3 Irreversible Cell Injury: Necrosis & Apoptosis

Front 1

Necrosis is a pathological process that may follow on from _________ ____ ______ the injury exceeds a point of no return

Back 1

Acute Cell Swelling

Front 2

Apoptosis is also called _______________ involving individual cells that ________ and _______ before death

Back 2

programmed cell death

Shrink and Fragment

Front 3

Examples of how cell death can be a physiological process…

Back 3

-part of embryogenesis

-growth

-depletion of redundant immune cells

Front 4

Examples of how cell death can be a pathologic process…

Back 4

-viral infections

-T cell cytotoxicity

-Hypoxia

-Drug induced

Front 5

Necrosis definition

Back 5

Describes the range of morphologic changes that occur following cell death in the living animal

Front 6

Necrosis Etiology

Back 6

-hypoxia,

-ischemia,

-oxidative (free radical),

-OR toxic damage to membranes and mitochondria

Front 7

Necrosis Pathogenesis

Back 7

-ATP depletion,

-Loss of membrane integrity,

-Loss of ion pumps (Ca, Na)

Front 8

The morphological appearance of necrosis is due to what 2 concurrent processes?

Back 8

Denaturation of proteins

Enzymatic Digestion of the Cell

Front 9

Explain the 2 ways that enzymatic digestion of the cell works?

Back 9

By endogenous enzymes derived from the lysosome of the dying cells (autolysis or self digestion)

By release of lysosome's content from infiltrating leukocytes

Front 10

What are the 3 nuclear changes that happen during necrosis? Define each.

Back 10

Pyknosis: shrunken dark nucleus with clumped chromatin

Karyorrhexis: rupture of the nuclear membrane leads to release of chromatin

Karyolysis: nuclear remnants begin to dissolve by enzymatic action (looks pale)

**loss of nucleus**

Front 11

What are the 3 cytosolic changes that happen during necrosis?

Back 11

-Cytoplasm becomes homogenous and eosinophilic

-Loss of RNA and ingestion of proteins

-Loss of adhesions to basement membranes

-Loss of integrity

Front 12

Necrosis of cell… picture

Back 12

Front 13

Gross appearance of necrosis - Renal Infarcts?

Back 13

Pale foci of necrosis cause by schema surrounded by a zone of hyperaemia (inflammatory response)

Front 14

What are the main forms of necrosis?

Back 14

1. Coagulation necrosis

2. Liquefactive necrosis

3. Caseous necrosis

4. Gangrene

5. Fat necrosis

Front 15

Coagulation (coagulative) necrosis is defined as…?

Back 15

Tissue necrosis characterized by preservation architecture and cellular outline

**basic outline of coagulated cell persists at least for a few days

Front 16

Coagulation necrosis is the most common manifestation of necrosis. What is it a characteristic of?

Back 16

Hypoxic/ischemic death (ex infarction) of cells in all tissues (except the brain)

Front 17

What predominates over enzymatic digestion in Coagulation?

Back 17

Protein Denaturation

Front 18

Gross appearance of Coagualtive Necrosis

Back 18

-Structure resembles normal tissue, but the colour and texture may be different

-Pale tissue due to coagulation of cytoplasmic proteins and decreased blood flow (renal or myocardial infarcts)

-Texture of affected tissue is different from normal

-Tissue may be swollen (individual cell swelling) or shrunken (cell/fluid loss)

-Necrotic area may be surround by local congestion or a thin, tan rim (inflammatory cells)

Front 19

Example of coagulative necrosis

Back 19

Renal Infarcts - was normally supplied with blood and only the lacking area is affected by the necrosis not the entire organ

Front 20

Microscopic Appearance of Coagulation necrosis

Back 20

-Original cell shape and tissue structure is preserved

-Cell are homogeneous and opaque

-Dead cells resemble an eosinophilic 'shadow' of the original cells

-Some maybe be mineralized

Front 21

Coagulative necrosis (microscopic) cytoplasmic and nuclear changes

Back 21

-cytoplasm increased eosinophilia (light pink staining on H&E) due to binding of eosin to altered protein and loss of ribosomes

-Cytoplasm may have a hyalinized (glassy) due to loss of glycogen particles

-Nuclei: pyknosis, karyorrhexis, karyolysis

Front 22

Necrosis of hepatocytes (picture)

Back 22

Front 23

Etiology of Coagulative necrosis

Back 23

-Infarction (occluded blood vessel)

-Bacterial exotoxins (damage blood vessels)

-Chemical toxins

-Viral replication

Front 24

Define Liquefactive necrosis…

Back 24

Complete destruction of the tissue

Front 25

What predominates over protein denaturation in liquefactive necrosis?

Back 25

Enzymatic digestion of necrotic cells

Front 26

Why is Liquefactive necrosis often seen in bacterial infections?

Back 26

-due to attraction of neutrophils which contain potent proteolytic enzymes

Front 27

The hypoxic damage of the brain/spinal cord that results in rapid enzymatic digestion of parenchyma and presence of focal areas of dissolution is know as?

