Mechanisms Flashcards
1
Q
Fully discuss 3 factors of irreversible hypoxic injury
A
- Cell membrane destruction due to protease activation
- Influx of Ca2+ from cytoplasm, ER and mitochondria
- Activation of destructive enzymes:
- ATPase: low ATP
- Phospholipase: decreased phospholipids
- Endonuclease: increased nuclear chromatin destruction
2
Q
Fully discuss 3 factors of reversible hypoxic injury
A
- Cell swelling due to reduced Na+ pump so get increased influx of Na+, Ca2+ and H20
- Reduced cellular pH due to increased glycolysis as a result of low ATP levels
- Destruction of protein synthesis due to detachment of ribosomes, leading to increased lipid deposition
3
Q
Destruction of mitochondria leads to what type of hypoxia?
Explain
A
Oxidative phosphorylation enzymes get destroyed so you get histiocytic hypoxia as oxygen in cells can no longer be used
4
Q
What features are seen in reversible hypoxic injury?
split it up into the 3 factors seen
A
- (Due to cell swelling): blebs, ER swelling, loss of microvilli
- (Due to reduced cell pH): increased chromatin clumping
- (Due to reduced protein synthesis): increased lipid deposition
5
Q
What are the effects of free radicals on a cellular level?
A
- Oxidise proteins, DNA and carbohydrates - denature, mutations
- Lipid peroxidation - forms more radicals
6
Q
Describe ischaemia-reperfusion injury
A
Return of blood flow brings
- Complement proteins, which activates the complement pathway
- Brings neutrophils, which stimulates inflammation
- Brings free radicals due to mitochondrial burst
7
Q
Name 3 heat shock proteins
A
Unfoldases
Stress proteins
Chaperonins
8
Q
What is dystrophic calcification?
A
When necrotic tissue calcifies
9
Q
Describe the 2 major types of necrosis
Give examples of each
A
- Coagulative, e.g. MI, occurs as denatured proteins coagulate
- Liquefactive, e.g. Cerebral infarct, occurs as protein undergo autolysis
10
Q
What are the 2 types of gangrene and what types of necrosis causes each of them?
A
- Dry gangrene (air) is caused by coagulative necrosis DC
2. Wet gangrene (bacteria) is caused by liquefactive necrosis LW
11
Q
What inflammatory marker is found to be high in cells that have undergone apoptosis?
A
Eosinophils
12
Q
What are the 4 steps of apoptosis?
A
- Initiation
- Execution
- Degradation and Phagocytosis
13
Q
What does Cytochrome C activate in apoptosis?
What is the function of the thing activated?
A
Cytochrome C activates caspases, which cleaves DNA in the cytoplasm and cleaves proteins in the cell membrane
14
Q
The cytoplasm in necrosis forms blebs as a result of oncosis (cell swelling), in apoptosis, what does the cytoplasm form as a result of oncosis?
A
Buds
15
Q
What is Mallory’s hyaline?
A
The breakdown and accumulation of keratin in hepatocyte cytoplasms as a result of alcohol abuse.
(Keratin gives the cells structural support)
16
Q
What are histamines effects in the formation of an exudate?
A
Histamine stimulates pain, arteriole vasodilation and leaky venules
1) AV: Initially vasoconstriction (s), then vasodilation (m), more leukocytes enter the area and capillary HP increases
2) LV: Histamines lead to the contraction of the endothelial cells lining the venule so proteins can leak out and enter the extracellular space (high capillary HP also causes this)
17
Q
Discuss 3 functions of neutrophils in inflammation
A
- Chemotaxis: be summoned to an area fo inflammation
- Phagocytosis: engulf the MO
- Killing of MO: oxygen dependent where free radicals are released into the phagosome then the mitochondria will undergo respiratory burst OR oxygen independent where enzymes, proteases and lysozymes, kill the MO in the phagolysosome
18
Q
Name 3 complement components involved in phagocytosis and discuss their MOA
A
C3a, C4a and C5a all produce tubes that stab into bacteria and kill them.
19
Q
List 4 local consequences of acute inflammation
A
- Damage to normal tissue (due to phagocytosis)
- Obstruction of tubes (due to swelling caused by exudate)
- Pain and loss of function (to aid rest)
- Loss of fluid
20
Q
List 4 complications of systemic inflammation
A
- Leucocytosis
- Fever
- Shock
- Acute phase response
21
Q
What is shock in inflammation?
A
Drop in blood pressure due to vasodilation and increase in exudate formation due to the increase in venule permeability
22
Q
Hereditary angio-oedema is an acute inflammatory disorder.
