NECROSIS AND APOPTOSIS

Cell injury L2

Dr. Maha ArafahAssistant ProfessorDepartment of PathologyKing Khalid University Hospital and King Saud UniversityEmail: marafah@ksu.edu.sa marafah @hotmail.com

Sunday, Oct 10, 201010:00 to 11:00 am

Objectives Define necrosis and apoptosis List the different conditions

associated with apoptosis, its morphology and its mechanism

List the different types of necrosis, examples of each and its features

Know the difference between apoptosis and necrosis

Objectives Define necrosis and apoptosis List the different conditions associated

with apoptosis, its morphology and its mechanism

List the different types of necrosis, examples of each and its features

Know the difference between apoptosis and necrosis

Cell Death

Death of cells occurs in two ways:

1. Necrosis--changes produced by enzymatic digestion ofcells after irreversible injury

2. Apoptosis--vital process that helps eliminate unwanted cells--an internally programmed series of events effected by dedicated gene products

AutolysisAutolysis is the death of individual cells and tissues after the death of the whole organism. The cells are degraded by the post-mortem release of digestive enzymes from the cytoplasmic lysosomes.

Objectives

Define necrosis and apoptosis List the different conditions associated

with apoptosis, its morphology and its mechanism

List the different types of necrosis, examples of each and its features

Know the difference between apoptosis and necrosis

Cell Death

Apoptosis

• Vital process.• Programmed cell death.• Can occurs in physiological or pathological

conditions.

Apoptosis

Physiologic process to die

This process helps to eliminate unwanted cells by an internally programmed series of events effected by dedicated gene products. It

serves several vital functions and is seen under various settings.

Remember: apoptosis require energy to die

Apoptosis

SEEN IN THE FOLLOWING CONDITIONS: A. Physiologic

1. During development for removal of excess cells during embryogenesis

2. To maintain cell population in tissues with high turnover of cells, such as skin, bowels.

3. To eliminate immune cells after cytokine depletion, and autoreactive T-cells in developing thymus.

4. Hormone-dependent involution - Endometrium, ovary, breasts etc.

Apoptosis

B. Pathologic

1. To remove damaged cells by virus2. Atrophy (virtually never

accompanied by necrosis). 3. To eliminate cells after DNA damage

by radiation, cytotoxic agents etc. 4. Cell death in tumors.

Morphology of Apoptosis

1. Shrinkage of cells

2. Condensation of nuclear chromatin peripherally under nuclear membrane

3. Formation of apoptotic bodies by fragmentation of the cells and nuclei. The fragments remain membrane-bound and contain cell organelles with or without nuclear fragments.

4. Phagocytosis of apoptotic  bodies by adjacent healthy cells or phagocytes.

5. Unlike necrosis, apoptosis is not accompanied by inflammatory reaction

Apoptosis: liver cells are dying individually from injury by viral hepatitis.

Liver biopsy - viral hepatitis: acidophilic body(councilman body)

(apoptosis, i.e., induced, or programmed, individual cell death). Vacuolar change is reversible.

Skin, apoptotic Keratinocyte

MECHANISMS OF APOPTOSIS

1. Chromatin condensation is mediated by calcium-sensitive endonuclease leading to internucleosomal DNA fragmentation.

2. Alteration in cell volume (shrinkage) due to action of

transglutaminase.3. Phagocytosis of apoptotic bodies is mediated by receptors on the macrophages.4. Apoptosis is dependent on gene activation and

new protein synthesis, e.g. bcl-2, c-myc oncogene

and p53.

Apoptosis summary

Apoptosis regulating genes

Oncogene Bcl-2 Bcl-2 overexpression prevents apoptosis Antagonized by cell death (ced) genes & others

(bax,bad) Localized to mitochondria, nuclear envelope and ER Bcl-2 overexpression is found in follicular lymphoma.

Tumor suppressor gene p-53 Will cause cells with DNA damage (eg amplified myc)

to go apoptosis Induce bax expression Reversed by overexpression of bcl-2

Genes that regulate apoptosis:

Objectives Define necrosis and apoptosis List the different conditions associated

with apoptosis, its morphology and its mechanism

List the different types of necrosis, examples of each and its features

Know the difference between apoptosis and necrosis

Necrosis

Necrosis is defined as the morphological changes that result from cell death within living tissues.

