4. Regeneration And Repair Flashcards
(99 cards)
1
Q
Stem cell definition
A
• A stem cell is an undifferentiated cell that can:
- continuously divide – proliferation, duplication, replication
- differentiate into various other kind(s) of cell
2
Q
2 characteristics of stem cells
A
Self renewal
Potency
3
Q
Self renewal
A
capable of dividing and renewing themselves, to keep the source of regrowth
• Dauaghter cell can become exactly like the original stem cell
4
Q
Potency
A
the capacity to differentiate into sdifferent kinds of specialized cell types for development and regeneration
• Daughter cell can proliferate further and differentiate into different cells
5
Q
4 types of potency
A
Totipotent
Pluripotent
Multipotent
Unipotent
6
Q
Totipotent
A
- fertilised egg and the cells produced by the first few divisions
- can differentiate into embryonic (to develop organs and tissues) and extraembryonic cell types (placenta)
- they can construct a baby!
7
Q
• Pluripotent:
A
- the embryonic stem cells (ESC), descendants of totipotent cells, cells from inner mass of blastocyst
- can differentiate into cells of any of the three germ layers or any tissues/organs.
8
Q
• Multipotent:
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• can produce a family of several types of cells (e.g. hematopoietic stem cells HSC differentiate into different blood cells, neural stem cells NSC into neurons and glia).
9
Q
Unipotent
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- can produce (differentiate) only one cell type (lineage specific)
- but have the property of self-renewal – specialised cells
10
Q
4 types of stem cells
A
Embryonic stem cells
Adult (or tissue-specific) stem cells
Induced pluripotent stem cells (iPSC) (from somatic cell to stem cell)
Cord blood (umbilical) stem cells
11
Q
Embryonic stem cells
A
• that exist only at the earliest stages of development
= Pluripotent
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Adult (or tissue-specific) stem cells
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- that appear after fetal development and remain in our bodies throughout life
- Multiple and uni potent
13
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Induced pluripotent stem cells (iPSC) (from somatic cell to stem cell)
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- From specialised cell converted back to stem cells
* Pluripotent
14
Q
Cord blood (umbilical) stem cells
A
Multipotent
15
Q
2 roles of adult stem cells
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- Regernation = The adult stem cells constantly replace the used cells
- Healing = The adult stem cells regrow for the regeneration and repair
16
Q
Adult stem cells → Bone Marrow-Derived Stem Cells
A
• Bone marrow produces multipotent hematopoietic stem cells (labile)
○ Produce wbc, rbc and platelets
○ Directly involved in healing
• Other stem cells from bone marrow-EPC, - endothelial progenitor cells ○ ESC = endothelial cells, angiogenesis ○ MSC = fibroblasts
17
Q
Skin stem cells
A
- Epidermis –epidermal stem cells at the basal layer, hair follicle stem cell (labile)
- Bottom of skin or bottom of hair follicles
- Activate and grow to replace lost skin
18
Q
GI epithelial stem cells
A
• –Intestinal mucosa –bottom of crypts (labile)
19
Q
Hepatocyte stem cells
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• –Liver –between hepatocytes and bile ducts (stable)
20
Q
4 examples of adult stem cells in different tissues
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Bone Marrow-Derived Stem Cells
Skin stem cells
GI epithelial stem cells
Hepatocyte stem cells
21
Q
Ageing and stem cells
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As age increases Ageing: stem cells decrease their ability of self-renewal and differentiation abilities
22
Q
Regenerative capcity of cells
- labile, stabile, permanent
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Outside of cell cycle – cell can’t reproduce itself
LABILE = Some cells e.g. epidermis skin cells) are constantly going through cell cycle – these are labile cells
PERMANENT = Cardiac monocytes and neurons = permanent cells, come out of the cell cycle permanantly – will never go back into cell cycle
STABLE = remain quiescent but can be activated when stimulated and go back into cell cycle to proliferaet (hepatocyte)
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Q
Labile definition
A
continuously dividing cells/tissues
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Stable definition
A
quiescent tissue, but cells can undergo rapid division in response to stimuli and can reconstruct the tissue of origin.
