1
Q
what is inflammation
A
it is the initial physiological response to tissue damage
2
Q
what can cause inflammation in the body
A
mechanical, thermal, electrical, chemical or infective agents
3
Q
what are the two types of inflammation that can occur
A
acute - lasts days
chronic - in response to ongoing and unresolved insult
4
Q
what can inflammation develop into
A
permanent tissue damage or fibrosis
5
Q
what are the characteristic features of acute inflammation (the five cardinal features)
A
redness (rubor) - secondary to vasodilation and increased blood flow
Heat (calor) - due to increased blood flow
swelling (tumour) - increased vessel permeability
pain (dolor) - stimulation of local nerve endings
loss of function
6
Q
what are the different phases of acute inflammation
A
vascular phase
cellular phase
7
Q
what occurs in the vascular phase of inflammation
A
- small blood vessels around the injury dilate
- blood flow to the area increases
- endothelial cells initially swell and then contract increasing space between them
- increase in vascular barrier permeability
- exudation of fluid leads to oedema
- increased tissue fluid acts as a medium for inflammatory proteins to move through
8
Q
what occurs in the cellular phase of acute inflammation
A
neutrophil migration which are attracted to the site of the injury via chemotaxis. Once in the region the neutrophils phagocytose foreign bodies
9
Q
what are the four stages of neutrophil migration
A
margination - cells line up against the endothelium
Rolling - close contact with and roll along the endothelium
Adhesion - connecting with the endothelial wall
emigration - cells move through the vessel wall to affected areas
10
Q
what are the outcomes of inflammation
A
complete resolution - total repair
fibrosis and scar formation
chronic inflammation
formation of an abscess
11
Q
what is an abscess
A
it is a localised collection of pus surrounded by granulation tissue
12
Q
what is contained within the pus of an abscess
A
necrotic tissue
dead and viable neutrophils
dead pathogens
13
Q
what causes abscess formation
A
when the primary insult of inflammation is a pathogenic bacterium and extensive tissue necrosis occurs
14
Q
how does an abscess form
A
the initial inflammatory exudate forces the tissue apart leaving a centre of necrotic tissue with the neutrophils and pathogens. Over time the inflammation will cease and if not drained the abscess will be replaces with scar tissue
15
Q
what are mediators of vasodilation
A
histamine
bradykinin
complement (C3a, C5a)
leukotrienes
prostaglandins
16
Q
what mediates mast cell degranulation
A
complement (C3a, C5a)
17
Q
what mediates chemotaxis of neutrophils
A
interleukins - IL-8
PAF
complement - C5a
histamine
18
Q
what helps mediate phagocytosis
A
complement - C3b
19
Q
what mediates pain
A
prostaglandins
bradykinin
histamine
20
Q
what mediates fever
A
interleukins - IL-1/6
TNF-a
prostaglandins
21
Q
what is a granuloma
A
aggregation of macrophages that forms in response to chronic inflammation
- focal aggregate of immune cells that forms in response to persistent inflammatory stimulus
22
Q
what are the different categories of granuloma
A
caseating - central region of necrosis (response to infection)
non-caseating - no central region of necrosis, response to contact with foreign material, sarcoidosis and crohns
23
Q
what is the pathophysiology of a granuloma
A
antigen from causative pathogen is taken up by the macrophage and is presented to CD4+ helper T cells
CD4+ helper T cells convert to the Th1 subtype
Th1 cells secrete IL-2 and INy
T cell proliferation and macrophage activation
macrophages and T cells secrete TNFa
increased accumulation of inflammatory cells
cycle continues
24
Q
what are infectious causes of granulomas
A
Infectious: bacterial- TB, leprosy.
Fungal - histoplasmosis, cryptococcosis, blastomycosis
parasitic - schistosomiasis
25
what are non infectious causes of granuloma formation
sarcoidosis
crohns
granulomatosis with polyangiitis
eosinophilic granulomatosis with polyangiitis
chronic granulomatous disease
foreign body granulomas
rheumatoid nodules
aspiration of food/other particulate matter into the lungs
26
what blood marker do all granulomas secrete
ACE
27
what is a thrombosis
it is a blood clot which forms in a vein (typically in the legs) which can block or restrict blood flow impacting circulation
28
what is an embolism
this is when an existing thrombus breaks away from the vein and travels through the heart and lodges elsewhere
29
what is the difference between arterial thrombi and venous thrombi
arterial thrombi, often associated with platelet aggregation, can cause strokes or heart attacks
venous thrombi, linked to stasis and coagulation system, can lead to DVT and PE
30
what is the common composition of venous thrombi
they tend to be rich in fibrin and red blood cells - ref thrombi
31
what are risk factors for developing venous thrombi
cancer
surgery
immobilization
pregnancy
medications
32
what causes formation of arterial thrombus
platelet aggregation and adhesion at the site of an arterial injury or rupture often in the context of atherosclerosis
33
what are risk factors for the development of arterial thrombi
smoking
hypertension
diabetes
obesity
hyperlipidaema
34
what is Virchows triad
Virchow's triad describes the three main factors that contribute to the formation of a blood clot (thrombosis): hypercoagulability, stasis (abnormal blood flow), and endothelial injury. These factors, when present together or individually, increase the likelihood of a thrombus forming in a blood vessel.
