Mechanisms Of Disease (S1-7) Flashcards
S2: Cellular Injury S3: Acute Inflammation S4: Chronic Inflammation S5: Regeneration And Repair S6: Haemostasis, Thrombosis And Embolism (306 cards)
1
Q
How can changes in environmental factors lead to changes in the cell? (S2)
A
A cell will show adaptations initially, such as shrinking. As the environmental conditions become more severe and less favourable, cellular injury and ultimately death may result
2
Q
What three factors determines the severity of cellular injury? (S2)
A
The type of injury, the severity of injury and the type of tissue.
3
Q
Name three causes of cellular injury and death. (S2)
A
Hypoxia, toxins and immune mechanisms… AND physical agents - such as physical trauma, extreme changes in temperature, pressure; radiation; micro-organisms and dietary deficiencies or insufficiency / excess
4
Q
What is hypoxia? How does it differ from ischaemia? (S2)
A
Hypoxia is where there is oxygen deprivation to tissues of the body. Ischaemia is where there is no supply of blood to a part of the body.
5
Q
Why is ischaemia more dangerous than hypoxia? (S2)
A
Ischaemia not only deprives part of the body of oxygen, but also of other important substrates such as glucose. It can be the result of a major blood clot or hypotension.
6
Q
What will happen to hypoxic cells? (S2)
A
Initially they may show adaptations such as shrinkage, but over time cellular injury and ultimately death will result.
7
Q
What are the 4 ways hypoxia can be classified? Give a brief explanation of each one and a couple of examples. (S2)
A
Hypoxaemic hypoxia - low arterial concentration of O2, reduced pO2 at altitude, or secondary to lung disease.
Anaemic hypoxia - decreased ability of Hb to carry oxygen… anaemia, CO poisoning
Ischaemic hypoxia - interruption to blood supply… blockage of a vessel, heart failure
Histiocytic hypoxia - inability for cells to utilise oxygen due to disabled enzymes which are utilised in oxidative phosphorylation… cyanide.
8
Q
How sensitive are neurones to hypoxia? And fibroblasts? (S2)
A
Neurones will die within a few minutes whereas fibroblasts in the dermis of the skin can last up to a day without oxygen.
9
Q
Why can O2 be a toxin? (S2)
A
Everyone has a baseline oxygen saturation. If, in ICU, we put someone who came in with a normal O2 sat of 90% on 100% several problems can occur such as the formation of reactive oxidative species! They are normally single oxygen atoms with one electron missing. They can damage nucleic acids and therefore be mutagenic.
10
Q
Name a handful of toxins bar the controversial O2. (S2)
A
Medicines e.g. chemotherapy, asbestos, alcohol… AND poisons, pollutants, pesticides/herbicides, narcotic drugs
11
Q
What are the two methods of immune mechanisms that can cause harm to cells? (S2)
A
Hypersensitivity reaction - here the host tissue is injured secondary to an overly vigorous immune reaction - seen in urticarial (hives), inflammation of the skin
Autoimmune reactions - immune system fails to differentiate between self and non-self - seen in Grave’s disease.
12
Q
Briefly outline the process of Grave’s disease (S2)
A
Antibodies are secreted which stimulate the TSH receptors on follicle cells resulting in increased production and release of T3 and T4.
13
Q
What are the four cell components that are principal targets of cell injury? (S2)
A
Cell membranes, nucleus, proteins and mitochondria.
14
Q
When there is hypoxia, cells produce less ATP by oxidative phosphorylation. At what levels (of ATP) do vital cellular functions become compromised? (S2)
A
5-10%
15
Q
When there is hypoxia, what is the first thing to go when ATP is depleted? (S2)
A
The Na+-pump which maintains the gradient between the inside and the outside of the cell (it is energy dependent).
16
Q
When there is hypoxia, what other things will happen? Are these reversible? (S2)
A
Oncosis –> Sodium and calcium start to rush in to the cell and water follows it.
Anaerobic respiration –> this leads to the build-up of lactic acid. It affects the cell’s enzymes and leads to the nucleus’s chromatin clumping and becoming abnormal. Reduced protein synthesis –> The ribosomes need energy to stick to the endoplasmic reticulum, therefore – when there is less ATP – protein synthesis is reduced, this effects cellular metabolism.
Yes they are reversible.
17
Q
Why is a high intracellular calcium bad? (S2)
A
Calcium, a very biologically active substance, is normally locked away in the endoplasmic reticulum and the mitochondria. When it is in the cytoplasm, it activates many enzymes, which is not what we want.
18
Q
When may cellular injury from hypoxia become irreversible? (S2)
A
Probably when calcium enters the cytoplasm. It activates ATPase (which breaks down ATP to ADP), phospholipase (breaks down cell membrane), protease (breaks down proteins in cell membrane) and endonucleases (breaks down DNA).
19
Q
What is ischaemia-reperfusion injury and why can the reperfusion cause injury? (S2)
A
Ischaemia-reperfusion injury is where blood flow is returned to a tissue previously subjected to ischaemia. The restoration of blood flow can cause injury due to:
Increased production of oxygen free radicals
Increased neutrophils after blood flow returns, resulting in more inflammation and increased tissue injury.
Delivery of complement proteins and activation of the complement pathway.
20
Q
What are free radicals? (S2)
A
They are reactive oxygen species - a single oxygen with one electron missing and are often produced through ischaemia-reperfusion injury and cellular ageing. They damage nucleic acids and can therefore be mutagenic.
21
Q
What are some of the useful functions of free radicals? (S2)
A
They are produced by leucocytes in the body and are involved in killing bacteria. They are also used in cell signalling.
22
Q
Name some ROS, which is the most dangerous? (S2)
A
OH.. ; O2- ; H2O2. OH.. is the most dangerous.
23
Q
How can OH.. be formed? (S2)
A
Radiation directly lysing water, giving OH..
Through the Fenton and Haber-Weiss reactions: H2O2 and O2- are substrates which explains why we seek to rapidly remove these if they are present in the body.
24
Q
What are the two defence systems of the body to prevent injury caused by free radicals? (S2)
A
The anti-oxidant system and the utilisation of heat shock proteins.
25
What is oxidative stress? (S2)
Oxidative stress is when there is an imbalance between free radical production and free radical scavenging leading to free radicals building up in the cell or tissue, causing cellular injury.
26
What are free radical scavengers? (S2)
Examples include vitamin A, C and E as well as glutathione. They neutralise free radicals.
27
What does the anti-oxidant system consist of? (S2)
1. Enzymes: SOD (superoxide dismutase) catalyses the reaction O2- H2O2 which is significantly less toxic to cells. Catalases and peroxidases complete the process of free radical removal: H2O2 H2O + O2
2. Free radical scavengers: ...
3. In the extracellular matrix, storage proteins (e.g. transferrin) sequester transition metals (e.g. iron and copper) which catalyse the formation of free radicals.
28
What are heat shock proteins? (S2)
They are important when the folding step in protein synthesis goes astray or when proteins denature due to cell injury. They ensure proteins re-fold correctly. If this is not possible the misfolded protein is destroyed.
29
In cells that are injured, what are the three main changes that can be seen with a light microscope? (S2)
1. Cytoplasmic changes – reduced pink staining of cytoplasm due to accumulation of water (reversible). Increased pink staining may be present due to detachment and loss of ribosomes from the endoplasmic reticulum and accumulation of denatured proteins (irreversible).
2. Nuclear changes – chromatin subtly clumped (reversible) may be followed by combinations of pyknosis (shrinkage), karryohexis (fragmentation) and karryolysis (dissolution) of the nucleus (irreversible).
3. Abnormal intracellular accumulations (covered later)
30
In cells that are injured (but at a stage that is still REVERSIBLE), what can be observed under an electron microscope? (S2)
Swelling - due to Na+ pump failure.
Cytoplasmic blebs, symptomatic of cell swelling.
Clumped chromatin due to reduced pH.
Ribosomes dissociate from ER. This is because maintaining the ribosomes' location is energy-dependent.
31
In cells that are injured (but at a stage that is IRREVERSIBLE), what can be observed under an electron microscope? (S2)
Further cell swelling
Combination of pyknosis, karryohexis and karryolysis.
Swelling and rupture of lysosomes – reflects membrane damage
Membrane defects
The appearance of myelin figures (which are damaged membranes)
Lysis of the ER due to membrane defects
Amorphous densities in swollen mitochondria
32
What is oncosis? (S2)
The spectrum of changes that occur in injured cells prior to death.
33
What is necrosis? (S2)
The morphologic changes that follow cell death in living tissue. This is largely due to the progressive degradative action of enzymes on a lethally injured cell.
34
What is apoptosis? (S2)
Self-induced cell death. A cell activates enzymes that degrade its own nuclear DNA and proteins.
35
Where is necrosis seen? (S2)
Necrosis is seen where there is damage to cell membranes (plasma and organelle). Lysosomal enzymes are released into the cytoplasm and digest the cell. Cell contents leak out of the cell and inflammation is often seen.