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Permanaent definition
Non dividing
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Example of labile tissues
* e.g. skin epithelia, epithelia GI tract, haematopoietic tissue…:
* normal state is active cell division: G1– M – G1
* usually rapid proliferation for regeneration from active stem cells
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Example of stable tissues
* e.g. hepatocytes, osteoblasts, fibroblasts:
* Resting state – G0 (quiescent mature cell and stem cells)
* speed of regeneration variable
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Example of permanent tissues
* e.g. neurones, cardiac myocytes:
* unable (?) to divide - G0 (terminally differentiated cells and no effective stem cells)
* no effective generation
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High regenerative capacity tissues
* Skin
* liver
* Blood cels
* Smooth muscle
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moderate regenerative capacity tissues
* Skelton muscle
* Kidney
* Bone
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Low regenerative capacity tissues
* heart
* Cartilage/ tendons
* Peripheral nerve
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3 Factors controlling regeneration and repair mechanisms
Cell to cell communication
Growth factors
Cell-cell and cell-stroma contact
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What is cell to cell communication
Uses:
• Local mediators (e.g. cytokines, growth factors-soluble signals)
• Systemic hormones (eg. growth hormone)
• Direct cell-cell or cell-stroma contact
Balance between stimulation and inhibition
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What are the growth factors involved in wound healing
* Polypeptides (local mediators and hormones)
* Bind to that act on cell surface receptors, stimulate transcription of genes that regulate cell proliferation and other effects.
* Determine if cell goes into cell cycle
Produced mostly by macrophages and other cells (local hormones)
Local hormones:
• Epidermal growth factor (EGF)-mitogenic for epithelial cells and fibroblasts
• Vascular endothelial growth factor (VEGF)-induces angiogenesis
• Platelet derived growth factor (PDGF)-causes migration and proliferation of fibroblasts
• Tumour necrosis factor (TNF)-induces fibroblast migration, fibroblast proliferation and collagenase secretion.
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What is Cell-cell and cell-stroma contact
---> Signalling through adhesion molecules
• Connexion and Cadherins (adhesion junctions binding cells together) bind cells to each other
• Integrins bind cells to the extracellular matrix = binding can send signals
Effect-Contact inhibition-Inhibits cell proliferation
Balance between stimulation and inhibition
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Regenerative medicine definition
---> application of stem cells
| A process of replacing, engineering or regenerating cells, tissues or organs to restore or establish normal function.
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2 examples of regenerative medicine
Cell therapy
• Original cells (blood transfusion…)
• Lab (ex vivo) expanded cells --> healing
Stem cell therapy
• Stem cells from embryo (e.g. cord blood…) from adult (bone marrow…) (FDA!)
• Induced stem cells from adult (FDA?)
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Process of skin tissue regeneration for burn injury
1. Get sample of healthy skin tissue
2. Send to lab
3. Lab – tissue digestion to isolate single cells (epithelial and stem cells)
4. Expand these cells into millions of cells using proper medium
5. Add cells to burn area = helps tissue regeneration
6. Restore normal skin cells instead of scar
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Cord blood stem cell treatment
1. Cord blood contains several type of stem cells
2. Many haemopoietic stem cells
3. Llots of MCS mesenchymal stem cells that can give rise to several cell types – fibroblasts
4. Fibroblasts are important in tissues
5. Endotherlial progenitor cells – angiogenesis
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Functions of MCS and other stem cells (when transplanted to the body)
* Differentiate and replace the cells
* Promote other cells regeneration
* Rejuvenate aged stem cells
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Induced pluripotent stem cells (iPSC)
Formation and Uses
1. Treat somatic cells with transcriptional factors (reprogramming factors)
2. Reprogram somatic cells → stem cells = pluripotent cells
3. = induced pluripotent cells
Uses:
• Personalized medicine/Precision medicine
• Overcome tissue rejection issue
• Drug test – which drugs are suitable to individuals
• Disease research
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Pros of stem cell use
* Medical benefits-regeneration and repair
* Diseases curing (including gene correction)
* Research for human disease
* Drug testing on human cells
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Cons of stem cell use
* Uncertainty of long term effect-need research
* Potential tumour growth = as stem cells proliferate alot
* Tissue rejection
* Ethical and legal aspects
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5 layers of blood vessels
```
○ Tunica intima
Internal elastic lamina
○ Tunica media
External elastic lamina
○ Tunica externa
```
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Tunica intima
* inner layer
* thinnest
* Single layer of endothelial cells
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Internal elastic lamina
* Dense elastic membrane
| * Sepreates tunica intima from media
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Tunica media
* Thickest layer
* Middle
* Smooth mucle cells,
* Elastic fibres
* Connective tissues
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External elastic lamina
• Serperates tunica media from tunica adventita
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Tunica adventita
* Outer layer
* Connective tissue
* Vessels and nerves
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Arteriosclerosis definition
○ hardening of arteries affecting the wall, thickens wall
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3 diseases included arteriosclerosis
* Atherosclerosis – affect large and medium sized artery
* Arteriolosclerosis – hardening of arterioles mainly kidney arterioles
* Monkeberg’s disease – calcification in media of large arteries
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Atherosclerosis definition
• Is the accumulation of intracellular and extracellular lipid in the intima and media of large and medium sized arteries
* Degernative process slowly progressive
* Acuumulation of fatty material in blood vessels walls
* Affects medium and large arteries
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What is atherosclerosis characterised by?
