Pathology - cell death Flashcards
1
Q
cell death - types and their main difference
A
- apoptosis –> intact cell membrane without significant inflammation
- Necrosis –> inflammation
2
Q
Apoptosis? requires?
A
programmed cell death that requires ATP
3
Q
Apoptosis pathways and their common features
A
- Intrinsic
- Extrinsic
both activate cytosolic caspases that mediate cellular breakdown (cytosolic proteases)
4
Q
Apoptosis - appearance
A
- deeply eosinphilic cytoplasm
- cell shrinkage
- pyknosis (nuclear shrinkage)
- nuclear basophilia
- membrane blebbing
- Karyorrhexis (nuclear fragmentation)
- formation of apoptotic bodies
- chromatin condensation
5
Q
apoptotic bodies - origin and fate
A
from cytoplasmic bleb –> they have lignands for macrophages receptors –> phagocytes by macrophages
6
Q
Karyorrhexis? (and mechanism)
pyknoseis
A
Karyorrhexis: nuclear fragmentation caused by endonucleases cleaving at internucleosomal regions
nuclear shrinkage: nuclear shrinkage
7
Q
Sensitive indicator (finding) of apoptosis
A
DNA laddering (fragments in multiples of 180bp)
8
Q
Intrinsic pathway is AKA
A
mitochondrial pathway
9
Q
Intrinsic (mitochondrial) pathway is physiologically involved in
A
tissue remodelling in embryogenesis
10
Q
Intrinsic (mitochondrial) pathway occurs when (pathophysiology and examples)
A
- a regulating factor is withdrawn from a proliferating cell population (eg. IL-2 after a completed immunologic reaction –> apoptosis of proliferating effector cells)
- 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
Q
Intrinsic (mitochondrial) pathway is regulated by
A
Bcl-2 family proteins such and BAX and BAK (proapoptotic) and BCL2 (antiapoptotic)
12
Q
Bcl-2 antiapoptotic effect
A
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
Q
APAF normally ….
A
binds to cyt C and induce activation of capsase 9, initiating caspase cascade
14
Q
BCL2 overexpression –> …and example
A
APAF-1 is overly inhibited –> decreased capsase activation –> tumorgenesis
example: Follicular lymhoma (t:14:18)
15
Q
Extrinisic (death receptor) pathway - pathways and mechanisms (and aka)
A
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
Q
Fas-FasL interaction is necessary in …. (and clinical relevance)
A
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
Q
Fas-FasL pathway –>
A
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
Q
Perforin apoptosis - mechanism
A
Cytotoxic cell bind to the cell perforin form a pore between the 2 cells –> granzyme passes through the pore and activate executioner caspases
19
Q
Cell necrosis?
A
Enzymatc degradation and protein denaturation of cell due to exogenous injury –> extracellular component leak. Inflammatory process (vs apoptosis)
20
Q
Cell necrosis - types
A
- coagulative
- Liquefactive
- Caseous
- Fat
- Fibrinoid
- Gangrenous
21
Q
coagulative necrosis - seen in
A
ischemia/infracts in most tissues (except brain)
22
Q
coagulative necrosis - due to/mechanism
A
ischemia or infraction
–> proteins denaturem then enzymatic degradation
23
Q
coagulative necrosis - histology
A
- Cell outilines preserved
- increased cytoplasmic binding of acidophilic dyes
24
Q
Liquefactive necrosis - seen in
A
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