36
How long do necrotic changes take to develop? (S2)
Necrotic changes develop over a couple of hours. It takes 4-12 hours after a MI for microscopic changes to be seen.
37
How are necrotic cells removed? What will happen if they remain? (S2)
Necrotic cells are eventually removed by enzymatic degradation and phagocytosis (by white cells). Necrotic tissue that remains may calcify, known as dystrophic calcification.
38
The balance between two key processes determines whether coagulative or liquifactive necrosis is seen, what are these? (S2)
Enzymatic degradation and denaturation of protein.
39
If protein denaturation is the more dominant process (than enzymatic degradation) which type of necrosis will we see? (S2)
Coagulative necrosis. This occurs when the proteins tend to ‘clump’ leading to solidity of the dead cells and consequently of the dead tissue. In most solid organs, when cause of death is ischaemia, coagulation necrosis is common.
40
If cell death is associated with a lot of neutrophils, which type of necrosis might this be? (S2)
The neutrophils release proteolytic enzymes so it would be liquifactive.
41
Does the pancreas display coagulative or liquifactive necrosis? (S2)
The pancreas shows coagulative necrosis, but as it is rich in proteolytic enzymes (such as trypsin) the changes are modified to a certain extent.
42
In cells which have coagulative necrosis, histologically what would be seen? Would this change? (S2)
The cellular architecture is preserved creating a ‘ghost outline’ of the cells. These changes will only be seen in the first couple of days. Appearances will change because dead tissue incites an acute inflammatory reaction with infiltration by phagocytes.
43
Why is liquifactive necrosis seen in massive neutrophil infiltration (i.e. in abscesses)? When is liquifactive necrosis often seen? (S2)
This is because neutrophils release proteases. It is often seen in bacterial infections and is also seen in the brain (this is a fragile tissue without support from a collagenous matrix).
44
Why is caseous necrosis known in this way? (S2)
Caseous is Latin for cheese; caseous necrosis can have a cheesy appearance macroscopically.
45
What is caseous necrosis often associated with? (S2)
Infections, especially tuberculosis.
46
Histologically what characterises caseous necrosis? (S2)
Amorphous (sturctureless) debris, not ghost outlines as seen in coagulative necrosis.
47
Which form of inflammation is caseous necrosis often associated with? (S2)
Granulomatous.
48
When does fat necrosis occur and when is it typically observed? (S2)
Fat necrosis occurs when there is destruction of adipose tissue. It is typically seen as a consequence of acute pancreatitis. During inflammation of the pancreas there is a release of lipases from injured pancreatic acinar cells. The lipases act on the fatty tissue of the pancreas and on fat elsewhere in the abdominal cavity.
49
Clinically how could fat necrosis be observed? (S2)
Fat necrosis causes release of free fatty acids which can react with calcium to form chalky deposits (calcium soaps) in fatty tissues. These will be seen on x-ray and with the naked eye at surgery and autopsy.
50
What is gangrene? (S2)
Gangrene is not a type of necrosis, it is merely a term used to describe necrosis visible to the naked eye.
51
What type of necrosis causes 'dry' and 'wet' gangrene respectively? (S2)
It can be ‘dry’ if due to coagulative necrosis, or ‘wet’ if due to liquifactive necrosis.
52
Why is wet gangrene very serious? (S2)
Wet gangrene is very serious, it is typically due to infection and can result in septicaemia. Gangrene is most commonly seen in ischaemic limbs. It is dead tissue; it cannot be salvaged.
53
What is an infarction? (S2)
Infarction is a cause of necrosis, namely ischaemia. Infarction can result in gangrene and is often due to thrombosis or embolism. They can occasionally be due to external compression of a vessel or twisting of vessels.
54
What type of necrosis can be seen in infarcted tissue? (S2)
The necrosis in infarcted tissue can be coagulative or liquifactive, e.g. ischaemic necrosis in the heart (MI) shows coagulative necrosis; ischaemic necrosis in the brain (cerebral infarction) shows liquifactive necrosis.
55
Where does a white infarct occur? (S2)
A white (anaemic) infarct occurs in ‘solid’ organs (those with good stromal support) after occlusion of an end artery. White infarcts occur in the heart, spleen and kidneys.
56
What is an end artery? (S2)
AWhn artery that is the sole source of arterial blood to a segment of an organ
57
Why is a white infarct known as a white infarct? (S2)
In white infarcts, the solid nature of the tissue limits the amount of haemorrhage that can occur into the infarct from adjacent capillaries. The tissue supplied by the end artery dies and appears pale white because of a lack of blood in the tissue.
58
How would white infarcts appear? (S2)
Most are wedge-shaped with the occluded artery at the apex of the wedge. Histologically white infarcts appear as coagulative necrosis.
59
Where does a red infarct occur? (S2)
A red (haemorrhagic) infarct occurs where there is haemorrhage into dead tissues. This can be in the lungs or the intestines due to:
1. In organs with dual blood supply, (e.g. the lung) occlusion of the main artery causes an INFARCT. The secondary artery is insufficient to rescue the tissue but allows blood to enter the dead tissue creating a RED infarct.
2. If numerous anastomoses are present, (e.g. intestines). The reasons that is red are similar to 1..
3. In loose tissue, (e.g. the lung) where there is poor stromal support for capillaries.
60
What do the consequences of the infarct depend on? (S2)
Is it an end artery?: whether the tissue affected has an alternative blood supply.
How quickly the ischaemia occurred? If slowly there is time for development of additional perfusion pathways.
How vulnerable a tissue is to hypoxia?
The O2 content of the blood? (an infarct in an anaemic patient may be more serious).
61
Is apoptosis a 'normal' process or does it only occur when cells are damaged? (S2)
It can be a normal physiological process occurring when cells which are no longer needed are removed to remain a steady state. It also occurs when a cell is damaged, particularly it’s DNA.
62
When is apoptosis seen? (S2)
This is seen during hormone-controlled involution and in cytotoxic T cell killing of virus-infected or neoplastic cells. It is also seen in embryogenesis.
63
How does apoptosis occur? (S2)
During apoptosis a cell activates enzymes that degrade its own nuclear DNA and proteins, however membrane integrity is maintained.
64
Does apoptosis require energy? (S2)
The process is energy-dependent.
65
How would apoptotic cells appear through a light microscope? (S2)
Apoptotic cells are shrunken and appear eosinophillic. There is chromatin condensation, pyknosis and nuclear fragmentation. If affects small cells or small clusters of cells.
66
How would apoptotic cells appear through an electon microscope? (S2)
Through an electron microscope apoptotic cells show cytoplasmic blebbing. This progresses to fragmentation into membrane-bound apoptotic bodies which contain cytoplasm, organelles and other nuclear fragments. The apoptotic bodies are eventually removed by macrophage phagocytosis.
67
Does apoptosis cause leakage of cell contents? (S2)
No leakage of cell contents occurs; apoptosis does not induce inflammation.
68
What are the key phases of apoptosis? (S2)
Apoptosis has three phases: Initiation, Execution and Degradation/Phagocytosis.
69
What are caspases and how do they act? (S2)
Apoptosis is triggered by two key mechanisms, intrinsic and extrinsic which both culminate in the activation of caspases. Caspases are proteases that mediate the cellular effects of apoptosis. They act by cleaving proteins breaking up the cytoskeleton and initiating the degradation of DNA.
70
Why is intrinsic apoptosis known so? (S2)
Intrinsic (mitochondrial) apoptosis has mitochondria as a central player. It is called intrinsic because all of the apoptotic machinery is within the cell.
71
What are a few of the triggers for intrinsic apoptosis? (S2)
DNA damage or withdrawal of growth factors or hormones. The triggers lead to increased mitochondrial permeability, resulting in the release of cytochrome c from mitochondria. This interacts with APAF 1 and caspase 9 to form an apoptosome that activates various downstream caspases.
72
What is the cause of extrinsic apoptosis? (S2)
Extrinsic (receptor-mediated) apoptosis is caused by external ligands such as TRAIL and Fas, that bind to ‘death receptors’.
73
Are mitochondria involved in extrinsic apoptosis? (S2)
No.
74
What happens during the degradation phase of apoptosis? (S2)
During the degradation phase of apoptosis the cell breaks into membrane bound bodies (apoptotic bodies). They express molecules on their surface that induce phagocytosis of the apoptotic bodies by either neighbouring cells or phagocytes.
75
What is p53? (S2)
It is the guardian of the genome, it mediates apoptosis in response to DNA damage.
76
What forms the apoptosome? (S2)
Cytochrome c, APAF 1, caspase 9: together are the apoptosome.
77
What does Bcl-2 do, what effect does this have? (S2)
Bcl-2 prevents cytochrome c release from the mitochondria, inhibiting apoptosis.
78
Give an example of a death ligand and a death receptor? (S2)
TRAIL, TRAIL-R
79
Are abnormal cellular accumulations toxic? (S2)
They can be, alternatively they can be harmless.
80
What can abnormal cellular accumulations consist of? (S2)
Normal cellular constituents, e.g. water, lipids, proteins..
