Necrosis, Apoptosis, Autolysis Flashcards
1
Q
Necrosis
A
Death of cells and tissues while the body is whole (still living)
- some cells and tissues are dead
2
Q
Necrobiosis
A
Natural death of cells or tissues through aging, as distinguished from necrosis or pathological death
3
Q
What are 2 examples of necrobiosis?
A
- enterocytes forming the crypts
- keratinocytes in the skin (slough)
4
Q
Apoptosis
A
Programmed cell death, requiring energy and certain enzymes
5
Q
Is apoptosis active or passive?
A
Active!
6
Q
When does apoptosis commonly occur?
A
Following DNA damage, is a safeguard against neoplasia
- repaired –> mitosis
- no appropriate repair possible –> apoptosis
7
Q
Process of apoptosis
A
Cell breaks up into small pieces surrounded by the cytoplasmic membrane
- no inflammatory response!!!
- quick, easy, unobtrusive
8
Q
Autolysis
A
Destruction of tissues or cells of an organism by the action of substances (enzymes) that are produced within the organism
9
Q
What is autolysis also known as?
A
Self digestion
10
Q
At what point does death occur?
A
When a cell, even given the proper substrates, can no longer resume the biochemical processes necessary for normal homeostasis
11
Q
Post mortem rot is an example of _______
A
Autolysis
12
Q
What are common causes of cell death?
A
- loss of blood supply (ischemia)
- loss of nerve supply
- loss of endocrine stimulation
- endotoxins
- mechanical/thermal injury
- chemical injury
- pressure
13
Q
Gross changes of cells
A
Necrotic tissue tends to be lighter in color (unless filled with blood, then darker) due to denaturing of proteins including cytochrome oxidases
14
Q
Pyknosis
A
Shrunken, dense nucleus
15
Q
Karyorrhexis
A
Fragmentation of the nucleus
16
Q
Karyolysis
A
Loss of the nucleus
17
Q
Cytoplasmolysis
A
Cytoplasm broken up and gone
- cell is basically gone
18
Q
Coagulation
A
Cytoplasm denser and stains more pink than before
- hypereosinophilia
19
Q
Coagulative necrosis - common causes
A
- complete loss of blood supply
- fat necrosis
- Zenker’s necrosis
20
Q
Caseous necrosis
A
Associated with granulomatous inflammation
21
Q
Liquifactive necrosis
A
Enzymatic breakdown of tissue
- ex: abscesses
- common in CNS due to high fat content
22
Q
Gangrenous necrosis
A
Archaic term applied to necrosis causes by loss of blood supply
- dry and wet
- also implies the body part has saprophytic bacterial infection
23
Q
Coagulative necrosis - overview
A
Coagulation of proteins in the tissue (breakdown of 3 and 4 structures)
- causes: local heat, local chemicals, ischemia, certain bacterial toxins
- significance: specific diagnostic lesion
24
Q
Gross characteristics of coagulative necrosis
A
Tissue retains original form and coherent strength!
- firm, pale, dry
- will eventually become friable
- surrounded by a reddened area (hyperemia)
25
Microscopic characteristics of coagulative necrosis
Tissue organization remains
- cell outline remains with loss of cellular detail
- nuclear changes
- cytoplasmic coagulation and hypereosinophilia
26
What are 4 causes of coagulative necrosis?
- local heat
- local chemicals
- ischemia
- certain bacterial toxins
27
Outcome of coagulative necrosis
- removal through slow digestion
- progression to liquefactive necrosis
- mineralization
- sequestration
28
Zenker's necrosis
Type of coagulative necrosis specific to striated muscle (skeletal, cardiac)
- causes: vitamin E deficiency, ischemic necrosis, certain bacterial toxins (Clostridium, Blackleg)
29
Gross appearance of Zenker's necrosis
- original outline persists
- muscle slightly swollen
- waxy appearance
- light in color
30
Microscopic appearance of Zenker's necrosis
Preservation of tissue organization and cell outlines
31
Saponification
Fat and glycerine combine with metallic ions (Na, K, Ca) to form soap
- fat necrosis
32
What are 4 common causes of fat necrosis?
