Irreversible Cell Injury

Front 1

What is necrosis?

Back 1

- Cell death in a living organism.

- May follow from acute cell swelling (if injury exceeds point of no return)

- Pathologic process

- Inflammation

- Often involves multiple cells with loss of membrane integrity

Front 2

What is apoptosis?

Back 2

- Programmed cell death

- Individual cells shrink and fragment before death

- Can be physiological (ie embryogenesis, growth, deletion of redundant immune)

- Or can be pathologic (ie viral infections, T cell cytotoxicity, hypoxia, drug induced, glands with blocked ducts, radiation damage)

- No inflammation

- Often involves single cells or small clusters with intact cell membranes and rapid removal by phagocytosis

Front 3

What is autolysis?

Back 3

- Process that involves self digestion or decomposition of tissues by their own enzymes

- Occurs in all tissues after death

- Tissues appear to fade with no inflammation

Different from putrefaction: putrefaction is tissue degradation that occurs after death and involves bacterial digestion of the tissue.

*Both processes are post-morterm change

Front 4

What processes cause the morphological appearance of necrosis?

Back 4

1. Denaturation of proteins

2. Enzymatic digestion of the cell (endogenous enzymes from lysosomes or enzymes from leukocytes)

Front 5

3 nuclear changes in necrosis:

Back 5

1. Pyknosis: shrunken dark nucleus with clumped chromatin

2. Karyorrhexis: Rupture of the nuclear membrane leads to release of chromatin.

3. Karyolysis: Nuclear remnants begin to dissolve by enzymatic action (appear pale)

4. Nucleus loss

Front 6

4 cytosolic changes in necrosis:

Back 6

1. Cytoplasm becomes homogenous and eosinophilic

2. Loss of RNA and digestion of proteins

3. Loss of adhesion to basement membranes

4. Loss of integrity

Front 7

What are the 5 forms of necrosis?

Back 7

1. Coagulative necrosis

2. Liquefactive necrosis

3. Caseous necrosis

4. Gangrene

5. Fat necrosis

Front 8

What defines coagulative necrosis?

Back 8

- Tissue necrosis with preservation of architecture and cellular outline.

- Most common type of necrosis

- Characteristic of hypoxic/ischemic death in call tissues except the brain

- Protein denaturation predominates over enzymatic digestion.

Front 9

What does coagulative necrosis look like microscopically?

Back 9

- Microscopically, cells are homogenous and opaque. Dead cells = eosinophilic shadow of the original cells. Some cells may be mineralized.

- Cytoplasm more eosinophilic due to loss of ribosomes and eosin binding on altered proteins.

- Cytoplasm may be hyalinized due to loss of glycogen particles.

- Nuclei show pyknosis, karyorrhexis and karyolysis

Front 10

What kind of membrane damage do the green, blue and purple arrows represent?

Back 10

Green: pyknosis

Blue: karyolysis

Purple: karyorrhexis

Front 11

4 etiologies of coagulative necrosis?

Back 11

1. Infarction (occluded blood vessels)

2. Bacterial endotoxins

3. Chemical toxins

4. Viral replication

Front 12

What is the gross appearance of coagulative necrosis?

Back 12

- Pale tissues due to coagulation of cytoplasmic proteins and decreased blood flow.

- Changed texture

- Tissues may be swollen or shrunk

- May be surrounded by congestion or a thin tan rim of inflammatory cells

Front 13

What is liquefactive necrosis?

Back 13

- Type of necrosis with complete destruction of the tissue

- Occurs when enzymatic digestion of necrotic cells predominates over protein degeneration

- Often seen in bacterial infections due to attraction of neutrophils (which contain proteolytic enzymes)

- Seen in hypoxic damage of the brain/spinal cord resulting in rapid enzymatic digestion of the parenchyma = known as malacia

Front 14

What is malacia?

Back 14

A form of liquefactive necrosis that occurs in the brain or spinal cord. Rapid enzymatic digestion of the parenchyma with focal areas of dissolution.

Front 15

What is the gross appearance of liquefactive necrosis?

Back 15

- Tissue is transforming into a soft viscous to fluid mass

- If process initiated by inflammation, then often contains pus (dead white blood cells)

Front 16

What is the microscopic appearance of liquefactive necrosis?

Back 16

- Architecture and cell details lost; margins not well defined

- A few neutrophils or macrophages may be present

- Clusters of amorphous necrotic material

Front 17

3 etiologies of liquefactive necrosis:

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1. Hypoxia in the CNS resulting in rapid enzymatic digestion of the parenchyma

2. Pus producing (pyogenic) bacteria

3. Abscesses filled with fluid pus

Note: Dehydration can transform liquefactive necrosis into something that looks like caseous necrosis.

Front 18

What is caseous necrosis?

Back 18

- Variant of coagulative necrosis with loss of tissue architecture and cellular details

- Typical of some bacterial diseases such as tuberculosis, caseous lymphadenitis, tularemia

- Seen during migration of parasites with secondary bacterial infection of parasitic tracts

- Common in birds and reptiles due to presence of heterophils instead of neutrophils (such as from bacterial infections aspergillosis and TB)

Front 19

What is the gross appearance of caseous necrosis?

Back 19

- Grey/white, dry (inspissated), friable, pasty areas of necrotic material

- Inspissation: process of thickening a liquid by dehydration or evaporation

- The friable material results from the nondegradable lipids of bacterial cell walls and dead leukocytes from the host

Front 20

What is the microscopic appearance of caseous necrosis?