Abnormal substances, exogenous: e.g. minerals; or endogenous: products of abnormal metabolism
Pigments
81
What are some examples of situations where there are abnormal cellular accumulations of lipids? (S2)
Steatosis and high cholesterol.
82
What is steatosis? (S2)
It is the accumulation of TAGs, often seen in the liver, the major organ of fat metabolism. Common causes of liver steatosis are alcohol abuse, diabetes mellitus, obesity and toxins (carbon tetrachloride). Mild steatosis doesn’t appear to have any effect on cell function.
83
Which cells can cholesterol accumulate in? What are they subsequently known as? (S2)
Cholesterol accumulates within smooth muscle cells and macrophages within atherosclerotic plaques. Cholesterol is also seen in macrophages within the skin and tendons of people with hyperlipidaemias. The macrophages form small masses called xanthomas. Microscopically these cells appear to have foamy cytoplasm – they are known as foam cells.
84
Histologically, how are abnormal cellular accumulations of proteins observed? (S2)
Proteins: seen as eosinophilic droplets or aggregates in the cytoplasm.
85
What are a couple of examples of abnormal cellular accumulation of protein? (S2)
Mallory’s hyaline is a damaged protein seen in hepatocytes in alcoholic liver disease. It is due to accumulation of altered keratin filaments.
In α1-antitrypsin deficieny, the liver produces a version of the protein α1-antitrypsin that is misfolded. This cannot be packaged by the ER and accumulates within this organelle; it is not secreted by the liver.
86
What would systemic deficiency in α1-antitrypsin result in? (S2)
Systemic deficiency in this enzyme means that proteases within the lung can act unchecked; the breakdown of lung tissue would result in emphysema.
87
What are examples of exogenous pigments that may accumulate in the cell? (S2)
Carbon/coal dust. Once inhaled it is phagocytosed by macrophages within lung tissue. It is seen as blackened lung tissue (anthracosis) or as blackened peribronchial lymph nodes. If particularly high exposure occurs (coal miners) the lungs can become fibrotic or emphysematous (coal worker’s pneumoconiosis).
Tattooing is another example. The pigments are phagocytosed by macrophages within the dermis which remain there indefinitely.
88
What are some examples of endogenous pigments that can accumulate in cells abnormally? (S2)
Lipofuscin: a brown pigment seen in ageing cells. A sign of previous free radical injury and lipid peroxidation.
Haemosiderin is derived from haemoglobin. It is yellow/brown and contains iron. It forms when there is systemic or local excess of iron.
Bilirubin is a bile pigment. It is deposited in tissues causing jaundice. It is often a result of haemolytic anaemia or abnormal liver function.
89
What is a common example of haemosiderin accumulation? (S2)
In the skin and subcutaneous tissues as a bruise. Haemosiderosis is seen in organs where there is a systemic overload of iron. It is seen in haemolytic anaemias, blood transfusions and hereditary haemochromatosis. When severe, liver, heart and pancreas damage can occur.
90
What is pathological calcification? (S2)
It is the abnormal deposition of calcium salts within tissues.
91
Pathological calcification can be either...? (S2)
Dystrophic or metastatic.
92
Where does dystrophic calcification occur?
Dystrophic calcification occurs in an area of dying tissue, in atherosclerotic plaques, in ageing or damaged heart valves (it can cause organ dysfunction, seen in the previous two sites) and in tuberculus lymph nodes.
93
With dystrophic calcification is there an abnormality in calcium metabolism or serum calcium concentration? (S2)
No.
94
What is metastatic calcification? (S2)
It is the abnormal deposition of calcium salt in normal tissues.
95
Why does metastatic calcification occur? (S2)
It occurs when there is hypercalcaemia which is secondary to disturbances in calcium metabolism. It is usually asymptomatic.
96
What are the four main causes of hypercalcaemia? (S2)
1. Increased secretion of PTH resulting in bone resorption. This could be due to parathyroid tumours or ectopic secretion of PTH-related protein by malignant tumours
2. Destruction of bone secondary to primary tumours of bone, such as leukaemia, Paget's disease, metastases to bone or immobilisation.
3. Vitamin D related disorders
4. Renal failure.
97
What is replicative senescence? Why does it occur? (S2)
As cells get older, They experience replicative senescence, a decline in their ability to replicate until they eventually cannot. After a certain number of divisions cells eventually reach replicative senescence. This is related to the length of chromosomes: the chromosomes’ telomeres (located at the ends) shorten after each cellular division. When the telomeres reach a critical length the cell can no longer divide.
98
Where can telomerase be found? What does it do? (S2)
Germ and stem cells contain telomerase which maintains the original length of the telomeres. Many cancer cells produce telomerase and so have the ability to replicate multiple times.
99
How is alcohol metabolised? (S2)
Ethanol (the alcohol) is metabolised by alcohol dehydrogenase, the cytochrome p450 enzyme CYP2E1 and catalase to acetaldehyde. This is metabolised by aldehyde dehydrogenase to acetic acid.
100
Can cytochrome P450 enzyme CYP2E1 be induced? (S2)
Yes it can. This means metabolic tolerance of alcohol can be increased as well as that of other drugs catalysed by CYP2E1.
101
Woman have lower concentrations of aldehyde dehydrogenase, what does this mean? (S2)
Women can drink less alcohol than men, but have the same alcohol levels in their blood.
102
Why can 'Asian flush' be observed in those from the orient? (S2)
‘Asian flush’ occurs in 50% of those from the orient. They have reduced activity of aldehyde dehydrogenase – the subsequent build-up of aldehyde dehydrogenase results in facial flushing.
103
What are the three major changes alcohol can have on the liver? (S2)
Fatty change – alcohol toxicity causes steatosis of the liver, causing hepatomegaly. This is acute, reversible and generally asymptomatic.
Acute alcoholic hepatitis – a binge of alcohol can result in this with focal hepatocyte necrosis, the formation of Mallory bodies and a neutrophillic infiltrate. It can give symptoms of fever, liver tenderness and jaundice. It is usually reversible.
Cirrhosis – seen in 10-15% of alcoholics, resulting in a shrunken liver. Histologically appears as micronodules of regenerating hepatocytes surrounded by bands of collagen. Irreversible and sometimes fatal.
104
How is paracetamol detoxified? (S2)
Paracetamol is detoxified in the liver through glucuronidation and sulphonation. Small amounts are metabolised by cytochrome p450 oxidation (CYP2E1) to a highly toxic metabolite, NAPQI. Glutathione detoxifies NAPQI, but If a paracetamol overdose is taken glutathione would be depleted, and NAPQI accumulates.
105
How does NAPQI interact with the liver? (S2)
NAPQI binds with sulfhydryl groups on liver cell membranes, causing hepatocyte necrosis and liver failure. Massive liver necrosis occurs 3-5 days after a large paracetamol overdose.
106
Why are some people more susceptible to paracetamol overdose? Which groups of people are? (S2)
This is due to having lower reserves of glutathione. These include: those who took alcohol with the paracetamol, the alcohol-dependent, those who have AIDS or are HIV positive, malnourished and those on enzyme-inducing drugs, e.g. carbamazepine.
107
What is the antidote for paracetamol overdose? When should it be given? (S2)
N-acetylcysteine, which increases hepatic glutathione. To decide whether it is required, from 4 hours after the overdose the serum concentration of paracetamol is measured. The INR (or prothrombin time) measured 24 hours after the overdose is a guide to the severity of the liver damage in these patients.
108
What does aspirin do? (S2)
Acetylsalicylic acid or aspirin acetylates platelet cyclooxygenase and blocks platelets’ ability to make thromboxane A2, a substance which activates platelet aggregation.
109
What are the consequences of aspirin overdose? (S2)
Major consequences are metabolic. Aspirin stimulates the respiratory centre which results in respiratory alkalosis. Compensatory mechanisms result in metabolic acidosis. Aspirin (in overdose) results in an increase in lactate, pyruvate and ketone bodies contributing to the acidosis (this is due to the fact it interferes with carbohydrate, fat and protein metabolism as well as oxidative phosphorylation).
110
If there is aspirin overdose what may be present?
Petechaie (small red spots on the body caused by haemorrhages in capillaries): as platelet cyclooxygenase is inhibited there is decreased platelet aggregation reducing clotting. Acute erosive gastritis, leading to GI bleeding may be present.
111
What is inflammation? (S3)
Inflammation is the response of living tissue to injury. It is initiated to limit tissue damage.
There are vascular and cellular reactions (accumulation of fluid exudate and neutrophils in tissues); it is controlled by a variety of chemical mediators derived from plasma or cells; it is protective (but can lead to local complications and systemic effects.
112
What is acute inflammation? (S3)
Acute inflammation is innate, immediate and early; it is stereotyped. It has a short duration.
113
What are the causes of acute inflammation? (S3)
```
Microbial infections – e.g. pyogenic organisms
Hypersensitivity reactions (acute phase)
Physical agents
Chemicals
Tissue necrosis
```
114
What are the clinical signs of acute inflammation? (S3)
```
Rubor (redness)
Tumor (swelling)
Calor (heat)
Dolor (pain)
and a loss of function.
