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Flashcards in Pathology - cell death Deck (150):
1

cell death - types and their main difference

1. apoptosis --> intact cell membrane without significant inflammation
2. Necrosis --> inflammation

2

Apoptosis? requires?

programmed cell death that requires ATP

3

Apoptosis pathways and their common features

1. Intrinsic
2. Extrinsic
both activate cytosolic caspases that mediate cellular breakdown (cytosolic proteases)

4

Apoptosis - appearance

1. deeply eosinphilic cytoplasm
2. cell shrinkage
3. pyknosis (nuclear shrinkage)
4. nuclear basophilia
5. membrane blebbing
6. Karyorrhexis (nuclear fragmentation)
7. formation of apoptotic bodies
8. chromatin condensation

5

apoptotic bodies - origin and fate

from cytoplasmic bleb --> they have lignands for macrophages receptors --> phagocytes by macrophages

6

Karyorrhexis? (and mechanism)
pyknoseis

Karyorrhexis: nuclear fragmentation caused by endonucleases cleaving at internucleosomal regions
nuclear shrinkage: nuclear shrinkage

7

Sensitive indicator (finding) of apoptosis

DNA laddering (fragments in multiples of 180bp)

8

Intrinsic pathway is AKA

mitochondrial pathway

9

Intrinsic (mitochondrial) pathway is physiologically involved in

tissue remodelling in embryogenesis

10

Intrinsic (mitochondrial) pathway occurs when (pathophysiology and examples)

1. a regulating factor is withdrawn from a proliferating cell population (eg. IL-2 after a completed immunologic reaction --> apoptosis of proliferating effector cells)
2. after exposure to injurious stimuli (radiation, toxins, hypoxia, misfolded proteins) --> P53 activation --> BAX/BAK --> mit and cyt C+ + APAF-1 --> initiator caspases (esp caspase 9) --> Executioner caspases

11

Intrinsic (mitochondrial) pathway is regulated by

Bcl-2 family proteins such and BAX and BAK (proapoptotic) and BCL2 (antiapoptotic)

12

Bcl-2 antiapoptotic effect

it prevents cyt C release by binding to and inhibiting APAF 1 (APAF normally binds to cyt C and induce activation of capsase 9, initiating caspase cascade)

13

APAF normally ....

binds to cyt C and induce activation of capsase 9, initiating caspase cascade

14

BCL2 overexpression --> ...and example

APAF-1 is overly inhibited --> decreased capsase activation --> tumorgenesis
example: Follicular lymhoma (t:14:18)

15

Extrinisic (death receptor) pathway - pathways and mechanisms (and aka)

aka: death receptor pathway
1. ligand receptor interactions --> FasL binding to Fas (CD95) or TNF-a binding to TNF
2. Immune cell --> cytotoxic T-cells or NK cells release of perforin and granzyme B)

16

Fas-FasL interaction is necessary in .... (and clinical relevance)

thymic medullary negative collection --> Mutation in FAS increases numbers of circulating self-reacting lymphocytes due to failure of clonal deletion
Defective Fas-FasL interaction -> autoimmune lymphoproliferatice syndrome

17

Fas-FasL pathway -->

FasL bind to Fas --> multiple Fas molecules coalesce, forming a binding site for death domain, containing adapter protein (FADD) --> activation of initiator caspases --> executioner caspases

18

Perforin apoptosis - mechanism

Cytotoxic cell bind to the cell perforin form a pore between the 2 cells --> granzyme passes through the pore and activate executioner caspases

19

Cell necrosis?