Describe its pathogenesis
A
Deficiency of C1-esterase inhibitors leading to
- rapid non itchy cutaneous angio-oedema as you get oedema of the dermis and hypo-dermis
- abdominal pain due to intestinal oedema
23
Q
Why do people with alpha 1 anti-trypsin deficiency, another acute inflammatory disorder, get liver cirrhosis?
A
Due to a lot of a1 anti-trypsin that has not been folded properly being unable to be pumped out of the sarcoplasmic reticulum, leading to a build up of this malfunctioned protein in the hepatocyte
24
Q
What is the pathophysiology of chronic granulomatous disease?
A
Phagocytes cannot make superoxide so phagocytes can engulf the bacteria but the bacteria does not die as the mitochondria cannot undergo respiratory burst
25
What lowers free copper in the blood?
Ceruloplasmin
26
Describe the calcium and phosphate levels in dystrophic calcification
Both normal
27
What type of hypoxia does CO poisoning cause?
How?
Anaemic hypoxia as CO binds to Hb and reduces Hb’s ability to bind to oxygen
28
What type of hypoxia does cyanide poisoning form and how?
Histiocytic hypoxia as cyanide irreversibly inhibits Cytochrome C oxidase leading to reduced oxidative phosphorylation in the mitochondria as oxygen present cannot be used.
29
What exudates are seen in blisters?
Describe their appearance and what they are made up of
Serous exudates are clear and made up of few WCC (as there is no MO infection) and have a high plasma protein content
30
Describe fibrinous exudates
Cloudy as they have high fibrin count (seen where blood vessel damage occurs due to inflammation)
31
When are purulent exudates typically found and why are they creamy/white?
Occur when a bacterial infection is present and they are creamy due to the high neutrophil content
32
Describe the pathogenesis of fibrosis in chronic inflammation
Cytokines stimulate fibroblasts to produce excess collagen
33
Where are the placement of the nuclei in Langerhan type giant cells?
Around the periphery
34
What 5 cells are present in hypersensitive granulomas
- Epithelioid cells
- Macrophages
- Giant cells (typically Langerhan’s)
- Fibroblasts
- Lymphocytes
(also see central caseous necrosis)
35
Chrons’ disease and Ulcerative colitis, which one has granulomas and crypt abcesses?
Chrons’ disease
36
Discuss 3 factors that aid cellular regeneration?
1. Growth factors
2. Cell-cell contact inhibition via cadherins preventing intact cells from proliferating and stimulating proliferation in damaged cells due to the loss of contact inhibition (damaged cells proliferate until they touch neighbouring ‘normal’ cells)
3. Electric currents + nerve impulses
37
Name 3 cells that produce growth factors
MEP
Macrophages
Endothelial cells
Platelets
38
Name 2 examples of labile tissue
Columnar epithelia of GI tract (surface epithelia) and haematopoietic stem cells
39
Name an example of stable tissue
Parenchyma of liver (turn into cells from their origin)
40
Name 3 types of permanent cells
Neurones, skeletal muscle, cardiac muscle
41
What is asymmetric replication and when is it typically seen?
In stem cell replication, there is always 1 daughter cell that remains as a stem cell, whereas the rest of the daughter cells turn into the end (non-diving) cell.
42
At what rate do the sprouting axons of the peripheral nervous system grow at?
1-3 mm/day
43
What are 3 effects of growth factors in cellular regeneration?
Locomotion
Angiogenesis
Inhibition of cell division
44
Name 2 growth factors
1. Vascular endothelial growth factor
| 2. Epidermal growth factor
45
Discuss 3 scenarios where you would get fibrous repair (a scar) instead of normal regeneration?
1. Necrosis of permanent tissue
2. Loss of collagen framework of necrotic stable and labile tissue
3. Chronic inflammation of necrotic stable and labile tissue
46
Describe the pathophysiology of fibrous repair
1. Blood clots
2. Neutrophils infiltrate and digest clot
3. Macrophages and lymphocytes infiltrate
4. Angiogenesis due to proliferation of endothelial cells + myo/fibroblasts make collagen, a GLYCOPROTEIN (THIS IS GRANULATION TISSUE)
5. Vessels, and other cells regress a part from collagen myofibroblats leading to the scar contracting as a result of the contraction of the fibrils in the myofibroblasts
47
Describe the formation of Type 1 fibrillar collagen
1. Alpha chains produced in ER of myo/fibroblasts
2. Vit C hydroxylation - proline and lysine to hydroxylysine and hydroxyproline
3. Procollagen x3 helix
4. Procollagen secreted out
5. Cleavage of procollagen to tropocollagen
6. Polymerisation of tropocollagen to microfibrils
7. Microfibrils -> fibrils -> (collagen) fibres
48
Describe some signs seen in Ehlers-Danlos syndrome and what is the cause of this?