```
115
What are the important tissue changes in acute inflammation? (S3)
1. Changes in blood flow (vascular)
2. Exudation of fluid into tissues
3. Infiltration of inflammatory cells (cellular).
116
What happens following a tissue injury?
In order:
1. Transient vasoconstriction of arterioles (few seconds)
2. Vasodilation of arterioles and then capillaries leads to an increase in blood flow (rubor and calor are seen)
3. Increased permeability of blood vessels
exudation of protein-rich fluid into tissues
slowing of circulation (tumor)
4. Concentration of RBCs in small vessels and increased viscosity of blood = stasis.
117
What is histamine? (S3)
Histamine is a chemical mediator involved in the immediate early response of inflammation.
118
What is histamine released from and in response to? (S3)
It is released from mast cells, basophils and platelets in response to many stimuli, such as:
physical damage, immunologic reactions, C3a, C5a, IL-1 factors from neutrophils and platelets.
119
Which mediators are involved in a persistent response? (S3)
Examples include leukotrienes, bradykinin although there are many chemical mediators involved with a persistent response.
120
What is Starling's Law? (S3)
Starling's Law is that fluid flow across vessel walls is determined by the balance of hydrostatic and oncotic (colloid osmotic) pressure comparing plasma and interstitial fluid.
121
Under which situations would there be an increase in fluid flow out of the vessel? (S3)
When there is increased hydrostatic pressure or if there is increased oncotic (colloid osmotic) pressure (albumin) in the interstitium.
122
What is hydrostatic pressure? (S3)
From inside the capillaries, think of hydrostatic pressure as the 'pushing force', pushing the fluid out of the capillaries. It's the result of the actual pressure of the fluid on the capillary walls.
123
What is oncotic pressure? (S3)
Oncotic pressure is the 'pulling force', pulling fluids from the surrounding tissue into the capillaries. It's the result of a difference in the concentration of solutes in the fluid inside the capillaries as opposed to outside them, because water will naturally seek a state of balance in the concentration of solute (particles).
124
What happens to oncotic pressure as fluid leaves the capillaries? (S3)
As fluid leaves the capillaries as a result of hydrostatic pressure, albumin and other large proteins cannot pass through the capillary walls. This results in a greater concentration of solutes inside the capillaries as opposed to outside of them, and the oncotic pressure rises, pulling more water into the capillaries in order to balance the solute concentration.
125
What happens when hydrostatic pressure is greater than oncotic pressure? And vice-versa? (S3)
Fluid will leave the capillaries...
| Fluid will enter the capillaries.
126
In acute inflammation, there is arteriolar dilatation: what does this result in? (S3)
An increase in hydrostatic pressure.
127
In acute inflammation, there is increased permeability of vessel walls: what does this result in? (S3)
Loss of protein into interstitium.
128
If there is an increase in hydrostatic pressure and a loss of protein into the interstitium what would this result in? (S3)
There would be net flow of fluid of the vessel. This is known as oedema.
129
What is oedema? (S3)
Excess of fluid in the interstitium. It can be transudate or exudate. It leads to increased lymphatic drainage.
130
Is fluid loss in inflammation transudate or exudate? (S3)
Fluid loss in inflammation has a high protein content: it is therefore exudate.
131
Is fluid loss due to hydrostatic pressure imbalance transudate or exudate? (S3)
Fluid loss due to hydrostatic pressure imbalance only has a low protein content: it is transudate (e.g. cardiac failure or venous outflow obstruction).
132
When might transudate be seen? (S3)
Cardiac failure or venous outflow obstruction.
133
What are some mechanisms of vascular leakage? (S3)
1. Endothelial cells contract (leaving gaps): histamines and leukotrienes cause this.
2. Cytoskeletal rearrangement (leaving gaps): cytokines IL-1 and TNF mediate this.
3. Direct injury: toxic burns, chemicals.
4. Leukocyte (WBC) factors such as toxic oxygen species and enzymes can leak out of inflammatory cells and contribute to fluid loss.
5. Increased transcytosis: channels across endothelial cytoplasm; mediated by vascular endothelial growth factor (VEGF).
134
What does fibrin do in inflammation? (S3)
In the context of inflammation, fibrin localises the inflammatory response. Fibrin keeps the area of tissue damage separate from the other tissues. This is in contrast to haemostasis where it stops blood from leaking out of vessels.
135
What is the most important cell involved in acute inflammation? (S3)
The neutrophil leucocyte or polymorphonuclear leucocyte. The terms neutrophil and polymorph are interchangeable. It is a type of granulocyte and WBC.
136
What are the four stages that allow infiltration of neutrophils? (S3)
1. MARGINATION: Stasis causes neutrophils to line up at the end of the blood vessels along the endothelium.
2. ROLLING: neutrophils roll along endothelium, sticking to it intermittently
3. ADHESION: the neutrophils then stick more avidly
4. EMIGRATION: neutrophils move through the blood vessel wall
137
How do neutrophils emigrate out of the blood vessel? (S3)
1. There is relaxation of inter-endothelial cell junctions.
2. Digestion of vascular basement membrane
These actions allow the neutrophils to move.
138
What is diapedesis? (S3)
The process of neutrophil movement. Neutrophil emigration can also be used.
139
What is chemotaxis? (S3)
The movement along a concentration gradient of chemoattractants. Chemotaxins are substances which neutrophils have receptors for on their surface and are attracted to. The process is essentially receptor-ligand binding which leads to rearrangement of the cytoskeleton (of the polymorph) and the cell produces pseudopod.
140
What are some important examples of chemotaxins? (S3)
Important chemotaxins are C5a, Leukotriene B4 and bacterial peptides
141
What are the three key steps of phagocytosis? (S3)
1. Contact
2. Recognition
3. Internalisation
142
In phagocytosis, what is recognition facilitated by? (S3)
It is facilitated by opsonins (Fc [fixed component of immunoglobulin] and C3b) which leads to cytoskeletal changes of the polymorph. The neutrophils then form pseudopods which surround and engulf the dead cell / bacteria.
143
What happens after the dead cell / bacteria has been engulfed by the neutrophil? (S3)
The phagosomes fuse with lysosomes to produce secondary lysosomes. After phagocytosis the neutrophils are activated; they may release toxic metabolites and enzymes which can cause damage to the host tissue.
144
What are the two mechanisms of phagocytes killing cells? (S3)
1. O2 dependent: produces superoxide and hydrogen peroxide (which are highly toxic). In polymorphs only there is H2O2-myeloperoxidase.
2. O2 independent: e.g. cells injured in an ischaemic tissue can be ‘killed’ by lysozyme and hydrolases. BPI or bactericidal permeability increasing protein can also be used.
145
How does exudation of fluid combat injury? (S3)
1. Distributing abundant plasma proteins to area of injury; these contain immunoglobulins (not vital), inflammatory mediators and fibrinogen (delivered to try and localise the inflammation).
2. Dilutes toxins through increasing concentration of plasma.
3. Increases lymphatic drainage delivering micro-organisms to phagocytes and antigens to the immune system.
146
What does increasing lymphatic drainage do? (S3)
Deliver more tissue fluid through the filter of the lymph node. The lymph node (or gland) is an important site of immune reactions.
147
How does infiltration of neutrophils combat injury? (S3)
Removes pathogenic organisms and necrotic debris.
148
How does vasodilatation combat injury? (S3)
Vasodilatation increases delivery of fluid and cells, it also increases temperature
149
How does pain and loss of function combat injury? (S3)
It acts as a signal to the body to rest.
150
What are the three families of chemical mediators? Give an example of each one. (S3)
1. Proteases (plasma proteins produced in the liver) circulate in inactive forms in the plasma, they are activated by the various cascades that activate proteins such as: clotting, complement (C3a and C5a) and kinins.
2. Arachidonic acid metabolites – prostaglandins and leukotrienes
3. Cytokines and chemokines (small cytokines) which are produced by WBCs. There are many of them but interleukins and TNF alpha are the most important.
151
What are the important chemical mediators in vasodilatation? (S3)
Histamine and prostaglandins.
152
What are the important chemical mediators to increase vascular permeability? (S3)
Histamine and leukotrienes.
153
What are the important chemical mediators in neutrophil chemotaxis? (S3)
C5a, LTB4 and bacterial peptides.
154
What are the important chemical mediators in phagocytosis? (S3)
C3b.
155
What are clinical sequelae? (S3)
Typically they are chronic conditions that can result from acute conditions.
156
What are some local complications of acute inflammation? (S3)
Swelling can cause blockage of tubes, e.g. bile duct, intestine.
Exudate can cause compression e.g. cardiac tamponade in pericarditis; if the inflammatory process is on the surface of an organ this would usually be worse.
Loss of fluid e.g. burns; or pain and loss of function (especially if prolonged)
157
What are some systemic complications of acute inflammation? (S3)
Fever: Endogenous pyrogens (things that increase temperature in the body) produced: Interleukin-1 and TNFα; prostaglandins are another example. Aspirin reduces fever.
Leukocytosis: increase in the white cell count in the blood. Interleukin-1 and TNFα produce an accelerated release of white cells from the marrow.