Back 27

MALACIA (can progress to a form of liquefactive necrosis)

**most commonly seen in the CNS

-can occur due to trauma

Front 28

Liquefactive necrosis - gross appearance

Back 28

-tissue liquified into soft viscous to fluid mass

-if initiated by inflammation then the liquid has dead WBC (pus)

Front 29

Liquefactive necrosis in the brain of a goat is called?

Back 29

Polioencephalomalcia - areas softening of the brain with dissolution of mostly grey matter

Front 30

Liquefactive nécrosais - microscopic appearance

Back 30

-tissue structure and cell details are lost (margins are not well defined)

-Few neutrophils or macrophages maybe be present as well as clusters of amorphous necrotic material

Front 31

Macrophages that are clearing out the necrotic tissue in liquefactive necrosis are called?

Back 31

Gitter Cells

Front 32

Etiology of liquefactive necrosis

Back 32

-Hypoxia in CNS = rapid enzymatic digestion of parenchyma

-Pus-producing bacteria (pyogenic bacteria)

-Abscesses filled with fluid pus

Front 33

Dehydration can transform liquefactive necrosis into something that looks more like ___________

Back 33

Caseous necrosis

Front 34

Define Caseous Necrosis ('cottage cheese')

Back 34

A variant of coagulation necrosis characterized by loss of tissue architecture and cellular details

Front 35

Etiology of caseous Necrosis

Back 35

-Bacterial diseases like TB, caseous lymphadenitis, tularaemia

-Migration of parasites with secondary bacterial infection of parasitic tracts

**common in birds and reptiles (cold blooded with heterophils rather than neutrophils) - fungal infection and bacterial like aspergillosis and TB

Front 36

Gross Appearance of Caseous necrosis

Back 36

-grey to white, dry (inspissated), friable, pasty areas of necrotic material (cheese like)

**friable material results from the non degradable lipids of bacterial cells walls and also dead leukocytes from the host

Front 37

Inspissation is?

Back 37

-The process of thickening a liquid by dehydration or evaporation

Front 38

Microscopic appearance of Caseous Necrosis…

Back 38

-Tissue structure and cell details are lost

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

-Necrotic cells DO NOT undergo complete dissolution like liquefactive necrosis

-May see deposition of mineral (calcium)

Front 39

Do necrotic cells (microscopic) retain cellular outline with caseous necrosis?

Back 39

No

Front 40

What is dystrophic mineralization?

Back 40

The deposition of mineral (calcium) as a blue granular material in the centre of a necrotic focus (caseous)

Front 41

Caseous necrosis is often observed in the centre of _________(type of chronic inflammation seen with TB)

Back 41

Granulomas

Front 42

If bacteria are proliferating in the lymph node and the inflammatory response is not getting rid of them, what will happen?

Back 42

Breakdown of tissue and inflammatory response

Front 43

Example of Caseous necrosis in sheep?

Example in cattle?

Back 43

-Caseous Lymphadenitis in sheep (including renal lesion)

-Tuberculosis in a cow -> lymph node gets replaced by numerous off-white nodules

-Shipping fever

Front 44

Describe the histologic features of caseous necrosis….

Back 44

-loss of tissue architecture and cell detail

Front 45

Define Gangrenous Necrosis

Back 45

Affect extremities, such as limbs, digits, or tips of ears (usually due to ischemia)

Front 46

What are the 3 types of gangrene?

Back 46

-Dry

-Moist/wet

-Gas

Front 47

Dry gangrene is a form of coagulation necrosis followed by what?

Back 47

Dehydration of affected area and mummification

Front 48

Dry gangrene: Location?

Back 48

Often involves distal portion of an extremity

Front 49

Dry gangrene: etiology?

Back 49

agents causing ischemia such as cold (frost bite), toxins (Salmonella endotoxin, ergot (fungus) and fescue)

Front 50

Dry gangrene: Gross appearance?

Back 50

Affected tissue is dry, shrivelled, brown, grey, or black

Front 51

Example of dry gangrene in pig

Back 51

Frost bite in ear tip or tail (ring of redness before darkened area)

Front 52

Moist/wet gangrene: define

Back 52

type of necrosis, (predominantly coagulative necrosis) modified by the liquefactive action of saprophytic bacteria (living in dead matter) causing putrefaction (decomposition)

Front 53

Moist/wet gangrene: location

Back 53

extremities, lung, udder

Front 54

Moist/wet gangrene: etiology

Back 54

Ischemia followed by contamination by saprophytic bacteria or aspiration of ingesta, medication (aspiration pneumonia)

Front 55

Moist gangrene: gross appearance

Back 55

-Tissue is soft, moist, reddish-brown to black

-Crepitant (gas bubble with palpation)

-Putrid odour

-Affected tissue may slough off

Front 56

Example of moist/wet gangrene in sheep?-

Back 56

Gangrenous mastitis

Front 57

Gas Gangrene: define

Back 57

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

Front 58

Gas Gangrene: etiology?