35
what are the two phases of haemostasis
primary - unstable platelet plug is formed
secondary - activation of coagulation cascade to stabilise the plug
36
what is the coagulation cascade
it is the activation of a series of clotting factors which aid in blood clotting
37
what are the three pathways of coagulation
extrinsic
intrinsic
common
38
what clotting factors are involved in the extrinsic clotting pathway
Factor III (tissue factor - activated 1st) and its interaction with factor VII
39
what factors are involved in the intrinsic clotting pathway
Factor XII
XI
IX
VIII
40
what factors are involved in the common pathway
X
V
II (thrombin)
I (fibrin)
XIII (stabilising factor which is activated by thrombin)
41
how does the extrinsic clotting pathway become activated
it begins when there is injury to the endothelial tissue, exposing factor III/tissue factor to the blood. This becomes bound to calcium and factor VIIa to activate factor X
Factor VII is in the blood and requires vitamin K to be activated
42
how is the intrinsic pathway activated in injury
The intrinsic pathway begins when factor XII is exposed to collagen, kallikrein and HMWK and activated. Factor XIIa activates XI. With calcium XIa activates IX. Then factor IXa, factor VIIIa and calcium form a complex to activate factor X
43
how is the common pathway activated in injury
the common pathway begins after factor X activation, with factor Xa, Va and calcium binding together forming the prothrombinase complex.
This then activates factor II into thrombin which then cleaves factor I into fibrin.
Thrombin also cleaves XIII into XIIIa which binds with calcium to create calcium crosslinks to stabilize the clot
44
what is the function of thrombin
activating platelets
activating factors V, VIII, IX
45
what coagulation disorders can cause dysregulation of the clotting cascade
haemophilia A/B/C
von Willebrand disease
Vitamin K deficiency
46
when is fibrin produced during the coagulation cascade
fibrin (factor 1a) is produced at the end of the coagulation cascade when fibrinogen is converted to fibrin by thrombin
47
what are the stages of coagulation/haemostasis when bleeding occurs
1. vascular spasm
2. platelet plug formation
3. coagulation cascade
4. fibrin clot formation
5. clot retraction and repair
48
what happens during vascular spasm
this is when a blood vessel is injured, it immediately constricts to reduce the blood flow to the sight of injury.
49
what occurs during haemostasis to cause platelet adhesion
the exposed extracellular matrix releases cytokines and inflammatory markers that lead to adhesion of the platelets and their aggregation at the site.
the platelet adhesion is mediated by interactions between receptors and proteins including tyrosine kinase receptors, glycoprotein receptors, G protein receptors and von Willebrand factor
50
what occurs during platelet activation during haemostasis
platelets that have adheres undergo changes
- they release their cytoplasmic granules that include ADP, thromboxane A2, serotonin and multiple other activation factors.
- they change their shape into a pseudopodal shape
51
how does platelet aggregation occur
through platelet adhesion and activation platelets stick together and the damaged endothelial surface leading to the formation of the primary platelet plug
52
how does fibrin clot formation occur in haemostasis
when fibrinogen is converted into fibrin it polymerises and forms a fibrin polymer mesh resulting in a cross linked fibrin clot. This reaction is catalysed by factor XIII that stimulates the lysine and glutamic side chains causing cross linking
53
what happens in clot resolution during haemostasis
activated platelets contract their internal actin and myosin fibrils in their cytoskeleton which leads to shrinkage of the clot volume.