Macrophages, T lymphocytes produce colony-stimulating factors.
158
What are predominantly seen in acute inflammation? And in chronic inflammation? (S3)
Neutrophilia is seen in acute inflammation (bacterial); in chronic inflammation there are lots of lymphocytes in the blood (viral).
159
What is acute phase response? And acute phase proteins? (S3)
Acute phase proteins are a class of proteins whose plasma concentrations increase (positive acute phase proteins) or decrease (negative acute phase proteins) in response to inflammation. This response is called the acute phase reaction (also called acute phase response).
160
What are some signs and symptoms of acute phase response? (S3)
Anorexia, fast pulse, altered sleep patterns and changes in plasma concentrations of acute phase proteins.
161
What is an example of an acute phase protein? (S3)
C-reactive protein (CRP) is an inflammatory marker.
162
What is shock? (S3)
A clinical syndrome of circulatory failure. It may occur if immunocompromised and micro-organisms and toxins spread.
163
What may happen in response to acute inflammation? (S3)
Complete resolution; Continued acute inflammation with chronic inflammation; Chronic inflammation and fibrous repair, probably with tissue regeneration; Death
164
If acute inflammation completely resolves, what changes will we see? (S3)
Morphology: changes gradually reverse, vascular changes stop: neutrophils no longer marginate, vessel permeability returns to normal, vessel calibre returns to normal.
Therefore exudate drains to lymphatics, fibrin is degraded by plasmin and other proteases, neutrophils die, break up and are carried away or phagocytosed, damaged tissue might regenerate.
165
If tissue architecture has been destroyed, is complete resolution possible? (S3)
No.
166
Do inflammatory mediators persist in the body for a long time? (S3)
No. All inflammatory mediators are extremely potent but have short half-lives.
167
How do chemical mediators get 'removed'? (S3)
Some mediators are inactivated by degradation, e.g. heparinise;
Inhibitors may bind, e.g. anti-proteases;
May be unstable e.g. some prostaglandins;
May be diluted in the exudate, e.g. fibrin degradation products;
Specific inhibitors of acute inflammatory changes, e.g. lipoxins, endothelin.
168
What causes bacterial meningitis? (S3)
Bacterial meningitis is caused by acute inflammation (due to bacteria such as Neisseria meningitidis) in the meningeal space between the arachnoid and the pia mater.
169
Why can bacterial meningitis sufferers die quickly? (S3)
Due to raised inter-cranial fluid. This is because of exudate building up in the small space between the brain and the skull.
170
What are some long-term consequences of bacterial meningitis? (S3)
Vascular thrombosis and reduced cerebral perfusion.
171
What is lobar pneumonia caused by? (S3)
Lobar pneumonia is caused by streptococcus pneumonia (‘Pneumococcus’). It is the acute inflammation of the lung.
172
What is the clinical course of lobar pneumonia? (S3)
Alveoli should contain air not fluid / exudate. Therefore hypoxaemia and breathlessness can be expected. worsening fever, prostration and a dry cough are typical other symptoms.
173
What can a skin blister be caused by? (S3)
Heat, sunlight and chemicals.
174
What are features of a skin blister? (S3)
Predominant features are pain and profuse exudate. The collection of fluid can strip off overlying epithelium which leaves the tissue more prone to infection.
175
What are the characteristics of the exudate of a skin blister? (S3)
There are relatively few inflammatory / polymorph cells meaning the exudate is clear. This is not the case if a secondary bacterial infection develops.
176
What can acute inflammation in serous cavities lead to? (S3)
There is a risk that exudate can pour into the cavity. This can result in ascites (gut) or a pleural (lungs) or pericardial (heart) effusion. This will lead to respiratory or cardiac impairment. There can be localised fibrin deposition. The fibrin in this area is sometimes called ‘bread and butter’ pericarditis – it is known as this because there is some white exudate on the heart.
177
What happens when there is an abscess? (S3)
Abscesses usually occur in solid tissues. Inflammatory exudate forces the tissue apart and there is liquefactive necrosis in the centre. It may cause high pressure and therefore pain (it can be resolved by surgical intervention to remove the liquefactive area). It may cause tissue damage and squash adjacent structures.
178
What are some examples of abscesses? (S3)
Spots and liver abscesses.
179
Why can liver abscesses be difficult to diagnose? (S3)
The liver is not innervated for pain, so the patient may present with only fever, raised white blood count etc.
180
What are some disorders of acute inflammation? (S3)
Disorders of acute inflammation are rare.
There are examples however:
Hereditary angio-oedema: there is oedema around the airways leading to airway obstruction.
Alpha-1 antitrypsin deficiency. Alpha-1 antitrypsin is a protease.
181
What is chronic inflammation? (S4)
It is the chronic response to injury with associated fibrosis.
182
How does chronic inflammation arise? (S4)
1. It may ‘take over’ from acute inflammation if the damage is too severe to be resolved within a few days.
2. May arise de novo. This can be from some autoimmune conditions (e.g. rheumatoid arthritis), some chronic infections (e.g. viral hepatitis) or from ‘chronic low-level irritation’.
3. May develop alongside acute inflammation in severe persistent or repeated irritation.
183
What does chronic inflammation look like? (S4)
It is characterised by its microscopic appearance which is more variable than in acute inflammation.
184
What is the function of macrophages? (S4)
Phagocytosis and destruction of necrotic debris and bacteria.
Processing and presentation of antigen to immune system.
Synthesis of cytokines and also complement components, blood clotting factors and proteases.
Control of other cells by cytokine release.
185
What is the function of B lymphocytes? (S4)
They differentiate into plasma cells and produce antibodies.
186
What is the function of T lymphocytes? (S4)
They are involved in control and some cytotoxic functions.
187
What chronic inflammatory reactions are eosinophils involved with? (S4)
They are involved in allergic reactions, parasitic infestations and some tumours.
188
What is the function of a fibroblast? (S4)
They make collagen. In chronic inflammation they are recruited by macrophages
189
How are 'giant' cells produced? (S4)
‘Giant’ cells are made by the fusion of macrophages through frustrated phagocytosis.
190
What are the types of 'giant' cells? What conditions are they typically seen in? (S4)
Langhans cells are commonly seen in tuberculosis sufferers. Touton cells are seen in sites of fat necrosis. There is also a foreign body type.
191
In rheumatoid arthritis what cell type is commonly seen? (S4)
Plasma cells.
192
In chronic gastritis what cell type is commonly seen? (S4)
Predominantly lymphocytes;
193
What is leishmaniasis? Which cells are commonly seen? (S4)
It is a protozoal infection. Macrophages.
194
What are the effects of chronic inflammation? (S4)
Fibrosis e.g. chronic cholecystitis and gastric ulceration
Impaired function e.g. cirrhosis, IBD
Improved function (rare) e.g. thyrotoxicosis, mucus secretion
Atrophy e.g. gastric mucosa, adrenal glands
Stimulation of immune response e.g. phagocyte-lymphocyte reaction
195
What is chronic cholecystitis? (S4)
Chronic cholecystitis is the chronic inflammation of the gall bladder. It is repeated attacks of acute inflammation which lead to chronic inflammation. Therefore there is repeated obstruction by gall stones and fibrosis of the gall bladder wall.
196
How is chronic cholecystitis treated? (S4)
It is treated with the surgical removal of the gall bladder.
197
What causes gastric ulceration? (S4)
Gastric ulceration can occur after acute (caused by alcohol and drugs) or chronic gastritis (caused by Helicobacter pylori). Ulceration occurs because of the imbalance of acid production and mucosal defence.
198
How is Helicobacter pylori treated? (S4)
Helicobacter pylori has a triple treatment. A PPI (proton-pump inhibitor), omeprazole and two antibiotics (clarithromycin and amoxicillin).
199
What is liver cirrhosis? (S4)
Liver cirrhosis is chronic inflammation with fibrosis leading to disorganisation of architecture. There is attempted regeneration by the liver.
200
What causes cirrhosis? (S4)
Common causes of cirrhosis are alcohol, infection (HBV and HCV), immunological, fatty liver disease and drugs and toxins.
201
Can cirrhosis be treated? (S4)
No. Liver cirrhosis cannot be reversed. But action can be taken to prevent further damage, i.e. through lifestyle changes or transplantation of a new liver if required.
202
What are inflammatory bowel diseases? (S4)
Inflammatory bowel disease is a group of idiopathic inflammatory diseases affecting the large and small bowel. Patients present with diarrhoea, rectal bleeding and other symptoms. The most common IBDs are ulcerative colitis and Crohn’s disease.
203
What are the characteristics and symptoms of ulcerative colitis and Crohn's disease? Can they be treated? (S4)
Ulcerative colitis is superficial; there is diarrhoea and bleeding. It is treated with immunosuppression and potentially surgical removal of the large bowel (colectomy). Crohn’s disease is transmural (involves the wall); there may be strictures – narrowing of the bowel that may lead to bowel obstruction or changes in the calibre of the faeces – or fistulae - where there is an abnormal connection between two epithelium-lined organs (such as the bowel and the skin). It can be treated with lifestyle modifications, diet/hydration and immunosuppression.