Enzymatc degradation and protein denaturation of cell due to exogenous injury --> extracellular component leak. Inflammatory process (vs apoptosis)

20

Cell necrosis - types

1. coagulative
2. Liquefactive
3. Caseous
4. Fat
5. Fibrinoid
6. Gangrenous

21

coagulative necrosis - seen in

ischemia/infracts in most tissues (except brain)

22

coagulative necrosis - due to/mechanism

ischemia or infraction
--> proteins denaturem then enzymatic degradation

23

coagulative necrosis - histology

- Cell outilines preserved
- increased cytoplasmic binding of acidophilic dyes

24

Liquefactive necrosis - seen in

bacterial abscesses
brain infracts (due to high fat content)

25

Liquefactive necrosis - due to/mechanism

Neutrophils release lysosomal enzymes that digest the tissue --> enzymatic degradation first, then proteins denature

26

Liquefactive necrosis - histology

early: cellular debris and macrophages
late: cystic spaces and cavitation (brain)
Neutrophils and cell debris seen in bacterial infection

27

Caseous necrosis - seen in

TB, systemic Fungi, Nocardia

28

Caseous necrosis - due to/mechanism

macrophage wall off the infecting microprganism --> granular debris

29

Caseous necrosis - histology

fragmented cells and debris surrounded by lymphocytes and macrophages

30

Fat necrosis - seen in

enzymatic: acute pancreatitis (saponification of peripancreatic fat
nonenzymatic --> traumatic (eg. breast injury)

31

Fat necrosis - due to/mechanism

damaged cells release lipase, which breaks down triglycerides in fat cells

32

Fat necrosis - histology

outlines of dead fat cells without peripheral nuclei
saponification of fat (combined with Ca2+) apears dark blue on H&E stain

33

Fibrinoid necrosis - seen in

immune reactions in vessels (eg. polyarterirtis nodosa, giant cell arteritis)

34

Fibrinoid necrosis - due to/mechanism

immune complexes combine with fibrin --> vessel wall damage

35

Fibrinoid necrosis - histology

vessels walls are thick and pink

36

Gangrenous necrosis - seen in

distal extremity, after chronic ischemia

37

Gangrenous necrosis - due to

dry: ischemia
wet: superinfection

38

Gangrenous necrosis - histology

coagulative (dry)
liquefactive superimposed on coagulative (wet)

39

H&E stains

acidic --> react with basic (cytoplasm) --> eosin
basic --> react with acidic (nuclei) --> basophilic

40

Cell injury is divided to

1. reversible with 02
2. irreversible

41

reversible with O2 cell injury - histology (and mechanism)

1. cellular/ER/mitochondrial swelling (low O2--> decreased oxidative phosp --> low ATP --> low activity of Na/k pump)
2. Ribosomal/polysomal detachment --> low protein synthesis (RER swelling --> detachment)
3. membrane bedding
4. nuclear chromatin clumping (anaerobic glycolysis --> low ph)
5. fatty change (low protein synthesis --> decreased apolipoportein synthesis) --> vacuoles of fat accumulate in cytoplasm
6. low glycogen (anaerobic)

42

reversible with O2 cell injury - cellular swelling - mechanism

low O2--> decreased oxidative phosp --> low ATP --> low activity of Na/k pump

43

reversible with O2 cell injury - low proteino synthesis

low O2 --> decreased oxidative phosp --> low ATP --> low activity of Na/k pump --> RER swelling --> Ribosomal/polysomal detachment --> low protein synthesis

44

reversible with O2 cell injury - nuclear chromatin clumping

anaerobic glycolysis --> low ph

45

irreversible cell injury - histology

1. mitochondrial permeability
2. mitchondria vacuolization
3. phospolipid-contating amorphous densities within mitochondria
4. Nuclear pyknosis (condensation)
5. karyorrhexis (fragmentation)
6. karyolysis (fading)
7. plasma membrane damage (degradaton of membrane phospholipid
8. Lysosomal rupture

46

irreversible cell injury - histology of mitochondria

1. mitochondrial permeability
2. mitchondria vacuolization
3. phospolipid-contating amorphous densities within mitochondria

47

irreversible cell injury - histology of nucleus

1. Nuclear pyknosis (condensation)
2. karyorrhexis (fragmentation)
3. karyolysis (fading)

48

nuclear karyolysis? and appearance

dissolution of the chromatin --> fading

49

ischemia?