Plasminogen then activates to plasmin which promotes the lysis of the fibrin clot restoring flow of blood
54
what does prothrombin time assess
the extrinsic and the common coagulation cascade function
55
what does activated partial thromboplastin time assess
the intrinsic and the common pathways of coagulation
56
what does thrombin time evaluate
evaluates the formation of fibrin in the final common pathway of coagulation
57
what is atherosclerosis
is a combination of atheromas (fatty deposits in the artery wall) and sclerosis (hardening or stiffening of the blood vessel walls)
58
which arteries does atherosclerosis affect
the medium and large arteries
59
what is atherosclerosis caused by
chronic inflammation and activation of the immune system in the artery wall which causes the deposition of lipids in the artery wall, followed by the development of fibrous atheromatous plaques
60
what do atheromatous plaques result in
stiffening, stenosis and plaque rupture
61
what does stiffening of the artery wall lead to
hypertension and strain on the heart
62
what does stenosis of the arteries lead to
reduced blood flow - angina
63
what does plaque rupture lead to
creation of thrombi which can block a distal vessel and cause ischaemia
64
what are non modifiable risk factors for atheroma formation
older age
family history
male
65
what are modifiable risk factors for atheroma formation
raised cholesterol
smoking
alcohol consumption
poor diet
lack of exercise
obesity
poor sleep
stress
66
what medical co-morbidities increase the risk of atherosclerosis
diabetes
hypertension
chronic kidney disease
inflammatory conditions such as rheumatoid arthritis
atypical antipsychotic medications
67
what is the initial stage of atheroma formation
endothelial dysfunction - the process begins with damage to the inner lining of the arteries making them more permeable to LDL cholesterol
68
how does plaque formation occur in the process of atherosclerosis
oxidized LDL cholesterol accumulates in the arterial wall, attracting immune cells (macrophages) that engulf the cholesterol and become foam cells. These cells along with lipids and cellular debris form a plaque
69
what occurs during plaque progression in atherosclerosis
over time the plaque formed can harden due to calcium deposits and develop a fibrous cap
70
what can happen to an atherosclerotic plaque
it can rupture leading to the formation of a thrombus (blood clot) at the site of rupture. This clot can completely occlude an artery causing an MI or stroke
71
what is the process of apoptosis
tightly regulated, active process where cells dismantle themselves in a controlled manner, producing small membrane-bound fragments (apoptotic bodies) that are then engulfed by phagocytes (like macrophages)
72
what is the biological function of apoptosis
Plays a crucial role in embryonic development, tissue homeostasis, immune system regulation, and eliminating potentially harmful cells
73
what is necrosis
An uncontrolled and passive form of cell death resulting from external factors that disrupt the cell's structure and function, leading to cell swelling and rupture.
74
what is the biological function of necrosis
Generally considered a pathological process, associated with tissue damage and inflammation.
75
what are the two main mechanisms that can trigger apoptosis
the intrinsic mitochondrial pathway
extrinsic cell death receptor pathway
76
what activates the intrinsic mitochondrial pathway
activated by cell stress, DNA damage, developmental cues, or lack of survival factors.
77
what triggers the extrinsic cell death pathway
external death signals, such as the binding of death ligands (e.g., FasL, TNF-α) to receptors on the cell surface.
78
what are the three stages of apoptosis
early
mid
late phase
79
what happens in the early phase of apoptosis
either: binding of death ligands and formation of the DISC complex (extrinsic) or by cellular stress activating pro-apoptotic Bcl-2 family proteins (intrinsic)
this leads to mitochondrial outer membrane permeabilization, activation and translocation of pro-apoptotic proteins to the mitochondria, cytochrome C release and activation of initiator caspases
As this happens phosphatidylserine translocate to the outer leaflet of the plasma membrane
80
what initiator caspases are activated in early phase apoptosis
caspase 8 for extrinsic
caspase 9 for intrinsic
81
what happens during mid phase apoptosis
activation of executioner (caspase 3, 6 and 7) which leads to cleavage of key substrates such as PARP and lamin A/C, cell shrinkage, cytoskeleton collapse, chromatic condensation and nuclear fragmentation
82
what happens in late phase apoptosis
DNA fragmentation, membrane blebbing and formation of apoptosis bodies which are then recognised and engulfed by phagocytes
83
what is cell hypertrophy
increase in the size of cells
84
what is hyperplasia
an enlargement of tissue caused by increase in the number of its cells
85
what is cell atrophy
the decrease in the size of cells which can lead to a reduction in the size of tissues or organs
86
what is cell metaplasia
cellular adaption where one type of cell is replaced by another mature cell type in response to a stimulus
87
what is cell dysplasia
it is abnormal growth and development of cells - precancerous conditions