204
What is rheumatoid arthritis? (S4)
Rheumatoid arthritis is an autoimmune disease. There is a localised and systemic immune response, the latter of which can affect other organs and cause amyloidosis. The localised chronic inflammation leads to joint destruction.
205
What is granulomatous inflammation? (S4)
Granulomatous Inflammation is inflammation with granulomas.
206
What are granulomas and when do they form? (S4)
It is a collection of immune cells known as macrophages. Granulomas form when the immune system attempts to wall off substances that it perceives as foreign but is unable to eliminate. e.g. bacteria, fungi and other foreign material. Granulomas arise with persistent, low-grade antigenic stimulation and hypersensitivity.
207
What are the main causes of granulomatous inflammation? (S4)
Mildly irritant ‘foreign’ material.
Infections: mycobacteria (TB, leprosy), syphilis and some fungal
Unknown causes: Sarcoidosis, Wegener’s granulomatosis, Crohn’s disease.
208
What is tuberculosis caused by? How does it cause TB? (S4)
Mycobacterium tuberculosis predominantly. The bacteria is difficult and slow to culture. It produces no toxins or lytic enzymes and causes tuberculosis through persistence and induction of cell-mediated immunity.
209
What are common histological features of tuberculosis? (S4)
Caseous necrosis and Langhans’ cells are common histological features in TB-sufferers.
210
What are the outcomes of tuberculosis? (S4)
- Arrest, fibrosis, scarring
- Erosion into bronchus --> bronchopneumonia --> TB in gastrointestinal tract
- Tuberculous empyema (collection of pus)
- Erosion into blood stream
211
What is miliary tuberculosis? (S4)
If there are many bugs spread across the body.
212
What is single organ tuberculosis? (S4)
When there are very few bugs, localised to one organ.
213
What is regeneration? (S5)
It is the replacement of dead or damaged cells by functional, differentiated cells (derived from stem cells).
214
How do stem cells have limitless proliferation? (S5)
Daughter cells either remain as a stem cell (maintaining the stem cell pool) or differentiate to a specialised cell type. In early life stem cells develop into many different cell types.
215
What does unipotent, multipotent and totipotent meant? Give an example of a cell of each type. (S5)
Unipotent: produce only one type of differentiated cell, e.g. epithelia.
Multipotent: produce several types of differentiated cell, e.g. haematopoietic
Totipotent: produce any type of cell, i.e. embryonic stem cells.
216
Cells have different propensities to regenerate. How are cells divided based on this? (S5)
LABILE. e.g. epithelial and haematopoietic – normal state is active cell division: G1 --> M --> G1; there is usually rapid proliferation.
STABLE, e.g. hepatocytes, osteoblasts, fibroblasts – which are in a resting state of G0; speed of regeneration is variable.
PERMANENT, e.g. neurones, cardiac myocytes – unable to divide – permanently in G0 and are so unable to regenerate.
217
What are the two factors controlling regeneration? (S5)
Growth factors and cell-to-cell/basement membrane contact aka 'contact inhibition'.
218
What are growth factors? (S5)
These are molecules that promote proliferation in the stem cell population. They are extracellular signals that send a signal to the nucleus of the stem cell promoting transcription (i.e. cell division). They promote expression of genes controlling the cell cycle.
219
What are some examples of growth factors? (S5)
Proteins: platelet-derived growth factor (PDGF), epithelial growth factor (EGF);
Hormones: oestrogen, testosterone and growth hormone.
220
How do growth factors 'send out their signals'? (S5)
Growth factors bind to receptors at the cell membrane. These receptors dimerize and gain a kinase ability, leading to a phosphorylation cascade. Ultimately transcription factors within the nucleus and genes which promote G1 – S phase of mitosis are activated leading to the cell having to commit to cell division.
221
How does contact between basement membranes and adjacent cells inhibit cell proliferation? (S5)
When cells are in contact with each other and with the basement membranes anti-proliferative signals are sent between the cells leading to ‘contact inhibition’. The loss of contact promotes proliferation. These signals are sent between the cells by adhesion molecules, e.g. E-Cadherin, they dimerize across the extracellular space. These mechanisms are deranged in cancer.
222
What are the key components of fibrous repair? (S5)
1. Cell migration
2. Formation of new blood vessels through angiogenesis
3. Extracellular matrix production and remodelling
Fibrous repair is initiated by combining these components to form granulation tissue.
223
Which cells are involved with cell migration in fibrous repair? What are their functions? (S5)
1. Inflammatory cells which have 2 functions: phagocytosis of debris (neutrophils and macrophages) as well as to act as chemical mediators (lymphocytes and macrophages).
2. Endothelial cells which are involved in angiogenesis.
3. (Myo)fibroblasts under the influence of pro-fibrotic growth factors produce extracellular matrix proteins e.g. collagen. Myofibroblasts are specialised fibroblasts that can contract, leading to wound contraction, bring the edges of a wound together aiding healing.
224
What is angiogenesis? (S5)
Essentially where pre-existing blood vessels sprout new vessels.
225
Why is angiogenesis important in wound healing? (S5)
Development of a good blood supply is vital to wound healing. It provides access to the wound for inflammatory cells and fibroblasts and also delivers oxygen and other nutrients. Malignant cells exploit many of the mechanisms of angiogenesis to promote tumour growth however.
226
What are the stages of angiogenesis? (S5)
1. Endothelial proteolysis of basement membrane
2. Migration of endothelial cells by chemotaxis
3. Endothelial proliferation (induced by proangiogenic growth factors such as VEGF)
4. Endothelial maturation and tubular remodelling
5. Recruitment of periendothelial cells.
227
What is the function of the extracellular matrix? (S5)
1. Support and anchor cells
2. Separates tissue compartments e.g. basement membrane
3. Sequesters growth factors
4. Allows communication between cells
5. Facilitates cell migration.
228
What is the most abundant protein in animals? (S5)
Collagen.
229
What are some of collagen's functions? (S5)
It provides an extracellular framework, support and structure for all the tissues of the body.
230
What is collagen composed of? (S5)
It is composed of triple helices of polypeptide alpha chains.
231
Which types of collagen are fibrillar? And amorphous? Give some examples of each. (S5)
Type I–III are fibrillar collagens e.g. bone and fibrocartilage (Type I); hyaline and elastic cartilage (Type II); Type IV-VI are amorphous e.g. the basement membrane (Type IV).
232
How is (fibrillar) collagen synthesised?
1. Polypeptide alpha chains are synthesised in the endoplasmic reticulum.
2. These chains undergo a variety of enzymatic modification steps post-transcription, including vitamin C dependent hydroxylation.
3. The alpha chains then align and cross-link to form a procollagen triple helix.
4. Soluble procollagen is then secreted and cleaved to form tropocollagen.
5. Tropocollagen then polymerises to form fibrils. Bundles of these fibrils form fibres which may be remodelled by collagenases.
233
What are some examples of defects in collagen synthesis? (S5)
Scurvy (vitamin C deficiency);
Ehlers-Danlos syndromes;
Osteogenesis imperfecta;
Alport syndrome.
234
What happens in scurvy? (S5)
Vitamin C deficiency results in inadequate hydroxylation of alpha chains leading to defective helix formation. The collagen lacks strength and is at risk of enzymatic degradation. Scurvy particularly affects collagen supporting blood vessels. It can result in haemorrhage or skeletal changes in infants.
235
What happens in Ehlers-Danlos syndromes? What about osteogenesis imperfecta and Alport syndrome? (S5)
There is defective conversion of procollagen to tropocollagen.
Osteogenesis imperfecta sufferers have brittle bones, they can also develop ocular problems. Some forms of the disease are incompatible with life.
Alport syndrome is a defect in Type IV collagen leading to haematuria, kidney and ocular problems.
236
What proteins (apart from collagen) form the extracellular matrix? What are their functions? (S5)
Matrix glycoproteins: these organise and orientate cells and support cell migration. e.g. Fibronectin
Proteoglycans are involved in matrix organisation, cell support and regulate availability of growth factors.
Elastin which provides elasticity of tissues.
237
What is the mechanism of fibrous repair? (S5)
1. Blood vessels are damaged, inflammatory cells infiltrate as a blood clot forms. There is acute inflammation around the edges as neutrophils infiltrate and digest the clot. This becomes chronic inflammation when macrophages and lymphocytes migrate into the clot.
2. Angiogenesis occurs in response to pro-angiogenic factors (produced by neutrophils). (Myo)fibroblasts become activated; they migrate and differentiate and produce the extracellular matrix. At this point we have our granulation tissue (seen underneath the eschar, or scab of a wound).
3. This granulation tissue undergoes maturation, comparatively long-lasting. The cell population falls; collagen increases, matures and remodels. Myofibroblasts contract: this reduces the volume of defect (this process decreases time for the wound to heal). Vessels differentiate and are reduced.
A fibrous scar is the result.
