Pathology Flashcards
1
Q
VINDICATE
A
V = vascular I = infectious/inflammatory N = neoplastic D = drugs/toxins I = idiopathic C = congenital/developmental A = autoimmune T = trauma E = endocrine/metabolic
2
Q
What sort of things can cause inflammation?
A
infection, trauma, foreign bodies, immune reaction, necrosis
3
Q
Vascular changes:
- What vascular changes are there?
- What are vascular changes mediated by?
- What do vascular changes result in?
A
- changes in flow and vessel caliber, vasodilatation, vasoconstriction
- mediated by histamine and nitric oxide
- they result in calor (increased heat) and rubor (redness/erythema)
4
Q
What do cellular changes involve?
A
Stasis, white cell margination, rolling, adhesion and migration
5
Q
Changes in blood flow in response to injury
A
Normally blood flows centrally within a vessel quite quickly. When vascular dilatation occurs, the rate of flow slows and cells can move peripherally, especially larger white cells resulting in white cell margination.
6
Q
Why do blood cells stick to vessels in inflammation?
A
Normally the blood vessels are slippy and blood doesn’t stick, however, in inflammation the vessels express various proteins on the luminal surface which have a matching protein on the white cell surface and the white cells stick through a lock and key mechanism with ligands
7
Q
Examples of proteins on the luminal surface in inflammation
A
Selectins - expressed on various cells including endothelial cells and white cells
Integrins - over 30 types. Bind to ICAM
Vascular Cell Adhesion Molecule (VCAM)
Intracellular Adhesion Molecule (ICAM)
8
Q
What happens in inflammation?
A
- Blood vessels dilate
- Margination, rolling and pavementing - white cell drifting to the side of the vessel. There is still low affinity so the cells bind quickly but are let go quickly
- Chemokines from the site of injury bind to proteoglycans on the endothelial cell surface
- Results in vascular permeability (leaky vessels, resulting in loss of proteins), change in osmotic pressure.
- Water follows protein causing swelling (tumour)
9
Q
What causes vessels to become ‘leaky’?
A
Usually from trauma/direct injury e.g. toxins or burns
Endothelial cell contraction - histamine, bradykinin, substance P, leukotrienes
White cells - self harm
Transcytosis - vascular endothelial growth factor mediated. cells squeeze themselves between the vessels
New vessel formation - VEGF makes new vessels but increases leakiness
10
Q
Chemotaxis
A
When cells move along a chemical gradient
11
Q
What is the chemical gradient in chemotaxis made up of?
A
Bacterial components, complement, leukotrienes and cytokines
12
Q
3 stages of phagocytosis
A
- recognition and attachment
- engulfment
- killing and degradation
13
Q
What contains mannose receptors?
A
Bacterial surface glycoproteins and glycolipids contain terminal mannose residues
14
Q
Opsonins
A
Bacteria etc are coated with proteins making them stand out from the crowd.
Include components from the complement cascade as well as immunoglobulin
15
Q
Describe engulfment in phagocytosis
A
Pseudopods ‘catch’ bacteria and vesicle formation occurs (phagosome). Phagosome joins with lysosome to form phagolysosome
16
Q
What is killing and degradation performed by?
A
Reactive oxygen species or reactive nitrogen species
17
Q
Clinical features of inflammation
A
Rubor (redness), Calor (heat), Tumor (swelling), Dolor (pain) and sometimes loss of function
18
Q
What is rubor caused by?
A
Increased perfusion with slow flow rate and increased vascular permeability
19
Q
What is calor caused by?
A
Increased perfusion with slow flow rate and increased vascular permeability
20
Q
What is tumor caused by?
A
Vascular changes
21
Q
What is dolor mediated by?
A
Prostaglandins and bradykinin
22
Q
What is the inflammatory cell that characterises acute inflammation?
A
Neutrophil - sometimes called polymorphs because there are many lobes in nucleus. Granulocytes and have both phagocytic and cytotoxic properties
23
Q
What 4 options are there after acute inflammation?
A
- Resolution
- Suppuration
- Repair, organisation and fibrosis
- Chronic inflammation
24
Q
When are mediators of inflammation produced?
A
Only for as long as the stimulus persists
25
How long do neutrophils survive outside the blood vessel?
Only a few hours
26
What does the degree of healing after inflammation depend on?
Site of injury - different organs have different capacities for repair due to different vascular supplies
Type of injury - severity, pathogenicity of organism
Duration of injury - can it be removed? is it sustained?
27
Resolution
Complete restoration of the tissue to normal after removal of inflammatory responses
28
When is resolution most likely to occur?