inadequate blood supply to meet demand

50

region most vulnerable to hypoxia/ischemia and subsequent infraction

1. Brain: ACA/MCA/PCA boundary areas boundary areas (watershed)
2. Heart: subendocardium
3. Kidney: a. Straight segment of proximal tubule (medulla) b. Thick ascending limb (medulla)
4. Liver: area around central vein (zone III)
5. Colon: splenic flexure, rectum (both watershed)

51

region most vulnerable to hypoxia/ischemia and subsequent infraction in kidney

a. Straight segment of proximal tubule (medulla)
b. Thick ascending limb (medulla)

52

region most vulnerable to hypoxia/ischemia and subsequent infraction in colon

a. splenic flexure
b. rectum (both watershed)

53

ischemia - watershed areas (border zones)

receive blood from most distal branches of 2 arteries with limited collateral vascularity --> susceptible to ischemia from hypoperfusion

54

neurons most valnerable to hypoxic-ischemic insults include

Purkinje cells of the cerebellum and pyramidal cells of the hippocampus and neocortex

55

Infarcts are divided to

1. red (hemorrhagic)
2. pale (anemic)

56

red (hemorrhagic) infarcts occur in

venous occlusion and tissues with multiple blood supplies, such as: 1. liver 2. lung 3. intestine 4. tests

57

Reperfusion injury

reperfusion (eg. after angioplasty) injury is due to damage by free radicals

58

pale (anemic) infarcts occur in

solid organs with a single (end-arteria) blood supply, such as: 1. heart 2. kidney 3. spleen

59

red (hemorrhagic) - organs example
pale (anemic) infarcts - organs example

red: 1. liver 2. lung 3. intestine 4. tests
pale: 1. heart 2. kidney 3. spleen

60

inflammation is characterised by

1. rubor (redness)
2. dolor (pain)
3. calor (heat)
4. tumor (swelling)
5. function laesa (loss of function)

61

vascular component to inflammation

1. increased vascular permeability
2. vasodilation
3. endothelial injury

62

cellular component to inflammation

Neutrophil extravasate from circulation to injured tissue to participate in inflammation through phagocytosis, degranulation and inflammatory mediator release

63

vascular and cellular component to inflammation

vascualr 1. increased vascular permeability 2. vasodilation 3. endothelial injury
component: Neutrophil extravasate from circulation to injured tissue to participate in inflammation through phagocytosis, degranulation and inflammatory mediator release

64

inflammation is divided to

1. acute
2, chrnic

65

acute inflammation is mediated by

1. neutrophil
2. eosinophil
3. antibody

66

acute inflammation - onset and duration / mediated by

rapid onset (sec to mins)
short duration (minutes to days)
mediated by 1. neutrophil 2. eosinophil 3. antibody

67

acute inflammation - outcomes

1. complete resolution
2. abscess formation
3. progression to chronic inflammation

68

chronic inflammation is mediated by

mononuclear cells (monocytes/macrophages, lymphocytes, plasma cells) and fibroblasts

69

chronic inflammation is characterised by

persistent destruction and repair

70

chronic inflammation is associated with

1. blood vessel proliferation
2. fibrosis
3. granulomas

71

chronic inflammation outcomes:

scarring and amyloidosis

72

granuloma:

nodular collection of epithelioid macrophages

73

Chromatolysis - definition and characteristics

reaction of neuronal cell body to axonal injury --> increased protein synthesis in effort to repair damaged axon. Characteristics: 1. round cellular swelling 2. Displacement of the nucleous to the periphery 3. dispersion of Nissle substance throughout cytoplasm

74

Chromatolysis is concurrent with ....(explain)

Wallerian degeneration: degeneration of the axonal distal to site of injury
Macrophages remove debris and myelin

75

Types of calcification (and the calcium status)

1. dystrophic --> usually normocalcemic
2. metastatic --> not normocalcemic

76

Dystrophic calcification?