238
What is fibrous repair controlled by? (S5)
1. Inflammatory cells are recruited by chemotaxis
2. Angiogenesis: pro-angiogenic factors are produced by platelets and extracellular matrix. Others produce angiogenic cytokines in response to hypoxia e.g. VEGF.
3. Fibrosis: macrophages produce various pro-fibrotic cytokines Interleukin 1 and TNFα.
These cytokines lead to fibroblast proliferation and lead to extracellular matrix production.
239
When does healing by "Primary Intention" occur? (S5)
When there is an incised wound (say by a scalpel) with apposed edges (the edges fall back with each other naturally).
240
How does healing by "Primary Intention" take place? (S5)
There is loss of contact inhibition for the keratinocytes. These cells therefore proliferate and regenerate the epidermis. The dermis undergoes fibrous repair. Sutures are out at ~10 days: with approx. 10% normal strength at site of wound (maturation of scar continues for up to 2 years). If the wound is clean and sutured granulation tissue will become scar tissue.
241
What type of wounds is healing by "Secondary Intention" seen in? (S5)
Seen in an infarct, ulcer, abscess or any large wound.
242
What happens in healing by "Secondary Intention"? (S5)
The wound edges are unapposed. The large clot dries to form an eschar (or scab). The epidermis regenerates from the base up. A lot more granulation tissue is required.
Compared with healing by “Primary Intention”, myofibroblasts produce more contraction to reduce the volume of defect. “Secondary Intention” also produces a larger scar and takes longer.
243
How are bone fractures healed? (S5)
1. Haematoma forms from ruptured vessels within marrow cavity and periosteum. Organising haematoma provides a framework for ingress of macrophages (remove necrotic tissue), endothelial cells (capillaries develop), fibroblasts and osteoblasts.
2. This specialised mixture of cells is called a callus. Bone is laid down in an irregular woven pattern. The external callus provides splint-like support. Initially there is a soft callus, this is replaced by a hard callus.
3. The woven bone is gradually replaced by more organised lamellar bone. Lamellar bone is gradually remodelled to the direction of mechanical stress.
244
How does the liver heal? (S5)
Live hepatocytes have some capacity to regenerate but hepatocyte architecture does not. The imbalance between hepatocyte regeneration and the ability to regenerate architecture leads to cirrhosis and nodules.
If acute damage --> regeneration;
If chronic damage --> cirrhosis.
245
How does muscle recover? (S5)
Cardiac / Smooth are permanent tissues (although vascular smooth muscle has limited regeneration) and will be replaced by a scar.
Skeletal muscle has a limited regenerative capacity due to satellite cells.
246
What is remarkable about how the heart muscle recovers? And bone? Cartilage? (S5)
In the heart there is fibrosis.
In bone there is callus formation.
Cartilage cannot regenerate as there is no blood supply to the tissue.
247
Can peripheral nerves regenerate? And the central nervous system? (S5)
There is Wallerian degeneration (which occurs in many neuro-degenerative diseases) as well as Proximal degeneration (distal proliferation (recovery of ~1mm/day))
The central nervous systehm has no regenerative capacity. Glial cells can proliferate however in a process known as gliosis.
248
What factors influence wound healing? (S5)
There are local factors...
1. Type, size location of wound
2. Apposition, lack of movement
3. Blood supply: arterial, venous
4. Infection: suppuration, gangrene, systemic
5. Foreign material: dirt, glass, sutures, necrotic tissue
6. Radiation damage
and general factors...
1. Age
2. Drugs (steroids) and hormones
3. General dietary deficiencies (protein) as well as specific (vitamin C and essential amino acids)
4. General state of health (chronic diseases e.g. diabetes) and cardiovascular status
249
What are the complications of fibrous repair? (S5)
Insufficient fibrosis: Wound dehiscence, hernia, ulceration; more common in the obese, elderly, those with malnutrition or taking steroids.
Excessive fibrosis: cosmetic scarring; keloid; cirrhosis; lung fibrosis
Excessive contraction: obstruction of tubes and channels (strictures); limitation of joint movement (contractures).
250
What is haemostasis? (S6)
It is the stopping of bleeding or clotting. It is the first stage of wound healing.
251
What does haemostasis depend on? (S6)
* Vessel wall constriction to limit blood loss: all vessels can do this.
* Platelet adhesion to the damaged vessel wall and adhesion to each other, they form a platelet plug – if a small injury.
* Coagulation system is a cascade where a series of inactive components are converted to active components. The last stages lead to the conversion of prothrombin to thrombin. This converts fibrinogen to fibrin – forming the clot.
* The Fibrinolytic system breaks down fibrin. Plasminogen --> plasmin (through the action of plasminogen activators); hence tPA (and streptokinase) can be used in fibrinolytic therapy.
252
What do platelets do when they are inactive i.e not immediately required? (S6)
When platelets are circulating through vessels with an intact, healthy endothelium, the platelets remain in their original, unactivated state.
253
What is the platelet release reaction? (S6)
The platelet release reaction takes place when platelets must be activated i.e when there is a break in the endothelium. The platelet release reaction requires energy (ATP) and ADP and thromboxane A2 (prostaglandin) cause platelet aggregation (through activation of the platelets). 5HT (hydroxytryptamine) and platelet factor 3 are also released (the latter is important in coagulation). The platelets coalesce after aggregation.
254
Why is tight regulation of the clotting cascade required? (S6)
1 ml of blood can generate enough thrombin to convert all the fibrinogen in the body to fibrin. Therefore tight regulation of factors is required and in the balance of pro-coagulant and anticoagulant forces.
255
Give examples of proteins that inhibit thrombin. (S6)
Anti-thrombin III and protein C and S (both of which can be defective through an inherited deficiency). Alpha 1 anti-trypsin is another example.
256
Name some anti-thrombotic compounds. (S6)
tPA, prostacyclin, thrombomodulin and nitric oxide.
257
Define thrombosis. (S6)
Thrombosis is the formation of a solid mass of blood within the circulatory system.
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What is Virchow's Triad? (Why does thrombosis occur?) (S6)
* Abnormalities in the vessel wall: atheroma, direct injury and inflammation.
* Abnormalities of blood flow: stagnation and turbulence
* Abnormalities of blood components: smokers, post-partum, post-op
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How do thrombi appear histologically? (S6)
Arterial thrombi appear pale, granular have lines of Zahn and a lower cell content.
Venous thrombi are soft, gelatinous, a deep red and have a higher cell content.
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What are the outcomes of a thrombosis? (S6)
* Lysis: the fibrinolytic system is active leading to the complete dissolution of the thrombus. Bloodflow is re-estabilshed; this is most likely when thrombi are small.
* Propagation: the progressive spread of thrombosis (distally in arteries or proximally in veins). This will occur because the original thrombus may stagnate blood flow, increasing the risk of another thrombus preceding it.
* Organisation: it is a reparative process, the ingrowth of fibroblasts and capillaries (similar to granulation tissue), but the lumen remains obstructed.
* Recanalisation: bloodflow re-established but usually incompletely. One or more channels formed through organising the thrombus.
* Embolism: part of the thrombus breaks off, travels through bloodstream and lodges at a distant site.
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What are the effects of thrombosis? (S6)
Arterial thrombi lead to ischaemia and infarction. Effects depend on site and collateral circulation (i.e. end arteries are far worse).
Venous thrombi lead to congestion, oedema, ischaemia and infarction.
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What is an embolism? (S6)
It is the blockage of a blood vessel by a solid, liquid or gas at a site distant from its origin. 90% of emboli are thrombo-emboli.
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What are some other types of embolism? (S6)
Air, amniotic fluid, nitrogen and tumour cells.
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What will happen if there is a thrombo-emboli in the systemic veins? (S6)
It will pass to the lungs - a pulmonary embolism.
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What will happen if there is a thrombo-emboli in the atheromatous carotid arteries? (S6)
It will pass to the brain.
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What will happen if there is a thrombo-emboli in the atheromatous abdominal aorta? (S6)
It will pass to arteries of the legs.
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What are some of the pre-disposing factors to deep vein thrombosis? (S6)
Deep vein thrombosis has several pre-disposing factors
| Immobility, post-operative, oral contraceptives, cardiac failure, pregnancy and post-partum.
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What are patients at high risk of DVT offered? (S6)
Prophylaxis, such as sub-cutaneous heparin and leg compression during surgery.
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What is the treatment for DVT? (S6)
Treatment for DVT is intravenous heparin and oral warfarin.
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Outline the prognosis of a pulmonary embolism. (S6)
A massive pulmonary emboli which reduce >60% in bloodflow will be rapidly fatal.
A major PE will occlude medium sized vessels – the patient will be SOB and may cough blood stained sputum.
A minor PE will block small peripheral pulmonary arteries. There may be SOB or there may be SOB.
Recurrent minor PEs lead to pulmonary hypertension.
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What is an atheroma? (S7)
It is the accumulation of intracellular and extracellular lipid in the intima and media of large and medium sized arteries.
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What is atherosclerosis? (S7)
It is the thickening and hardening of arterial walls as a consequence of atheroma.
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What is arteriosclerosis? (S7)
It is the hardening of the walls of the arteries and the arterioles. This is usually due to high blood pressure or diabetes mellitus.