In necrosis, death of a large number of cells in one area occurs.

These changes occur because of digestion and denaturation of cellular proteins.

Morphology of necrosis:

1. Cellular swelling or rupture

2. Denaturation  and coagulation of cytoplasmic proteins

3. Breakdown of cell organelles

4. Breakdown of nuclear DNA

The results of cell death can include:

Cessation of function of a tissue or organ. Release of cellular enzymes, these can

sometimes be detected in the blood and used as markers of the extent or timing of damage to a particular organ, e.g. cardiac enzyme after myocardial infarction.

Initiation of the inflammatory response (vital reaction).

 

Patterns of Necrosis: In Tissues or Organs

As a result of cell death the tissues or organs display one of these six macroscopic changes:

1. Coagulative necrosis2. Liquifactive necrosis3. Caseous necrosis4. Fat necrosis5. Gangrenous necrosis6. Fibrinoid necrosis

Patterns of Necrosis In Tissues or Organs

1. Coagulative necrosis: Denaturation of intracellular protein leads to the

pale firm nature of the tissues affected. The cells show the microscopic features of cell death but the general architecture of the tissue and cell ghosts remain discernible for a short time.

The outline of the dead cells are maintained and the tissue is somewhat firm.

Example: kidney and heart injury caused by ischaemia.

Kidney: ischemia and infarction (loss of blood supply and resultant

tissue anoxia).

Coagulative necrosis

Removal of the dead tissue leaves behind a scar

Infarcts (vascular distribution) are wedge-shaped with a base on the organ capsule.

Coagulative necrosis: is due to loss of blood supply

Spleen

Necrosis of the liver induced by herpesvirus. Herpesvirus invades liver cell nuclei producing nuclear ('ground

glass') mildly basophilic inclusions.

Coagulative Necrosis 

Changes in the cytoplasm and the nucleus  

Karyolysis Pyknosis

Karyorrhexis

Acute renal tubular necrosis (ischemia) :increased eosinophilia and pyknosis in necrotic cells

Normal

Necrotic

Coagulative necrosis:

Remember: True coagulation necrosis involves groups of cells, and is almost always

accompanied, by acute inflammation (infiltrate)

Patterns of Necrosis In Tissues or Organs

2. Liquefactive necrosis: The dead cells undergo disintegration

and affected tissue is liquefied. This results from release of hydrolytic

lysosomal enzymes and leads to an accumulation of semi-fluid tissue.

Example: cerebral infarction. Abscess

Cerebral infarction - this will liquefy eventualy

Liquefactive necrosis in brain leads to resolution with cystic spaces.

Liquefactive necrosis in the brain: in a patient suffered a "stroke"

Liquefactive necrosis of the brain: macrophages cleaning up the necrotic cellular debris

Removal of the dead tissue leaves behind a cavity

… a mess - so many cells have died - the

tissue is not recognizable. Nuclei

have become pyknotic (shrunken and dark),

undergone karorrhexis (fragmentation) and

karyolysis(dissolution)

Necrotic myocardium

Liquefactive necrosis: two lung abscesses

Removal of the dead tissue leaves behind a cavity or scar

Localized liquefactive necrosis liver abscess

Removal of the dead tissue leaves behind a scar

Patterns of Necrosis In Tissues or Organs

3. Caseous necrosis:

A form of coagulative necrosis but appear cheese-like.

The creamy white appearance of the dead tissue is probably a result of the accumulation of partly digested waxy lipid cell wall components of the TB organisms. The tissue architecture is completely destroyed.

Example: tuberculosis lesions fungal infections

Coccidioidomycosis blastomycosis histoplasmosis

Caseous necrosis in a hilar pulmonary lymp node

infected with tuberculosis.

Caseous necrosis:confluent cheesy tan granulomas in the lung in a patient with tuberculosis

Caseous necrosis: confluent cheesy tan granulomas in the lung in a patient with tuberculosis.