Ca2+ deposition in abnormal tissues 2ry to injury or necrosis --> not directly associated with serum Ca2+ levels (normocalcemic)

77

Dystrophic calcification is seen in (9)

1. TB (lungs and pericardium)
2. liquefactive necrosis of chronic abscess
3. fat necrosis
4. infracts
5. thombi
6. schistosomiasis
7. Monckeberg arteriolosclerosis
8. Congential CMV and toxoplasmosis
9. psammoma bodies

78

Dystrophic calcification tend to be ... (and example)

localized (eg. calcific aortic stenosis)

79

Metastatic calcification? (and examples)

widespread depositiom of Ca2+ in normal tissue 2ry to
1. hypercalcemia (eg. 1ry hyperparathyroidism, sarcoidosis, hypervitaminosis D
2. high calcium-phosphate product (chronic renal failure with 2ry hyperparathyroidims, long-term dialysis, caciphilaxis, warfarin)

80

drug that is associated with metastatic calcification

warfarin

81

Calciphylaxis, is a syndrome of

vascular calcification, thrombosis and skin necrosis (mostly in patients with chronic kidney disease, but can occur in the absence of renal failure) --> results in chronic non-healing wounds (usually fatal)

82

Metastatic calcification predominantly in (locations) and why

interstitial tissues of kidney, lung and gastric mucosa
--> these tissues lose acid quickly --> high pH favors deposition

83

Leukocyte extravasation predominantly occurs in

postcapillary venules

84

WBCs exit from blood vessels at site of ...... in ....(number) steps (and steps)

tissue injury and inflammation in 4 steps
1. margination and rolling
2. Tight-binding
3. Diapedesis
4. Migration

85

Leukocyte extravasation - margination and rolling - MOLECULES

Vascular stroma - Leukocytes
E-selectin - Sialyl-Lewis
P-selectin - Sialyl-Lewis
GlyCAM-1, CD34 - L-selectin

86

Leukocyte extravasation - Tight-binding - molecules

Vascular stroma - Leukocytes
ICAM-1 (CD54) - CD11/18 integrins (LFA, Mac-1)
VCAM-1 (CD106) - VLA-4 integrin

87

Leukocyte extravasation - diapedesis?

WBC travels between endothelial cells and exits blood vessel

88

Leukocyte extravasation - diapedesis - molecules

Vascular stroma - Leukocytes
PECAM-1 (CD31) - PECAM-1 (CD31)

89

Leukocyte extravasation - Migration?

WBC travels through interstitium to site of injury or infection guided by chemotactic agents

90

Leukocyte extravasation - Migration - molecules

Vascular/stroma: Chemotactic products released in response to bacteria
--> 1. C5a 2. IL-8 3. LTB4 4. Kallikrein
5. Platelet-activating factor
Leukocyte: various

91

Leukocyte extravasation - molecules for every step

1. margination and rolling
E-selectin - Sialyl-Lewis
P-selectin - Sialyl-Lewis
GlyCAM-1, CD34 - L-selectin
2. Tight-binding
ICAM-1 (CD54) - CD11/18 integrins (LFA, Mac-1)
VCAM-1 (CD106) - VLA-4 integrin
3. Diapedesis
PECAM-1 (CD31) - PECAM-1 (CD31)
4. Migration
C5a, IL-8, LTB4, Kallikrein, Platelet-activating factor

92

Leukocyte adhesion deficiency type 1 - mechanism

Low CD18 integrin subunit --> defective tight-binding

93

Leukocyte adhesion deficiency type 2 - mechanism

low Sialyl-Lewis X --> defective margination and rolling

94

Leukocyte adhesion deficiency (type 1) - mode of inheritance / prestnation / findings

(AR)1. reccurent bacterial skin and mucosa infection
2. absent pus formation
3. impaired wound healing
4. delayed separation of umbilical cord (>30 days)
findings: 1. increased neutrophils 2. no neutrophils at infection site

95

Free radicals damage cell via

1. membrane lipid peroxidation
2. protein modification
3. DNA breakage

96

Free radicals damage is initiated via (6)