- pancreatic fat necrosis
- vitamin E deficiency
- traumatic fat necrosis
- metabolic fat necrosis
33
Pancreatic fat necrosis
Secondary to pancreatic disease with release of lipase and other enzymes that break down fat
34
Vitamin E deficiency
Manifested as steatitis leading to fat necrosis
| - cats eating a diet high in rancid oxidized fats
35
Traumatic fat necrosis
Due to lying on a hard surface (large animals)
| - presents as firm tissue beneath the skin
36
Metabolic fat necrosis
Mesenteric and omental fat become firm (necrotic) around the viscera
- causes obstructions (bovine abdominal cavity)
37
Gross appearance of fat necrosis
Loss of shine
- dull, opaque
- firm, soap like consistency
38
Micro appearance of fat necrosis
Cell outlines remain
- cytoplasm replaced by pale blue soap material (solid to stippled)
- soap will remain thru the staining process
39
Outcome of fat necrosis
Saponified fat remains in the abdominal cavity
| - may have no effect or can cause mechanical effects (stops peristalsis)
40
What substance is present within adipose cells of fat necrosis?
Soap
41
Causes of caseous necrosis
```
Bacterial infection (bacterial proteases and neutrophil proteases cause tissue breakdown)
- or caused by some chemicals (turpentine)
```
42
Gross appearance of caseous necrosis
- dry but slightly greasy
- firm, no cohesive strength, usually pale to white
- easily separated with a blunt instrument (finger)
43
Micro appearance of caseous necrosis
- loss of all tissue outline (no discernible tissue)
- amorphous, granular debris, mass
- infiltrated with multinucleated giant cells
- often surrounded by fibrous connective tissue capsule
44
What is typical of caseous necrosis?
Granular tissue with loss of all tissue architecture
45
Outcome of caseous necrosis?
- encapsulation
- liquefaction
- mineralization
46
Causes of liquefactive necrosis in the CNS
- low amounts of coagulative protein
- high amounts of lipids (tends to liquefy)
- creates a low pH
47
Malacia
Abnormal softening of tissues
| - used to describe liquefactive necrosis in the CNS
48
Abscess
Liquid center (pus)
- focus of liquefactive necrosis that is surrounded by a connective tissue capsule
- bacteria and neutrophils release proteolytic enzymes that liquefy tissue
49
Gross appearance of liquefactive necrosis
Fluid filled cavity in a tissue
- white to pale tan, brown, red, green liquid
- consistency of cream or pudding
- frequently more foul smelling than other necrosis
- surrounded by fibrous connective tissue capsule
50
Micro appearance of liquefactive necrosis
Pink, proteinacious fluid (or hole)
| - edges made up of frayed tissue
51
How would you describe the gross appearance of liquefactive necrosis lesions?
Discrete, fluid-filled cavities, containing white to pale tan creamy liquid
52
Why is liquefactive necrosis expected in the CNS?