- minimal cell death
- tissue has capacity to repair (e.g. GI yes, CNS no)
- good vascular supply (delivery of white cells and rapid removal or injurious agents)
- injurious agents are easy removed (cuts/wounds cleaned)
29
Suppuration
Formation of pus or noun for pus. Contains living, dying and dead cells, neutrophils, bacteria and inflammatory debris. AKA abscess
30
Organisation
Scarring
31
When is organisation more likely to occur?
- if injury produces lots of necrosis
- if injury produces lots of fibrin not easily cleared
- poor blood supply (cannot remove debris)
- tissue type
- damage is deep - mucosa where damage goes beyond the basement membrane favours healing by organisation and repair rather than resolution
32
What type of injuries are erosions and abrasions?
Injuries where the basement membrane is still intact. These heal rapidly with complete resolution. Superficial injuries
33
What is a common response in all tissues in healing?
Granulation tissue formation
34
Granulation tissue
Defect is slowly infiltrated by capillaries and then myofibroblasts.
There are deposits of collagen and smooth muscle cells
It looks very red due to constituents
New vessels come in from side and they are leaky
35
What is chronic inflammation characterised by?
Lymphocytes (small round blue cells) and macrophages are sometimes present
36
When is chronic inflammation favoured?
- if there is suppuration - walled off pus, scarring
- persistence of injury - foreign material, keratin
- infectious agent - virus, persistence of infection
- type of injury - autoimmune e.g. transplant rejection
37
Granulomas may be seen in the presence of what?
Foreign bodies, endogenous substances (bone, keratin, crystals), exogenous substances (talc, asbestos, suture material), specific infections, parasites, worms, eggs, syphilis, mycobacterium (TB)
38
What is a granuloma?
An aggregate of epitheliod histiocytes
39
Which type of necrosis occurs in the presence of tuberculosis granulomas?
Caseous necrosis
40
Infarction
Death of tissue after loss of oxygen
41
How does hypoxia cause cell injury and acute inflammation?
No oxygen means no ATP
Na/K ATPase fails and increased K means swelling
Calcium pump fails therefore increased calcium
>Calcium stimulates ATPase (inhibits ATP), phospholipase (membrane damage), proteases (membrane and cytoskeleton damage), endonuclease (DNA damage and breakdown), mitochondrial permeability (release pro-death factors)
42
How long is the safety window of inflammation (e.g. MI) in the myocardium?
20 minute window
43
First signs of cell death
Cells shrink, become redder, nucleus shrinks and becomes darker, marginal contraction bands appear
44
Coagulative necrosis
cell death with some structure of cells left as 'ghost outline' before complete phagocytosis of materials
45
After an MI, when is the greatest chance of cardiac rupture?
About 3-7 days
46
Restitution in the heart
Neutrophils fade away and are replaced by fibroblasts which lay down collagen (occurs after 2 weeks and is complete by 6 weeks)
47
Issues with scarring in the heart
Scar tissue has replaced an area of muscle and heart can't pump as well, resulting in weak heart and picture of heart failure
Nerve bundles may be damaged affecting the pacemaker
48
2 options for cell death
Necrosis or apoptosis
49
Necrosis:
- Does it require energy?
- Is it physiological or pathological?
Necrosis requires energy
| It is always pathological
50
Liquefactive necrosis
Liquid viscous mass (no cell structure remains), there is pus, occurs in the brain, associated with localised bacterial and fungal infections
51
Caseous necrosis
'cheesy necrosis'
granulomatous inflammation with central necrosis
often associated with tuberculosis
microscopic
ask for culture, PCR and look for result of Ziehl Neelson stain
52
Apoptosis:
- Does it require energy?
- Is it physiological or pathological?
- Which type of white cell is removed?
Apoptosis requires energy
It can be pathological or physiological (we sometimes need cells to die off)
It involves the removal of self-reactive lymphocytes
53
When does pathological apoptosis occur?
In response to injury e.g.:
| - radiation, chemotherapy, viral infection, cancers, graft vs host disease
54
2 pathways of apoptosis
Extrinsic - something comes along from the outside
| Intrinsic - cells own mechanisms sense something is wrong
55
Describe the extrinsic pathway of apoptosis
- It is a death receptor initiated pathway, and involves cell membrane receptors with 'death domain'
- Death receptors such as tumour necrosis factor and Fas are recognised
- Fas allows recognition of self
- Apoptosis occurs in lymphocytes
56
Describe the intrinsic pathway of apoptosis
- It is a mitochondrial pathway
- Growth cells promote anti-apoptotic molecules in mitochondrial membrane
- When these are removed they are replaces by Tax or Bak and the permeability of mitochondria is increased
- Proteins that stimulate caspases are released
- Cytopchrome C controls it
57
Caspases
Family of protease enzymes that when activated, cause apoptosis to occur
58
Function of p53
Allows cells to sense DNA damage, halts the cell cycle and if DNA can't be repaired then stimulates caspases and induces apoptosis
59
What can occur if there is too little or too much apoptosis?