88
what is ischemia
it is a restriction of blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen
89
what is infarction
tissue death caused by a lack of blood supply to the affected area
90
what is the definition of neoplasm
a new and abnormal growth of tissue in a part of the body, especially a a characteristic of cancer
91
what is a benign tumour
non cancerous, do not invade nearby tissues, do not spread to other parts of the body
92
what are intermediate stage tumours
they can be locally aggressive or rarely metastasize
93
what are malignant tumours
cancerous - invade surrounding tissues and spread
94
what is the TNM staging for cancer
T - describes the size and extent of the primary tumour
N - cancer spread to nearby nodes
M - cancer spread to different parts of body
95
what is stage vs grade of tumour
stage: describes the extent of the tumour spread, including size, involvement of lymph nodes and distant mets
grade: describes the macroscopic appearance of the tumour cells and how closely they resemble normal cells
96
what is a carcinoma
tumours arising from epithelial cells
97
what is a sarcoma
tumours arising from mesenchymal cells (connective tissue, bone, muscle)
98
what is myeloma
tumours of plasma cells
99
what is leukaemia
tumours of blood forming cells
100
what is lymphoma
tumours of lymphoid cells
101
what is the name of a benign tumour and malignant tumour for glandular epithelium
1. adenoma
2. Adenocarcinoma
102
what is the name of a benign tumour and malignant tumour for surface/squamous epithelium
1. papilloma
2. squamous carcinoma
103
what is the benign and malignant tumours of fibroblasts
1. fibroma
2. fibrosarcoma
104
what are the benign and malignant tumours of cartilage
chondroma
chondrosarcoma
105
what are the benign and malignant tumours of striated muscle
1. rhabdomyoma
2. rhabdomyosarcoma
106
what are the benign and malignant tumours of smooth muscle
1. leiomyoma
2. leiomyosarcoma
107
what is the benign tumour of blood vessels called
haemangioma
108
what is the malignant tumours of endothelium caused
angiosarcoma
109
what are the benign and malignant tumours of fat
1. lipoma
2. liposarcoma
110
what are the benign and malignant tumours of bone
1. osteoma
2. osteosarcoma
111
what are the benign and malignant tumours of the liver
1. hepatoma
2. hepatocellular carcinoma
112
what are the different methods of cancer cell spread
direct extension - invasion
lymphatic system spread
bloodstream spread - hematogenous spread
113
what is direct spread of cancer cells
- cancer cells directly invade and grow into surrounding tissues and structures
114
what is lymphatic spread of cancer cells
- cancer cells break away from primary tumour and enter lymphatic vessels
- cancer cells travel through vessels to lymph nodes
- metastasis via the lymph system can lead to metastasis in nearby or distant lymph nodes
115
how does hematogenous spread of cancer cells occur
cancer cells enter blood vessels and travel via bloodstream
to establish new tumours these cells exit the bloodstream and invade surrounding tissues developing a blood supply
116
what are the steps of hematogenous spread of cancer cells
invasion
circulation
adhesion and invasion
colonization
angiogenesis
117
what is the process of invasion during hematological spread
loss of cell cell adhesion capacity allows malignant tumour cells to dissociate from the primary tumour mass and changes in the cell matrix interaction enables cells to invade the surrounding stroma - including secretion of substances to degrade the BM and ECM (metalloproteinases, cathepsin D, urokinase)
118
how do cancer cells prevent detection during metastasis
platelet tumour emboli
lack of immune recognition
119
how do tumour cells migrate into the vascular lumen
movement of tumour cells is stimulated by
- tumour cell derived cytokins
- cleavage products of EMC
- growth factors like IGF 1-2
- hepatocyte growth factor
tumour cells invade the vessel wall by degrading the wall with proteolytic enzymes
120
what does homing of the tumour cells at a metastatic site depend on
location of the primary tumour
vascular drainage of the tumour
tropism of particular tumours for particular tissues - adhesion molecules, chemokine receptors, favourable for cell growth
121
how do tumours invade new tissues in hematogenous spread
after reaching the site extravasation from the vascular channels occur by adhesion for tumour cells to endothelial cells. This process involves adhesion molecules such as integrins, laminin and CD44. Adter adhering they secrete proteases which causes vessel wall degradation
122
what is the most common mode of spread by sarcomas/carcinomas
hematogenous
123
which tumours metastasise to bone
BLT KP - breast, lung, thyroid, kidney, prostate
124
what are examples of hereditary cancer syndromes
BRCA1 and 2: breast, ovarian
Lynch syndrome/HNPCC (MLH1, MSH2/6) which are involved in DNA repair: colorectal, endometrial
FAP (APC gene) leads to numerous polyps in the colon and rectum
Li-Fraumeni syndrome (TP53)
125
which cancers are screened for in the UK
Breast cancer - screening offered to women aged 50-71
Cervical cancer - women and people with a cervix from age 25
Bowel cancer - 60-74 home testing kits
126