•Characterized by intimal lesions called: atheroma, atheromatous or fibro-fatty plaques
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Pathogenesis of atherosclerosis
Endothelial injury causes:
• Platelet adhesion, platelet derived growth factor release, smooth muscle cell (SMC)proliferation and migration
• Accumulation of lipid, LDL oxidation, uptake of lipid by smooth muscle cells and macrophages
• Migration of monocytes (WBC and when inside the tissue --> macrophage) into intima
To form atherocsclerotic lesions
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. Conditions that lead to edothelial injury
* Hyperlipidaemia
* Hypertension
* Smoking
* Homocysteine
* Hemodynamic factors
* Toxins
* Viruses
* Immune reations
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Cause of atherosclerois
→ response to injury hypothesis
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Steps of Response to injury hypothesis (causing atherosclerosis)
1. Injury to the endothelium (dysfunctional endothelium)
2. Chronic inflammatory response
3. Migration of SMC – smooth muscle cells from media to intima - activate macrophage
4. Proliferation of SMC in intima - smc and macrophages engulf lipids → formation of fatty streak
5. Excess production of Extra cellular Matrix- to support lesion and form fibrous cap
6. Enhanced lipid accumulation'
* Formation of the atheroscloretic plaque
* Fibrofatty atheroma centre – dead cells in the centre due to lack of blood supply
* Formation of fibrous cap – roof of lesion that encases it and prevents repture and release of contents
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3 intimal lesions in atherosclerosis
* Formation of the atheroscloretic plaque
* Fibrofatty atheroma centre – dead cells in the centre due to lack of blood supply
* Formation of fibrous cap – roof of lesion that encases it and prevents repture and release of contents
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Main components of fibro-fatty plaque
* Lipid containing macrophages
* Extracellular matrix
* Cells, Proliferating smooth muscle cells
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How to visually differentiate between artery and vein
• compare the thickness of the wall
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2 most important causes of endothelial dysfunction are:
| Response to injury hypothesis
1. Hemodynamic disturbances (HTN)
2. Hypercholesterolemia
Inflammation is also an important contributor
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Lesions progression (progression of atherosclerosis)
Initial lesion – macrophages then migrate
Fatty streak – intracellular lipid accumulation
Intermeidate lession - intracellular lipid accumulation
Atheroma - intracellular lipid accumulation, core on extracellular lipid
Fibroatheroma – fibrotic/calcific layers
Compliacted lesion – haemorrhage and thrombosis
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Plaques
Fatty streaks can grow and become plaques
* White to yellow
* Spots
* Fibrosis, necrosis
* Vary from 0.3 to 1.5 cm in diameter, but can coalesce to form larger masses
* Extension of vessels into media and intima
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Microscopic features of atherosclerosis
Early changes
- proliferation of smooth muscle cells
- accumulation of foam cells
- extracellular lipid
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Microscopic features of atherosclerosis
Later changes
* fibrosis
* necrosis
* cholesterol clefts
* +/- inflammatory cells
* disruption of internal elastic lamina
* damage extends into media
* ingrowth of blood vessels
* plaque fissuring
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Stable atherosclerotic plaque
* Fibrous cap is thick, seperates lesion from lumen
| * Necrotic core contains necrotic debris, red blood cells, cholesterol esters / clefts
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Vulnerable atherosclerotic plaque
* Thin fibrous cap
* Necrotic core superated from lumen by thin fibrous cap
* thin cap fibroatheromas are considered to be vulnerable to rupture of the fibrous cap and sudden coronary artery
* Cap may rupture and components may be released
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5 steps for forming vulnerable or stable plaques
1. Normal aretery
2. Endothelial dysfunction
3. Fatty streak
4. More fibrosis and matrix = fibro fatty plaque
5. Weakness of cap may lead to vulnerable plaque
• Risks of aneuysm and repture, accumulation by thrombus, critical stenosis
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Simple plaque
* Raised yellow/white
* Irregular outline
* Widely distributed
* Enlarge and merge
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Complicated plaque
* Thrombosis
* Haemorrhage into plaque
* Calcification
* Aneurysm formation
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Common sites of atherosclerosis
---> usually elastic arteries. Large and medium muscular arteries
* Abdominal aorta
* Coronaries
* Popliteal artery
* The internal carotid arteries
* The vessels of the circle of Willis
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How can atherosclerosis cause clinical complications