This is characteristic of a poorly -understood subtype of immune injury,

seen in certain granulomatous diseases (tuberculosis and certain

fungal infections (coccidioidomycosis, blastomycosis and histoplasmosis)

The macrophage-derived protein tumor-necrosis factor alpha

("cachectin") is the principal toxin that causes cells to undergo

caseous necrosis

Pulmonary tuberculosis:tubercle contains amorphous finely granular, caseous ('cheesy') material typical of caseous necrosis.

Removal of the dead tissue leaves behind a scar

Caseous necrosis is characterized by acellular pink areas of necrosis, surrounded by a granulomatous inflammatory process.

N

Patterns of Necrosis In Tissues or Organs

4. Fat necrosis: This can result from direct trauma or enzyme

released from the diseased pancreas. Example:

Necrosis of fat by pancreatic enzymes. Traumatic fat necrosis in breastAdipocytes rupture and the released fat undergoes

lipolysis catalyzed by lipases. Macrophages ingest the oily material and a giant cell inflammatory reaction may follow. Another consequence is the combination of calcium with the released fatty acids.

Fat necrosis secondary to acute pancreatitis

Fat Necrosis Specific to adipose tissue with triglycerides.With enzymatic destruction(lipases) of cells, fatty  acids are precipitated as calcium soaps.

Grossly- chalky white deposits in the tissue.Microscopically – amorphous, basohilic /purple deposits at the periphery of necrotic adipocytes. 

Patterns of Necrosis In Tissues or Organs

5. Gangrenous necrosis: This life-threatening condition occurs

when coagulative necrosis of tissue is associated with superadded infection by putrefactive bacteria.

These are usually anaerobic gram-positive Clostridia spp. Derived from the gut or soil which thrive in conditions of low oxygen tension.

Patterns of Necrosis In Tissues or Organs

5. Gangrenous necrosis: Gangrenous tissue is foul smelling and black. The bacteria produce toxins which destroy

collagen and enable the infection to spread rapidly. If fermentation occurs, gas gangrene ensues.

Infection can become systemic (i.e. reach the bloodstream, septicaemia).

The commonest clinical situation is gangrene of the lower limb caused by poor blood supply and superimposed bacterial infection. This is a life-threatening emergency and the limb should be amputated.

Example: necrosis of distal limbs, usually foot and toes in diabetes.

“Wet" gangrene “ of the lower extremity in patient with diabetes mellitus:

1. liquefactive component from superimposed infection on

2. coagulative necrosis from loss of blood supply.

Patterns of Necrosis In Tissues or Organs

6. Fibrinoid necrosis: typically seen in vasculitis and glomerular

autoimmune diseases

Fibrinoid necrosis:• fibrin appear bright red amorphous material

• affect blood vessels and the glomerulus , infiltrated with fibrin

Fibrinoid necrosis of an artery

Fibrinoid necrosis: afferent arteriole and part of the glomerulus are infiltrated with fibrin, (bright red amorphous material)

Depending on circumstances: 1. necrotic tissue may be walled off by scar tissue, 2. totally converted to scar tissue, 3. get destroyed (producing a cavity or cyst), 4. get infected (producing an abscess or "wet gangrene"), 5. or calcify.

If the supporting tissue framework does not die, and the dead cells are of a type capable of regeneration, you may have complete healing.

Outcome of necrosis

Objectives Define necrosis and apoptosis List the different conditions associated

with apoptosis, its morphology and its mechanism

List the different types of necrosis, examples of each and its features

Know the difference between apoptosis and necrosis

Difference between apoptosis and necrosis

Coagulation Necrosis ApoptosisStimuli Hypoxia, Toxins Physiologic and pathologic

conditions

Histologic appearance

Cell swelling, coagulation necrosis disruption of organelles

Single cell, chromatin condensation, apoptotic bodies

DNA breakdown

Random and diffuse internucleosomal

Mechanism ATP depletion membrane injury

Gene activation, endonucleases, proteases

Tissue reaction

Inflammation No inflammation, phagocytosis of apoptotic bodies

Energy Not needed Needed

TAKE HOME MESSAGES:

Apoptosis is a form of programmed cell death which could be physiological or pathological.

Necrosis is a deathof group of cells aecondary to injury. It is associated with inflammatory reaction, (unlike apoptosis).

Necrosis has many types which include Coagulative, liquefaction, gangrenous, caseous and fat necrosis.