1. radiation therapy (cancer therapy)
2. metabolism of drugs (phase 1)
3. redox
4. nitric oxide
5. transition metals
6. WBC (neutrophils, macrophages) oxidative burst

97

Free radicals can be eliminated by

1. scavenging enzymes (eg. catalase, superoxide dismutae, glutathione peroxidase)
2. spontaneous decay
3. antioxidants (vitamins A,C,E)
4. certain mental carrier proteins (transferrin, cerulolasmin)

98

glutathione peroxidase requires

selenium

99

Free radicals injury - example

1. oxygen toxicity
2. Drug/chemical toxicity
3. Mental storage disease

100

Free radicals injury - mental storage disease

1. hemochromatosis (iron)
2. Wilson disease (copper)

101

Free radicals injury - oxygen toxicity

1. retinopathy of prematurity (abnormal vascularization)
2. bronchopulmonanry dysplasia

102

Free radicals injury - Drug/chemical toxicity

1. carbon tetrachloride
2. acetaminophen overdose (hepatotoxicity)

103

Inhalation injury?

pulmonary complication associated with smoke and fire

104

Inhalation injury is caused by
many patients 2ry to

1. heats
2. particules smaller than one μm diameter
3. irrintants (eg. NH3)

105

Inhalation injury - complications

1. chemical tracheobronchitis
2. edema
3. pneumonia
4. ARDS

106

Inhalation injury - bronchoscopy shows (and when)

severe edema, congestions of bronchus and soot deposition
18h after inhalation injury--> resolution 11 days after injury

107

scar formation - tensile strength regained at (when)

70-80% of tensile strength regained at 3 months --> little additional tensile strength will be regained afterward

108

scar formation - types

1. hypertrophic
2. keloid

109

hypertrophic vs keloid according to collagen syntehsis

hypertrophic --> increased
keloid --> highly increased

110

hypertrophic vs keloid according to organization

hypertrophic --> parallel
keloid --> disorganized

111

hypertrophic vs keloid according to extension of scar

hypertrophic --> confined to borders of original wound
keloid --> extends beyond borders of original wound with "clawlike" projection

112

hypertrophic vs keloid according to scar evolution over years

hypertrophic --> possible spontaneous regression
keloid --> possible progressive growth

113

hypertrophic vs keloid according to frequency

hypertrophic --> frequent
keloid --> infrequent

114

hypertrophic vs keloid according to predisposition

hypertrophic --> none
keloid -->high incidence in ethnic group with darker skin

115

keloid - high incidence in

ethnic group with darker skin

116

Tissue mediators - molecules and action

1. PDGF --> induces vascular remodelling and SMC migratin
stimulates fibroblast growth for collagen synthesis
2. FGF --> stimulates angiogenesis
3. EGF --> stimulates cell growth via tyrosine kinase (eg. EGFR/ErbB1)
4. TGF-β --> a. Angiogenesis b. fibrosis c. Cell cycle arrest
5. Metalloproteinases --> tissue remodelling
6. VEGF --> stimulates angiogenesis

117

Tissue mediators - action of VEGF

stimulates angiogenesis

118

Tissue mediators - action of metalloproteinases

tissue remodelling

119

Tissue mediators - action of TGF-β

1. Angiogenesis
2. fibrosis
3. Cell cycle arrest

120

Tissue mediators - action of EGF

stimulates cell growth via tyrosine kinase (eg. EGFR/ErbB1)

121

Tissue mediators - action of FGF

stimulates angiogenes

122

Tissue mediators - PDGF is secreted by

activated platelets and macrophages

123

Tissue mediators - action of PDGF

induces vascular remodelling and SMC migratin
stimulates fibroblast growth for collagen synthesis

124

Phase of wound healing (and when)

1. inflammatory (up to 3 days after wound)
2. Proliferative (day 3-weels after wounf)
3. Remodelling (1 week - 6+ months after wound)

125

Phase of wound healing - cells

1. inflammatory: platelets, neutrophils, macrophages
2. Proliferative: fibroblasts, myofibroblasts, endothelial cells, keratynocytes, macrophages
3. Remodelling: fibroblasts

126

Phase of wound healing - inflammatory phase?