Back 20

- Tissue architecture and cell details lost (do not retain cellular outline)

- Necrotic areas consist of dead cells persisting as amorphous, coarse, granular debris

- But do not undergo complete dissolution as in liquefactive necrosis

- May see dystrophic mineralization: deposition of calcium as a blue granular material in the centre of a necrotic focus

- Caseous necrosis often seen in the center of granulomas (type of chronic inflammation seen in TB)

Front 21

A classic sheep example of caseous necrosis?

Back 21

Caseous lymphadenitis

Front 22

What defines gangrenous necrosis?

Back 22

Gangrene is a type of necrosis affecting extremities, such as limbs, digits or tips of ears. Usually a result of ischemia.

Front 23

What are the 3 types of gangrene?

Back 23

1. Dry gangrene

2. Moist/wet gangrene

3. Gas gangrene

Front 24

What is dry gangrene?

Back 24

- Form of coagulation necrosis followed by dehydration and mummification

- Often at the distal portion of extremities

- Caused by agents that cause ischemia (ie extreme cold, toxins [ie: salmonella endotoxin, ergot, fescue])

- Gross appearance: tissue is dry/shrivelled/brown/gray/black

Front 25

What is moist/wet gangrene?

Back 25

- Predominantly coagulative necrosis modified by the liquefactive action of saprophytic bacteria causing putrefaction

- Seen on extremities, lung and udder

- Caused by ischemia followed by contamination of saprophytic bacteria or aspiration of ingesta/medication (aspiration pneumonia)

- Tissue appears soft, moist and reddish brown to black with a putrid odour

- Tissue is crepitant: may feel gas bubbles

- Affected tissue may slough off

Front 26

What is gas gangrene?

Back 26

- Necrosis characterized by production of gas bubbles in the necrotic tissue by invading bacteria.

- Caused by anaerobic bacteria such as Clostridium chauvoei (black leg), Clostridium perfringens, Clostridium septicum.

- Affected tissue is dark-red/black, contains many gas bubbles

Front 27

What is fat necrosis?

Back 27

- Type of necrosis affecting body fat stores

- Fat that is free in connective tissue elicits an inflammatory response and phagocytosis

- Saponification of fat: fatty acids combine with calcium, precipitating insoluble calcium soaps

Front 28

3 causes of fat necrosis

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1. Trauma: rupture of adipocytes with release of lipase that splits the neutral fat in adipose cells.

2. Enzymatic necrosis of fat, such as in cases of pancreatitis with release of pancreatic lipases from adjacent damaged pancreatic duct system

3. Idiopathic

Front 29

What is the gross appearance of fat necrosis?

Back 29

- Firm/hard

- White and chalky

- Cut surfaces may be gritty

Front 30

What is the microscopic appearance of fat necrosis?

Back 30

- Areas of coagulative necrosis

- Cholesterol crystals

- Basophilic calcium deposits

- Surrounded by inflammatory cells (macrophages, giant cells)

Front 31

Outline of the mechanism of apoptosis

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1. Induction

2. Control and regulation

3. Execution

4. End: apoptotic body phagocytosed

Front 32

What are the 2 pathways for inducing apoptosis?

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1. Intrinsic pathway/mitochondrial pathway:

- release of proapoptotic molecules (Cyt C and AIF) from mitochondria

- initiates caspase activation cascade

2. Extrinsic pathway/death-receptor-initiated pathway:

- stimulus triggers a self-programmed, genetically determined, energy-dependent sequence of events

- initiated by cell signalling involving death receptors (TNFR1, Fas)

Front 33

What are the regulatory molecules involved with apoptosis?

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- Anti-apoptotic BcI-2 and BcI-X (found in mitochondrial membrane)

- When their levels decrease, membrane leaks = release cytochrome C and AIF (initiates caspase activation cascade)

Front 34

What happens in the execution phase of apoptosis?

Back 34

- Activated caspase enzymes act as protease and digest the cytoskeleton

- Some enzymes also target enzymes involved in DNA transcription, replication and repair

- ie caspase 3 is a DNAase

Front 35

What is the histological appearance of apoptosis?

Back 35

- Single cells shrunk

- Cytoplasm condensation

- Chromatin condensation

- Nuclear fragmentation

- Cytoplasmic buds formed that are phagocytosed by neighboring cells as apoptotic bodies

- No inflammatory response

Front 36

What type of necrosis?

Back 36

Coagulative necrosis on a bull testis and a kidney.

Front 37

What type of necrosis?

Back 37

Renal infarct resulting in coagulative necrosis. Will be wedge shaped.

Front 38

What type of necrosis?

Back 38

Microscopic view of coagulation necrosis of an adrenal gland.

Front 39

What is this?

Back 39

Malacia, a form of liquefactive necrosis.

Front 40

What type of necrosis is this?

Back 40

Caseous necrosis of the liver

Front 41

What is this?

Back 41

Renal lesions as a result of caseous lymphadenitis

Front 42

What caused this caseous necrosis in a bovine lymph node?

Back 42

Tuberculosis

Front 43

What kind of necrosis?

Back 43

Caseous necrosis: loss of tissue architecture and cell detail

Front 44

This is the leg of a steer. What type of necrosis? What caused it?

Back 44

- Gas gangrene

- Black leg

- Clostridial myositis

Front 45

What type of necrosis?

Back 45

Traumatic fat necrosis in a dog