*only need 3 but I’ve written a whole list*
Collagen Type V mutation thus collagen lacks TENSILE STRENGTH so:
- hypermobile joints, more prone to dislocation
- poor wound healing
- colon, large artery and corneal rupture
- hyperextensible skin
49
In osteogenesis imperfecta, why do they have:
A) blue sclera
B) fragile skeletons
A) not enough collagen in the sclera so it is translucent
| B) too little bone tissue so not enough collagen
50
Alport’s syndrome is an X linked mutation mostly affecting males.
What effect does this mutation have?
What triad of signs are typically seen?
Type IV collagen is abnormal leading to:
Dysfunction of the:
- GBM (so have haematuria in childhood then get Chronic renal failure)
- cochlea of ear (sensorineural hearing loss)
- lens of eye
Side note:
‘A comes before E like 4 comes before 5’
A - Alport syndrome, 4 - type IV collagen malfunction
E - Ehlers Danlos syndrome, 5 - type V collagen malfunction
51
Bone remodelling process
Hot - Haematoma forms
Teacher - Tissue dies
In -Inflammation
A - Angiogenesis
School - Soft callus forms - trabeculae of spongy bone
Can - Hard callus forms - bony callus of spongy bone
Love -Lamellar bone
Reece - Bone remodelling - Conversion of spongy/cancellous bone to cortical/compact bone
52
In primary intention wound healing, what tissue dies before the wound healing can occur?
(A low number of) epithelial cells and connective tissue
| Collagen and elastin are both examples of connective tissue
53
What triggers the extrinsic pathway?
Thromboplastin released from damaged cells next to the haemorrhage
(Thromboplastin/Factor III/Tissue factor (all the same thing, just different names) is an enzyme released from platelets and other damaged cells and it converts Prothrombin -> Thrombin)
54
Im haemostasis, what does the platelet bind to?
Subendothelium
55
What makes up the subendothelium?
Basement membrane, collagen
56
Measuring fibrinogen levels and TT thrombin time includes which pathways?
Both include the common pathway
57
How are Haemophilia A and B inherited?
What is the primary biological effect of the mutations?
What clotting test will be affected and how would it be effected?
X linked recessive (so mostly only affect men)
Haemophilia A has a factor VIII (8) deficiency
Haemophilia B has a factor IX (9) deficiency
As both of these coagulants are involved in the intrinsic pathway, the PTT time will be longer
58
What is the pathogenesis of von Willebrand disease?
Autosomal dominant disease leading to von Willebrand factor deficiency so get reduced platelet aggregation and reduced factor VIII stabilisation
(Thus PTT increases - more factor VIII broken down in intrinsic pathway)
59
What does your platelet count have to be (at a minimum) for you to be classed to have thrombocytopenia?
What does the bleeding appear as?
100 x 10^9/L
Petechiae (bleeding from capillaries)
60
Name 3 abnormalities in clotting in Thrombophilia
Discuss if they are high or low
- low Antithrombin III
- low Protein C
- high factor V Leiden (in common pathway)
61
Which thrombi is pale, granular, with lines of Zahn
Arterial thrombi
62
How does a fat emboli come about?
Bone fracture then bone marrow fat breaks up and releases oil. The oil then coalesces and enters a gaping venule
63
Macroscopically, what do you see in atherosclerosis?
Fatty streaks (in the intima)
Simple plaque
Complicated plaque
64
Give 3 examples of complicated plaque
Ulceration
Calcification
Aneurysm into plaque
65
Name 4 later microscopic changes seen in atherosclerosis
Fibrosis
Necrosis
Cholesterol clefts
Plaque fissuring
66
What is the pathophysiology of homozygous familial hyperlipidaemia?
Low LDL-R so high circulating LDL so more atherosclerotic plaque so a lot of them have a MI before 20
67
Discuss 4 reasons why obesity can lead to atherosclerosis
1. Reduced HDL - less LDL metabolised by liver
2. Prone to DM - leads to hypercholesterolaemia
3. Prone to hypertension - damages endothelial cells leading to LDL oxidation
4. Hypertriglyceridaemia
68
Thrombomodulin function
Activate protein C
69
What does CDK stand for?
What activates CDKs?
What is the function of CDKs?
