellular agingcell have a finite life span

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