1. Progressive lumen narrowing due to high-grade plaque stenosis.
• Because of lesion most of lumen has stenosis (70%) affect blood flow
2. Acute atherothrombotic occlusion (key pathology)
• Plaque ruptured, so components are released to blood strea
3. Thrombus embolisation into the distal arterial bed
• Fragmentation of material of atherosclerotic lesion
4. Ruptured abdominal atherosclerotic aneurysm
• Weakness of structure and stability of blood vessel walls
• Lead to haemorrhage and death
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Clinical complications of atherosclerosis
* Myocardial infarction (heart attack), ischaemic heart disease(IHD)
* Cerebral infarction (stroke)
* Aortic aneurysms
* Mesenteric occlusion
* Peripheral vascular disease (gangrene of the legs)
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Myocardial infarction - caused by atherosclerosis
1. Blockage in artery
2. Muscle damage
3. Myocardial infarction
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Classical appearance of myocardial infarction
approximately 2–3 weeks in age shows the formation of granulation tissue characterized by loss of myocytes, neovascularization, loose collagen deposition, fibroblasts, and hemosiderin containing macrophages
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Cerebral infarction
---> blockages in cerebral artery
| = liquefactive necrosis
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Intestinal infarction
• Marked dark red ischaemic small bowel
| ○ Due to bockage of main blood supply
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Peripheral vascular disease
* When atherosclerosis affects popliteal, femoral or iliac artery
* May end up with gangrene due to loss of blood supply
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Abdominal aoritc aneurysms
* Localized enlargement of the abdominal aorta
* Cause no symptoms except when ruptured ---> severe complication
* Occasionally, abdominal, back, or leg pain may occur
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Sacular aneurysm – looks like a sac
* Complication = disecting, rupture inner layer of arterial wall so blood fills gap between 2 layers
* Lumen of artery can be occluded
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Non modificable risk factors of atherosclerosis
* Age = slowly progressive throughout adult life
* Gender = women protected relatively before menopause due to loss of oestrogen
* Genetic predisposition = Familial hyperlipidaemia
* Genetically determined abnormalities of lipoproteins – defect in lipoprotein metabolism = high lipid level
* Lead to early development of atherosclerosis
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Familial hyperlipidaemia
• Genetically determined abnormalities of lipoproteins – defect in lipoprotein metabolism = high lipid level
• Lead to early development of atherosclerosis
• Associated physical signs
• Argus = white grey ring around cornea of eye
• Tendon xanthomas = cholesterol deposits around knuckles
Xanthelasma = yellowish deposite of cholesterol under skin around eylids
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Modifiable risk factors - atherosclerosis
* Hyperlipidaemia
* Cigarette smoking
* Alcohol
* Infection
* Hypertension
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Hyperlipidaemia
* high plasma cholesterol associated with atherosclerosis
* LDL most significant = bad one might lead to atherosclerosis
* HDL protective = level increase with exercsise decrease with smoking
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Hypertension
• Mechanism uncertain on how it causes atherosclerosis
• Endothelial damage caused by raised pressure
'
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Diabetes mellitus
* DM also associated with high risk of ccerebrovascular and peripheral vascular disease.
* Related to hyperlipidaemia and hypertension
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Cigarrette smoking
Powerful risk factor for ischaemic heart disease (IHD)
• Mode of action uncertain
-coagulation system
-increased platelet aggregation
• Increased inflamamtion, damage to blood vessel wall
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Alcohol consumption
* >5 units /day associated with increased risk of IHD
* Alcohol consumption often associated with other risk factors. eg smoking and high BP but still an independent risk factor
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Infections that can cause atherosclerosis
* Chlamydia pneumoniae
* Helicobacter pylori
* Cytomegalovirus
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Cells involved in atherosclerosis
* Endothelial cells
* Platelets
* Smooth muscle cells
* Macrophages
* Lymphocytes
* Neutrophils
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Endothelial cells
* Key role in haemostasis
* Altered permeability to lipoproteins
* Production of collagen
* Stimulation of proliferation and migration of smooth muscle cells
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Platelets
* Key role in haemostasis
| * Stimulate proliferation and migration ofsmooth muscle cells
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Smooth muscle cells
* Take up LDL and other lipid to become foam cells
| * Synthesise collagen and proteoglycans
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Macrophages
* Oxidise LDL
* Take up lipids to become foam cells
* Secrete proteases which modify matrix
* Stimulate proliferation and migration of smooth muscle cells
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Lymphocytes
• Stimulate proliferation and migration of smooth muscle cells
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Neutrophils
• Secrete proteases leading to continued local damage and inflammation
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Atherosclerosis - prevention
* No smoking
* Reduce fat intake
* Treat hypertension
* Not too much alcohol
* Regular exercise/weight control
• BUT some people will still develop atherosclerosis
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Atherosclerosis interventions
* Stop smoking
* Modify diet – low fat diet, high fiber
* Treat hypertension
* Treat diabetes
* Lipid lowering drugs
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Haemostasis
Clotting