Cyclin-dependent kinase
Cyclin activates them
They phosphorylase retinoblastoma proteins. Typically RB proteins (a tumour suppressor gene) keep cells at the R point (G1 end) but when the cell is ready to divide, RB is phosphorylated by activated CDK
70
Stable, labile and permanent tissue.
Which one under goes hypertrophy and hyperplasia?
Hypertrophy:
Permanent
Hyperplasia:
Stable
Labile
71
Give an example of compensatory hypertrophy
When you have one kidney removed, the kidney remaining will undergo hypertrophy
72
Anaplasia definition
Very poor cell differentiation
73
What are myelomas?
Malignant neoplasms of plasma cells
74
Describe the process of malignant metastasis
1. Growth and invasion of basement membrane at primary site
2. Transport via, blood, lymph of transcoloemic spread to secondary site and lodge there
3. Grow at secondary site to form new tumour (colonisation)
75
Discuss 3 factors that are needed for proper malignant invasion?
Altered:
Proteolysis - more matrix metalloproteinases so connective tissue, basement membrane and stroma can be broken down
Adhesion - less E-cadherins binding malignant cells to each other and less integrins binding malignant cells to stomal proteins
Motility - actin cytoskeleton changed
76
Name 5 cancer sites that are most likely to spread to the bone
```
Lungs (Bronchus)
Thyroid
Breast
Prostate
Kidney
```
77
How can human papilloma virus lead to cervical carcinoma?
Discuss fully
E6 (released from HPV) can inhibit p53 so DNA repair and apoptosis, of faulty genes and cells, does not occur
E7 (released from HPV) can inhibit RB protein so faulty cells push past the restriction point and start dividing
(p53 and RB proteins are tumour suppressor genes)
78
Name 2 oncogenes
ras
HER-2
79
What is the function of ras?
Encodes for G proteins which forces the cell past the restriction point
80
What alterations in growth control are made in tumour growth?
1. Growth signals
2. Resistance to anti-growth signals
3. Cell immortalisation
4. Angiogenesis
5. Apoptosis resistance
6. Invasion and metastases
81
What is genetic instability?
High frequency of mutations in the genome of the cell lineage
82
The care taker gene is a tumour suppressor gener
What is its main function?
DNA repair
83
Describe the grading system for breast carcinomas?
Bloom Richardson system:
1. Tubular formation
2. Pleomorphism
3. High mitotic no.
84
Pleomorphism definition
Variation in shape and size of nuclei
85
CA 125 levels will be high in what cancer?
Ovarian cancer
86
What are the 3 main categories of opsonins?
Give 2 examples of each
Acute phase proteins:
- MBL
- CRP
Antibodies:
- IgG
- IgM
Complement proteins:
- C3b
- C4b
87
How do anti-oxidants neutralise ROS?
Donating an electron
88
Name 2 proteins that are involved in the neutralisation of ROS by sequestering iron and copper.
Which protein does what?
With the removal of iron and copper, what does this now mean?
Ceruloplasmin sequesters (takes away) copper
Transferrin sequesters iron
So iron and copper are unable to catalyse the production of new free radicals
89
Diapedesis definition
Entry of RBC through intact endothelial cells lining a blood vessel wall
(Neutrophil:
Chemotaxis -> Migration -> Diapedesis -> Phagocytosis)
90
Describe the pathophysiology behind Achondroplasia
FGF3 receptor gene mutation so FGF cannot fulfil its normal function of promoting collagen formation from cartilage.
Endochondral ossification is affected.
91
Factor VIIa and Factor VIIIa both convert Factor X to Factor Xa in the common pathway.
State what pathway, intrinsic or extrinsic, Factor VIIa and Factor VIIIa belong to.
State what triggers each pathway and what tissue factor is initially released.
Factor VIIa - Extrinsic pathway
Factor VIIIa - Intrinsic pathway
Extrinsic pathway is triggered by trauma leading to the release of tissue factor VII.
Intrinsic pathway is triggered by endothelial damage of blood cells promoting the release of tissue factor XII.
92
What are 4 possible outcomes from acute inflammation
1. Complete resolution
2. Fibrosis and scarring (occurs when there is significant inflammation)
3. Chronic inflammation (due to repeated insult)
4. Abscess formation
(An abscess is a localised collection of pus surrounded by granulation tissue. Pus contains necrotic tissue with suspended dead and viable neutrophils and dead pathogens. It forms when the primary insult is a pyogenic bacterium and extensive tissue necrosis occurs.)
93
If an abscess is not drained, what will happen to it?
It will be replaced by scar tissue