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What are some common sites of atheroma? (S7)
The aorta (especially abdominal), coronary, carotid, cerebral and leg arteries.
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What is 'normal' arterial structure (from innermost to outermost)? (S7)
Endothelium, subendothelial connective tissue, internal elastic lamina, muscular media, external elastic lamina and the adventitia.
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Briefly outline the macroscopic features of atheroma and how they progress. (S7)
Fatty streak (although whether it is actually a precursor to atheroma is debatable), simple plaque, complicated plaque.
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What features can be seen in a fatty streak in an artery? (S7)
Lipid deposits in the intima. They are yellow and slightly raised.
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What features can be seen in a simple plaque? (S7)
A simple (atheromatous) plaque is raised and yellow/white in colour. They have an irregular outline and are widely distributed. They enlarge and as they do so, they so coalesce. It is an unruptured plaque.
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What complications can occur in a complicated plaque? (S7)
A complicated plaque is rough, ruptured epithelium. Platelets can stick to it causing thrombus formation. Other complications include haemorrhage into a plaque and calcification and damage to elastic tissue – an aneurysm forms through a stretching of the arteries, the pulse wave goes through the artery stretching it and the normal elastic recoil of the artery is lost. As fibrosis takes place the artery gets fixed in a more expanded state – this is the aneurysm.
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What are the microscopic early changes of atheroma? (S7)
Proliferation of smooth muscle cells and accumulation of foam cells (macrophages/SMCs that ingest fat) and there is extracellular lipid.
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What are the microscopic later changes of atheroma? (S7)
Fibrosis, necrosis, cholesterol clefts (cholesterol deposition in the tissue, not the plaque) and presence of inflammatory cells (which is very variable). There is disruption to the internal elastic lamina and damage extends into the media. There is ingrowth of blood vessels (new, leaky capillaries form, can contribute to haemorrhage into plaque) and plaque fissuring (where the blood pressure and movement of the blood in the lumen leads to a shearing force causing the fissure of the plaque to open up).
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What is the response to endothelial damage? (S7)
--> Platelets --> PDGF --> smooth muscle proliferation: this proliferation and migration takes the lipid with it. Macrophages/SMCs phagocytose the fat becoming foam cells.
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What are some of the clinical effects of atheroma? (S7)
Ischaemic heart disease
Cerebral ischaemia
Mesenteric ischaemia
Peripheral vascular disease.
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What are the outcomes of ischaemic heart disease? (S7)
Sudden death, myocardial infarction, angina pectoris (chest pain on exercise), arrhythmias, cardiac failure.
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What are the outcomes of cerebral ischaemia? (S7)
A transient ischaemic attack (TIA), stroke (cerebral infarction) or multi-infarct dementia.
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What are the outcomes of mesenteric ischaemia? (S7)
If chronic: ischaemic colitis, malabsorption or if acute: an intestinal infarction.
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What are some of the symptoms of peripheral vascular disease? (S7)
Intermittent claudication (calf pain on exercise and only on exercise; this can progress to ischaemic rest pain and even gangrene).
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What is Leriche syndrome? (S7)
It is where there is intermittent claudication but due to atheromatous plaques in the iliac artery. The claudication pain is in the buttocks and it is often associated with impotence.
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What factors increase the risk of atheroma? (S7)
```
Age
Gender
Hypertension
Hyperlipidaemia
Cigarette smoking
DIabetes mellitus
Alcohol
```
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How do age and gender influence the risk of atheroma? (S7)
Age: slowly progressive throughout adult life, risk factors operate over years
Gender: women protected relatively before menopause; presumed hormonal basis.
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How does cigarette smoking increase the risk of atheroma ? (S7)
Cigarette smoking: risk factor for IHD, but falls after giving up. Its mode of action is uncertain but if affects the coagulation system, reducing prostacyclin (PGI2, an inhibitor of platelet-activation) and leading to increased platelet aggregation.
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How does diabetes mellitus increase the risk of atheroma? (S7)
Diabetes mellitus: doubles IHD risk and the protective effect in premenopausal women is lost. DM is also associated with high risk of cerebrovascular and peripheral vascular disease. The reason may be linked to hyperlipidaemia and hypertension.
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How does alcohol increase the risk of atheroma? (S7)
Alcohol: >5 units/day increases risk of IHD. Alcohol consumption often associated with other risk factors (e.g. smoking, high BP), but small amounts may be protective.
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How does hypertension increase the risk of atheroma? (S7)
Hypertension: strong link between IHD and high systolic/diastolic blood pressure. Mechanism uncertain; endothelial damage caused by raised pressure?
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How does hyperlipidaemia increase the risk of atheroma? (S7)
Hyperlipidaemia: high plasma cholesterol associated with atheroma; LDL most significant – HDL protective. Lipid in the blood is carried on lipoproteins. They carry cholesterol and triglycerides (TG). They have a hydrophobic lipid core and a hydrophilic outer layer of phospholipid and apolipoprotein (A-E) Genetic variations in Apo E are associated with changes in LDL levels. Polymorphisms of the genes result in 6 Apo E phenotypes. These polymorphisms can act as risk markers for atheroma.
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What are chylomicron's function? (S7)
Chylomicrons transport lipid from intestine to liver.
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What are VLDL's and LDL's functions? (S7)
VLDLs carry cholesterol and TG from liver. TG are removed leaving LDLs which are rich in cholesterol and carry cholesterol to non-liver cells.
298
What are HDL's function? (S7)
HDLs carry cholesterol from periphery back to liver.
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Why does familial hyperlipidaemia lead to early development of atheroma? (S7)
In familial hyperlipidaemia there is genetically determined abnormalities of lipoproteins. This leads to early development of atheroma.
This could be due to variations in apolipoprotein metabolism or variations in apolipoprotein receptors.
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What are the associated signs seen in familial hyperlipaemia? (S7)
Corneal arcus, tendon xanthomas and xanthelasma.
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What are some other risk factors for atheroma? (S7)
Infection may be a risk factor: Chlamydia pneumoniae, helicobacter pylori and cytomegalovirus may increase the risk of atheroma.
Other factors include lack of exercise, obesity, soft water, oral contraceptives and stress and personality type?!
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What are the 4 theories on atheroma that helped give the unifying theory? (S7)
Encrustation theory proposed by Karl Rokitansky. Plaques were stuck onto the wall of the artery, formed by repeated thrombi and had lipid associated with them,
Insudation theory: Virchow thought there was endothelial injury. This led to inflammation and increased permeability to lipid from plasma.
Monoclonal hypothesis: Benditt and Benditt proposed that a crucial role for atheroma formation was smooth muscle proliferation. Each plaque is monoclonal and it might represent abnormal growth control; is each plaque a benign tumour? Could atheroma have a viral aetiology?
Response to injury hypothesis: plaques were a result of endothelial injury and hypercholesterolaemia would damage endothelial cells. Injury increases permeability and allows platelet adhesion. Monocytes penetrate endothelium and smooth muscle cells proliferate and migrate. This was furthered by the suggestion that LDL, especially oxidised, may damage endothelium.
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What is the unifying hypothesis of atheroma? (S7)
The processes involved in atheroma are thrombosis, lipid accumulation, the production of intercellular matrix and interactions between cell types.
Everything starts with endothelial injury which is subtle and cannot readily be seen. Endothelial injury can be due to raised LDL, ‘toxins’ e.g. cigarette smoke, hypertension, haemodynamic stress.
Endothelial injury causes platelet adhesion, PDGF release, smooth muscle cell proliferation and migration. There is insudation of lipid, LDL oxidation and uptake of lipid by smooth muscle cells and macrophages. There is migration of monocytes into intima.
The stimulated smooth muscle cells produce matrix material. Foam cells secrete cytokines causing further smooth muscle cell stimulation and recruitment of other inflammatory cells.
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What cells are involved in atheroma formation? (S7)
Endothelial cells: key role in haemostasis. Have an altered permeability to lipoproteins. They secrete collagen and stimulate proliferation and migration of smooth muscle cells.
Platelets: key role in haemostasis. Stimulate proliferation and migration of smooth muscle cells (PDGF).
Smooth muscle cells: take up LDL and other lipid to become foam cells. Synthesise collagen and proteoglycans (other intercellular matrix substances that may become abnormal during atheroma).
Macrophages: oxidise LDL. They take up lipids to become foam cells. They secrete proteases which modify the matrix and stimulate proliferation and migration of smooth muscle cells.
Lymphocytes: the production of tumour necrosis factor (TNF) may affect lipoprotein metabolism. They also stimulate proliferation and migration of smooth muscle cells.
Neutrophils: secrete proteases leading to continued local damage and inflammation.
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How can atheroma be prevented? (S7)
No smoking, reduce fat intake, treat hypertension, not too much alcohol and regular exercise / weight control. This will not eliminate the risk however.
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How would you intervene in a patient with atheroma? (S7)
Tell them to stop smoking, modify diet, and treat hypertension and diabetes, give them lipid lowering drugs (i.e. statins).