1. clot formation
2. Increased vessel permeability and neutrophil migration into tissue
3. macrophages clear debris 2 days later

127

Phase of wound healing - proliferative phase?

1. deposition of granulation tissue and type III collage
2. angiogenesis
3. epithelial cell proliferation
4. dissolution of clot
5. wound ocontraction (myofibroblasts)

128

Phase of wound healing - remodeling

1. type III collagen replaced by type I collagen
2. increased tensile strength of tissue

129

Granoulomatous disease - mechanism

Th1 secrete IFN-γ, activating macrophages --> macrophages secrete TNF-α --> induce and maintains granuloma formation

130

Diagnosing sarcoidosis requires ..... on biospy

noncaseating granulomas

131

Granoulomatous disease is associated with

hypercalcemia due to calcitriol (1,250OH2 vit D3) production

132

causes of Granoulomatous disease - groups

1. bacterial
2. fungal
3. parasitic
4. chronic granulomatous disease
5. Autoinflammatory
6. foreign material

133

causes of Granoulomatous disease - bacterial.

1. Mycobacteria (TB, leprosy)
2. Bartonella hensele (cat scratch disease)
3. Listeria monocytogenes (granulomatosis imperfecta)
4. Treponela pallidum (3ry syphilis)

134

causes of Granoulomatous disease - Fungal

endemic mycoses (eg. histioplasmosis)

135

causes of Granoulomatous disease - parasitic

schistosomiasis

136

causes of Granoulomatous disease - foreign material

1. berylliosis
2. hypersensitivity pneumonitis
3. talcosis

137

causes of Granoulomatous disease - autoinflmmatory

1. sarcoidosis
2. crohn
3. Primary biliary cirrhosis
4. Sabacute (de Quervain/granulomatous) thyroiditis
5. wegener
6. Churg-Strauss
7. Giant cell arteritis
8. Takayasu arteritis

138

vasculitis that causes Granoulomatous disease

1. wegener
2. Churg-Strauss
3. Giant cell arteritis
4. Takayasu arteritis

139

Exudate vs transudate according to cells and appearance

Exudate --> cellular --> cloudy
transudate --> hypocellular --> clear

140

Exudate vs transudate according protein levels

Exudate --> high
transudate --> low

141

Exudate vs transudate according LDH

Exudate --> high (vs serum)
transudate --> low (vs serum)

142

Exudate vs transudate according specific gravity

Exudate --> more than 1.020
transudate --> less than 1.012

143

Exudate is due to

1. lymphatic obstruction (chylous)
2. inflammation/infection
3. malignancy

144

Transudate is due to

1. increased hydrostatic pressure (eg. NF, Na+ retention)
2. decreased oncotic pressure (eg. cirrhosis, nephrotic syndrome

145

erythrocyte sedimentation rate (ESR) - description

Products of inflammation (eg. fibrinogen) coat RBCs and cause aggregation. The denser RBCs aggregates fall at a faster rate within pipete tube

146

erythrocyte sedimentation rate (ESR) is often co-tested with

CRP levels

147

Causes of increased erythrocyte sedimentation rate (ESR)

1. most anemias
2. infections
3. inflammation (eg. giant cell, poymyalgia rheumatic)
4. Cancer (eg. metastasis, MM)
5. Renal disease (end-stage or nephrotic syndrome)
6. Pregnancy

148

Causes of decreased erythrocyte sedimentation rate (ESR)

1. sickle cell anemia (altered shape)
2. polycythemia (increased RBCs dilute aggregation factor)
3. HF
4. Microcytosis
5. Hypofibrinogenemia

149

inhallation injury may present secondary to

1. burns
2. CO inhallation
3. arsenic poisoning

150

nephrotic syndrome - ESR

increased