Back 58

Anaerobic bacteria such as Clostridium chauvoei (cause black leg) or C. perfingens, C. septicum

**Clostridium sp. are usually ubiquitous in environment (infect with right conditions)

Front 59

Gas Gangrene: gross appearance?

Back 59

Affected tissue is dark-red to blackened contains multiple gas bubbles

-rancid butter smell

Front 60

Example of gas gangrene in cattle?

Back 60

Clostridial myositis - black leg

Front 61

Define Fat Necrosis

Back 61

Type of necrosis affecting body fat stores

Front 62

Fat Necrosis: etiology

Back 62

-Trauma = rupture of adipocytes with release of lipase that splits the neutral fat in adipose cells

-Enzymatic necrosis of fat in cases of pancreatitis with release of pancreatic lipase's form adjacent damaged pancreatic duct system

-Unknown (idiopathic)

Front 63

What does the fat elicit in fat necrosis?

What does this cause the fatty acids to do?

Back 63

Fat (free in connective tissue) = inflammatory response and phagocytosis

FA combine with calcium resulting in the formation of precipitates of insoluble calcium soaps ('saponification of fat')

Front 64

Fat necrosis: gross appearance?

Back 64

Affected tissue is firm to hard, white, with chalky appearance, cut surfaces are occasionally gritty

Front 65

Fat necrosis: Microscopic appearance?

Back 65

-Areas of coagulative necrosis with cholesterol crystals

-basophilic calcium deposits

-surrounded by inflammatory cells (macrophages and giant cells)

Front 66

Example of fat necrosis?

Back 66

Pancreatitis

Front 67

Histological appearance of fat necrosis….

Back 67

Blue material is saponified fat (mineral deposits)

Front 68

Define Apoptosis!

Back 68

Individual cell death as a result of activation of genetically programmed 'suicide' pathway

Front 69

How do you differentiate between apoptosis and necrosis?

Back 69

Mechanism of cell death

Front 70

What are the two processes that suggests apoptosis is the selective elimination of cells?

Back 70

Physiological or Pathological

Front 71

Examples of physiological apoptosis

Back 71

-Embryogenesis or normal growth

-deletion of immune cells

Front 72

Ex of pathological apoptosis

Back 72

-viral infections

-toxins

-radiation damage

-hypoxia

-drug induced

-glands with blocked ducts

Front 73

Apoptosis invokes death of _________ with intact cell membranes and rapid removal by phagocytosis with ______ or __ inflammation.

Back 73

death of single cells (or small clusters)

little or no

Front 74

Necrosis often involves multiple cells with loss of cell _______________, commonly associated with an inflammatory response

Back 74

cell membrane integrity

Front 75

What are the two apoptosis pathways?

Back 75

Intrinsic (mitochondrial pathway)

Extrinsic (death receptor-initiated pathway)

Front 76

Steps of the Intrinsic (mitochondrial pathway)..

Back 76

1. INDUCERS

2. CONTROL AND REGULATION
3. EXECUTION

4. END RESULT

Front 77

During apoptosis, a stimulus results in self programmed, genetically determined, and energy dependent sequence of events involving ______ receptors (TNFR and Fas).

This is what pathway?

Back 77

Death

Extrinsic or death receptor-initiated pathway

Front 78

What does the intrinsic pathway involve?

Back 78

The release of proapoptotic molecules (Cty C and AIF) from mitochondria that initiate the caspase activation cascade

Front 79

Can the two pathways have overlap?

Back 79

Yes

Front 80

Where are the regulatory molecules like anti-apoptotic Bcl-2 and Bcl-X found?

What happens when these levels decrease?

Back 80

Mitochondrial membrane

The membrane leaks releasing cytochrome C and AIF

Front 81

Fill in the blanks execution phase...

-activated capase enzymes act as ________ digesting the __________

-Other target enzymes involved in _________, _______, and _________

-Capase 3 is a _______

Back 81

-activated capase enzymes act as Proteases digesting the cytoskeleton

-Other target enzymes involved in DNA transcription, replication, and repair

-Capase 3 is a DNAase

Front 82

The end result of apoptotic bodies that are….

What do they express that causes their removal?

Back 82

membrane bound and contain organelles and other cytosol components.

Express new ligands that are recognized by phagocytic cells

Front 83

Extrinsic pathway

Back 83

Front 84

Intrinsic pathway

Back 84

Front 85

Apoptosis: histological features

Back 85

∗ Usually single cells shrunken,

∗ Condensation of cytoplasm,

∗ Chromatin condensation,

∗ Nuclear fragmentation,

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

∗ Absence of inflammatory response,

Front 86

Is it possible to have necrosis and apoptosis in the same tissue?

Back 86

Yes

Front 87

Apoptosis rat pancreas and mouse brain (lower)

Back 87

Front 88

Mouse liver infected by hepatitis virus causes coagulative necrosis (star) and apoptosis (arrows)

Back 88