Low amounts of coagulative protein and high amounts of lipids, which tend to liquefy
53
Outcome of liquefactive necrosis
- walled off
- remain as fluid
- resorbed
- replaced by scar tissue
54
Putrefactive
Necrotic tissue invaded by saprophytic bacteria
55
Causes of moist gangrene
- twisted intestine (gangrenous enteritis), devitalized intestine
- lung due to aspiration (gangrenous pneumonia)
- anywhere where conditions are right
56
Gross appearance of moist gangrene
Swollen, soft, pulpy, dark in color with putrefactive smell
| - in vivo: insensitive (no viable blood supply), cold (no body head)
57
Causes of dry gangrene
Seen in extremities due to vascular compromise or ischemia (tail, ears, toes)
- ergot
- not as many bacteria proliferating
58
Gross appearance of dry gangrene
- tissue is shrunken, wrinkled, leathery, often firm
- can be pale or darker than normal
- marginal hyperemia
59
Consequences of necrosis, assuming animal survives
- organ dysfunction (especially conducting organs)
- necrotic tissue removed
- defect filled by fibrous connective tissue (scar formation, contracture)
60
Calcification of dead tissue
Way to neutralize the effects of necrotic tissue
- can have mechanical effects depending on organ
- dystrophic mineralization
61
Liquefaction and removal
Slow and imperceptible
| - removed by lymph drainage
62
Abscess formation is a result of
Liquefaction and encapsulation
63
Liquefaction and migration
Migration of liquid along any plane of least resistance
- pressure builds up due to influx of cells, which causes migration
- migratory tracts (fistulas, phlegmon)
64
Encapsulation with sequestration
Isolated by encapsulation
| - commonly seen with necrosis of bone (bone sequestra) and muscle
65
Involucrum
Connective tissue capsule around a sequestrum
66
Desquamation
Shedding of dead tissue from a surface
67
Erosion
Loss of epithelium with an intact basement membrane
- cells will regenerate with an intact BM
- heals by regeneration (no scar)
68
Ulceration
Destruction of the basement membrane
| - always heals by scarring (connective tissue)
69
Slough
Shedding of a large amount of tissue (second and third degree burns)
70
Necrosis is a ____ form of cell death
Passive
- occurs in the absence of energy, does not require metabolism
- frequently affects large numbers of cells (infarct)
- associated with injurious insults
71
What are the 4 common results after an injurious stimulus to a cell?
- decrease in ATP
- membrane damage
- increase intracellular Ca
- reactive oxygen species
72
What are the 7 mechanisms of necrosis?
- mitochondrial ATP production stops
- plasma membrane energy- dependent Na pumps shut down
- Na/H2O enter cell
- cell swelling, membrane stretching
- glycolysis allows cell to function at a decreased level
- failure of Ca pumps allowing Ca to enter cells
- Ca activation of enyzme systems
73
What happens when mitochondrial ATP production stops?
ATP depletion and decreased ATP synthesis are associated with hypoxic and chemical injury
- ATP depletion to <5% to 10% of normal levels has widespread effects
74
What happens during glycolysis?
- glycogen stores are depleted
- lactic acid accumulates
- cell pH drops --> induction of Heat Shock Response
75
Effects of increased intracellular Ca
- disruption of protein synthetic apparatus
- detachment of ribosomes
- decreased protein synthesis
76
What damages mitochondria?
Increases in cytosolic Ca
77
What is considered to be a "deathblow" for the cell?
Loss of proton motive force due to increase in permeability of the inner mito membrane
78
What triggers apoptotic death pathways in the cytoplasm?
Leakage of cytochrome c
79
Unfolded protein response
Attempt to prevent protein denaturation
- protein denaturation starts
- damage to all membranes of organelles
- ER and other organelles swell
- more changes in membrane permeability with massive influx of Ca
80
Scenarios of apoptosis
- deletion of un-needed cells during embryogenesis
- normal involution
- regression of hyperplasia
- deletion of genetically unstable cells
- activation of viruses
- activation by immune cells
81
Does apoptosis elicit inflammation?
No
82
Can cells undergo necrosis without apoptosis?
Yes, if the injury is so severe and rapid
83
Process of apoptosis
Cell contracts --> broken off fragments have a plasma membrane that does not elicit inflammation --> phagocytosis of apoptotic cells and fragments
84
Does the cell swell during necrosis or apoptosis?