Too little = cancers, autoimmune diseases
| Too much = neurodegenerative disorders
60
Morphology of apoptosis
- Cells shrink (pyknosis)
- Chromatin condensation (nucleus clumps and breaks up)
- Cytoplasmic blebs (cytoplasm breaks up)
- Macrophages 'hoover' everything up
61
Which things can cause cellular ageing?
```
Many causes such as:
Oxidative stress (free radical damage) or accumulation of metabolism by-products (lipofuscin)
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62
3 kinds of growth receptors
- Receptors with tyrosine kinase activity
- 7 transmembrane G protein-coupled receptors
- Receptors without tyrosine kinase activity
63
Why are there lots of opportunities for faults in the tyrosine kinase pathway?
Due to the number of steps
64
What are mistakes in signal for growth and cell cycle progression important for?
Cancer development
65
4 main stages of the cell cycle
G1, S, G2, M
66
What is each step in the cell cycle controlled by?
A series of cyclin dependent kinases (CDKs) that activate each other and other enzymes in a step-wise fashion
67
What is each cyclin dependent kinase activated by?
Each CDK is activated by a specific cyclin and cyclin levels vary throughout the cycle
68
G1 - growth 1 (the first step in the cell cycle)
- What happens to the cell and what is this due to?
- Which CDK is activated and what is it activated by?
- What does this CDK phosphorylate? (activate)
- The cell gets bigger due to increased protein synthesis
- CDK4 is activated by cyclin D
- CDK4 phosphorylates the retinoblastoma protein, which is important in normal cell growth and malignancy
69
What is the retinoblastoma usually bound to?
E2F
70
- What does E2F do?
| - When is E2F able to give a green light to cell division?
- E2F usually kicks off cell division but is stopped from doing so by the retinoblastoma protein
- When the Rb is phosphorylated by CDK4, it cannot bind to E2F and E2F is then able to give a green light to cell division
71
S phase - synthesis phase
- What role does E2F have in this phase?
- Which CDK is activated and what is it activated by?\
- What does this CDK do?
- E2F initiates DNA replication and increases levels of cyclin A
- CDK2 is activated by cyclin A
- CDK2 also promotes DNA replication
72
What should happen to the cell by the end of S phase in cell division?
The cell should have 2 copies of the genome
73
G2 - the second growth phase?
| - What happens to the cell in this phase?
The cell gets bigger and more protein synthesis occurs
74
In cell division, when does the main checkpoint occur and what is the main checkpoint protein?
The main checkpoint occurs at the end of G2 and the main checkpoint protein is p53
75
Normal functions of p53 in cell division
- p53 checks for mistakes and if there are any, the cell cycle is paused
- Repair is then attempted, if successful, then the cell can progress, if unsuccessful, cell undergoes apoptosis
76
What happens if cells avoid being checked by p53?
They can keep dividing despite having faults in DNA and this is an important step in the development of cancer
77
Give an example of cells which are terminally differentiated
| What do these cells exhibit instead?
Neurons are examples of cells which are terminally differentiated. They exhibit replicative senescence (process involving shortening telomeres)
78
Telomeres:
- What are they?
- What sequence of bases do they consist of?
- Caps on chromosomes
| - Consist of TTAGGG repeats
79
Why are chromosomes capped?
It provides protection and stops chromosome ends from degradation and fusion
80
Hayflick limit
50-70 divisions. With every division the number of repeats gets smaller. The hayflick limit is the number of repeats that the cells can usually withstand
81
What switches telomeres on and off?
Stem cells. This allows telomeres to divide more than the hayflick limits allows
82
Hyperplasia:
- What is it?
- What is it in response to?
- What affect does it have on the organ?
- Is it physiological or pathological?
- Hyperplasia is increase in cell number
- It is always in response to an external stimulus and will regress on withdrawal of stimulus
- It usually results in increased organ volume
- It can be physiological or pathological
83
Examples of physiological hyperplasia
Hormonal - breast tissue growth at puberty, hyperplasia of the endometrial lining of uterus in pregnancy
Compensatory - occurs after loss of tissue e.g. liver and bone marrow. Not common in many tissues
84
Examples of pathological hyperplasia
Hormonally induced - excess oestrogen leads to endometrial hyperplasia and abnormal menstrual bleeding which is often post-menopausal, or prostate hyperplasia in response to androgens meaning older men will need to urinate more frequently
85
Why is infection a stimulus for hyperplasia?