Necrosis
85
Necrosis or apoptosis: fragmentation of the nucleus into nucleosome size fragments
Apoptosis
86
Necrosis or apoptosis: disruption of plasma membrane
Necrosis
87
Necrosis or apoptosis: cellular contents intact, may be released in apoptotic bodies
Apoptosis
88
Necrosis or apoptosis: adjacent inflammation
Necrosis
89
Necrosis: physiologic or pathologic role
Invariably pathologic (culmination of irreversible cell injury)
90
Apoptosis: physiologic or pathologic role
Physiologic, means of eliminating unwanted cells
| - may be pathologic after some form of cell injury (especially DNA damage)
91
Active form of cell death
Apoptosis
- mediated by caspases
- does not elicit inflammation
- acts at the individual cell level
- balance to mitosis
- uses highly conserved cellular machinery
92
Characteristic DNA ladder formation occurs with ______
Apoptosis
93
What happens to cells that have apoptosed?
Phagocytosis by macrophages and surrounding cells
94
Embryogenesis
Physiologic situations of apoptosis
| - implantation, organogenesis, developmental involution, metamorphosis
95
Hormone dependent involution
Physiologic situation of apoptosis
- post partum endometrial cell breakdown
- regression of the lactating mammary glands after weaning
- prostatic atrophy after castration
96
Death of senile cells
Cells that have served their purpose (neutrophils)
| - often deprived of normal survival signals
97
Cell death induced by cytotoxic T cells
Form of physiologic apoptosis
- defense mechanism against viruses and tumors
- same mechanism acts in rejection of transplants
98
Pathologic situations of apoptosis
- cell death following injury
- cell injury in some viral disease
- pathogenic atrophy in some organs
- cell death in some tumors
99
Biochemical features of apoptosis - protein cleavage
Via activation of several members of a cysteine protease family called caspases
- present as proenzymes that must be activated to induce apoptosis
- break up nuclear scaffold and cytoskeleton
- also activate DNAses
100
Biochemical features of apoptosis - DNA breakdown
Apoptotic cells exhibit characteristic breakdown of DNA into 50-300 kb pieces
- intranucleosomal cleavage into multiple 180-200 bp fragments by Ca and Mg dependent endonucleases (ladders on a gel)
- necrotic cells develop a smear on gel
101
Biochemical features of apoptosis - phagocytic recognition
Apoptotic cells express phosphatidylserine in outer layer of membrane
- allows for early recognition, resulting in phagocytosis without the release of proinflammatory cellular components
- disposes of cells with minimal compromise to surrounding tissue
102
Mechanisms of apoptosis
- extrinsic (death receptor-initiated pathway)
- intrinsic (mitochondrial pathway)
- cytotoxic T cell (bypass) method
- ligands for phagocytic cell receptors
103
Extrinsic (death receptor) pathway
Initiated by engagement of cell surface death receptors
- Fas cross linked by a ligand (FasL)
- 3 or more FasL molecules come together to form a binding site for FADD
- FADD binds to pro-caspase 8 which cleave each other to become active
- initiation of caspase cascade
- apoptosis
104
Intrinsic (mitochondrial) pathway
Result of increased mitochondrial permeability and release of pro-apoptotic molecules into the cytoplasm
- withdrawal of growth factors or cell stress --> leakage of cytochrome c
- cytochrome c binds to Apaf-1 in the cytoplasm
- caspase 9 is activated
- caspase cascade
- apoptosis
105
Cytotoxic T cell (bypass) method
Cytotoxic T-lymphocytes recognize foreign Ag present on infected cell membranes
- CTLs release perforins (allowing entry of granyzme B)
- granzyme B cleaves proteins at aspartate residues and activates several caspases
- method used by immune privileged sites (brain, cornea, gonads)
106
Bypass mechanism for cells that refuse suicide via extrinsic or intrinsic pathways
Bypasses upstream signaling events
| - directly induces the effector phase of apoptosis
107
Somatic death
Difficult to pinpoint the exact time
- not all tissues die at the same time!
- neurons: 3 minutes
- cardiac muscle: 20 min
- parenchymal cells: 1 hour
- chondrocytes: several days