Lymph nodes contain machinery for fighting infection. As they fight infection they undergo hyperplasia
86
What type of tissue is a risk site for the development of cancer?
Hyperplastic tissue. Cancer keeps growing in the absence of a stimulus
87
Hypertrophy:
- What is it?
- What is it often a response to?
- Is it pathological or physiological?
- Increase in cell size, not number
- It is often a response to mechanical stress
- It can be physiological e.g. in skeletal muscle, cardiac muscle, but can often progress to pathological, especially in cardiac muscle
88
Atrophy:
- What is it?
- Is it physiological or pathological?
- Reduction in cell size
| - It can be physiological or pathological
89
Physiological atrophy:
- Where does it occur?
- Give an example
- It occurs in embryological structures and can remain physiological or pathological
- An example is that the uterus undergoes rapid atrophy after parturition
90
Pathological atrophy:
- What is it a result of?
- Give examples of things that can lead to pathological atrophy
- It is a result of decreased workload
- Being in a cast for a long time, loss of innervation, blocked blood supply (usually associated with atherosclerosis), loss of hormonal stimulation, inadequate nutrition, ageing
91
Pressure atrophy?
- What is it due to?
- Where can it be seen?
- It is due to endogenous or exogenous structures
| - It can be seen in normal tissue adjacent to tumours
92
Mechanism of atrophy
Reduced cellular components, protein degradation, cells 'digested' in lysosomes and degraded in many cases by ubiquitin proteastome pathway, some hormones promote degradation and atrophy (e.g. glucocorticoids)
93
Define cancer
Uncontrolled cell proliferation and growth that can invade other tissues
94
Neoplasia:
- What is it?
- Is it benign or malignant?
- Neoplasia means new growth, not in response to a stimulus
| - It can be benign, premalignant or malignant
95
Precursor lesions
Dysplasia, metaplasia and sometimes hyperplasia
96
Metaplasia:
- What is it?
- How does it occur?
- Reversible change in one mature cell type to another mature cell type which is usually premalignant
- It occurs as a result of a change in signals delivered to stem cells causing them to differentiate down a different line
97
What can metaplasia result in response to?
Cytokines, growth factors and other chemicals in the cells' microorganisms. It commonly occurs as a response to noxious stimuli
98
Metaplasia in the lung - what is the change to cells?
Bronchial epithelium are usually present in the lungs and they contain cilia which allow clearance of mucosa. These cells are not good with thermal or chemical injury (e.g. smoking) and then turn to squamous epithelia
99
Dysplasia:
- What is it?
- Is low grade or high grade most abnormal?
- Dysplasia means disordered growth. It is growth of abnormal cells not in response to a stimulus
- High grade is most abnormal and closest to becoming malignant
100
What is carcinoma in-situ?
Dysplasia affecting the whole of the epithelium. It applies to non-glandular epithelium and is very high grade
101
Risk factors for cancer
Genes, smoking, alcohol, UV radiation, other radiation, drugs, infections, obesity
102
Weinberg's Hallmarks of Cancer
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Increase growth signals
Remove growth suppression
Avoid apoptosis
Achieve immortality
Become invasive
Make your own blood supply (angiogenesis)
Loss of spell DNA spell checks
Avoid the immune system
others
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103
Examples of inherited predispositions to cancer
BRCA gene - breast cancer gene
RB gene - retinoblastoma (autosomal dominant)
APC gene - familial adenomatous polyposis (autosomal dominant and 100% chance of bowel cancer before 50 years old)
104
Double hit hypothesis
One working gene is enough. You need two faulty copies to have a functional problem. Those who have already inherited one faulty copy are at an increased risk
105
Which things can cause chemical carcinogenesis
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Smoking
Aflatoxin (fungus on peanuts)
Beta-naphthylamine (chemical dyes)
Nitrosamines (food preservative)
Arsenic - skin cancer
```
106
Initiators and promoters in chemical carcinogenesis
Initiators - long lasting genetic damage but not sufficient to cause cancer. Must be followed by a promoter
Promoters - requires initiators to have caused damage. Time period can vary after initiation
107
What does chemical carcinogenesis do?
All seem to cause DNA damage - may have changed the DNA or how the DNA is working. They all seem to cause specific and recurrent genetic alteration based on the chemical involved
108
Test for chemical carcinogenesis
Ames' test - if the same genetic defect is caused every time the cells are treated with the same chemical then it is a carcinogenesis
109
Which type of cancers is smoking a big risk factor for?
Lung cancer (esp. small cell), head and neck cancer, cancers in your tongue and throat, bladder cancer and cervical cancer (along with HPV)
